CDG e Conferences & Workshops

Good Monitoring Practices

GLOBAL CONSENSUS
A Whitepaper by Nancy J Stark, PhD

It may be a coincidence, but it seems to me that the device industry emerged from a long sleep after the August 31, 2010 CDRH Webinar on Preliminary Internal Evaluations of the 510(k) process. The webinar entertained questions from the audience regarding two preliminary reports published by: 1) the 510(k) Working Group, and 2) the Task Force on Utilization of Science in the Regulatory Decision-Making Process. Both groups were comprised of representatives from across CDRH to assess the challenges faced by Center management and staff in the 510(k) process and to assess how effectively science is used to evaluate 510(k)s.

One recommendation of the 510(k) Working Group was to "define the term 'clinical data' in order to foster a common knowledge among review staff and manufacturers about what constitutes 'clinical data' ". Recommendations by the Task Force on...Science... were to "continue to engage in the development of...international consensus standards, which, when recognized by FDA, could help establish basic guidelines for clinical trial design, performance, and reporting," and for the Center "to expand its ongoing efforts related to clinical trials...to include clinical trials that support 510(k)s". Possibly the most significant and repeated recommendation made in the reports was to improve the overall quality of clinical trials.

Good monitoring is essential
Think about what happens in a clinical trial. A manufacturer located in one state or country contracts with an investigator in another state or country to conduct a clinical trial that may last from a month to as long as several years. Like all human beings, investigators lose interest in the trial, deviate from the protocol to experiment with their own ideas, enroll subjects in competing studies, or generally misbehave, without regular eyeball contact from the sponsor.

Monitoring is the mechanism by which a sponsor remains engaged with an investigator. Monitors are the individuals charged with maintaining that eyeball contact.

Types of monitoring visits
Clinical trials are implemented in 'project management' phases of prestudy design, study initiation, implementation (duration) and close-out. Monitoring activities are often designed to parallel the process of the clinical trial. While the transition from one phase to another is not carved in stone, I've tried to describe transition points that are commonly used and easy to conceptualize.

 

Prestudy 'visits'
Pre-investigation or assessment visits are intended to select investigators and prepare sites for the study. They are better perceived as a process in which the capabilities and business relationship of the sponsor and investigator are established.

Both FDA and ISO envision this as a time for sponsors to assure that investigators understand the investigational nature of the device, the requirement to wait for IRB approval, the need for informed consent, agreement that records will be created and made available for monitoring, and that contractual obligations are mutually understood and agreed to. This is also the time during which budget agreements and financial arrangements are made between sponsor and site. The period of time may take several months, visits, phone calls, and email messages and can be thought of as spanning from project conception to first subject consented.

Initiation visits

The main focus of the initiation process is investigator and study staff training. Training may begin with an investigator's meeting if there are many investigators involved in the study. Or investigative sites may be trained one at a time and may include practice on simulated patients or live animals. The importance of training the investigator to device use cannot be over-emphasized. Even investigators familiar with your type of device will need to review special features, materials, software, hardware, instructions for use, and protocol requirements. Misuse of an investigational device by an investigator may come back on the sponsor as a failure to adequately train the user and may be considered an adverse event.

During this phase the monitor will set up record-keeping systems by building Investigator Regulatory Binders, Coordinator's Study Manuals, Subject Binders, Source Document Verification Logs and sponsor files.

It is a common practice for subjects to be consented but not considered enrolled in a study until they have passed subsequent screening procedures and been exposed to the device. But the practice of viewing consent and enrollment as separate events is now frowned on by FDA. They are concerned that subjects may be consented, and then dropped from the study without documentation about why. The preferred viewpoint is that consent and enrollment take place at the same moment. Then if a subject later fails screening, the reasons are documented and the subject is exited from the study. Study initiation culminates when the first device is placed on the first subject.

Routine monitoring visits
A routine monitoring visit is an on-site visit in which the monitor observes the process of the study, compliance to protocol, compliance to regulations, completeness of documentation, and verifies accuracy of data on the case report forms against source information. Case report forms should be verified for accuracy, logic, completeness, legibility, and contemporaneousness; electronic forms should be checked for traceability (i.e., who filled out the screen.) Monitoring should take place on a periodic basis, but I suggest you allow no more than 2-3 days of work to accumulate at a site.

Monitoring requires an extensive skill set. It requires an intimate knowledge of clinical regulations and company procedures, knowledge of the device function and possible malfunctions, knowledge of the disease or condition being studied, the ability to solve problems and work independently, and the ability to write a comprehensive and lucid report that captures the progress of the study and action items for the future.

Monitoring Reports >> Action Item Database >> Open Action-Item Checklist

Monitors need a special kind of personality. They should be people who can work with busy sites, who love data, who can sift through pieces of information and fit them together, who do not leave details unaddressed, and who cannot tolerate an unbalanced checkbook.

Off-site monitoring
Off-site monitoring is an alternative to travel when a site is known as well-organized. Data can be transmitted by fax, pdf, or electronic means and checked for everything but accuracy to source files.

Close-out visits
Close-out visits deal with ending issues and have the goal of making the site inspection-ready. All open action items are addressed, open queries resolved, and reports filed. Close-out visits are like filing income taxes, if you've done a good job of record-keeping all year long the close-out visit will go quickly; if not, it could take days.

If you liked the whitepaper, take the workshop
If you liked this whitepaper, then take the workshop. The learning objective is to review the skills of monitoring in order to help assure quality in clinical trials. This is an intermediate level course, participants are expected to have a basic knowledge of clinical research and device regulations. Sign up here or phone us at 773-489-5706.

A quiz, of course
The five-hour workshop is following by a half-hour online quiz, taken on your own time within the following two weeks. The quiz is designed to test your learning of the concepts discussed in the lecture and your ability to apply those concepts to real-life issues.

You will receive, we will discuss
[x] Printable PowerPoint slides.
[x] Clear example distinguishing intended use, indications, claims and warning.
[x] Monitoring procedures and templates.
[x] Recent monitoring warning letters.
[x] A graded quiz with immediate test results.
[x] One computer connection for one learner (each learner must log-in individually).
[x] Certificate of Attendance and 0.55 CEUs.
[x] A copy of the CRA Handbook 2010 (electronic) with registration by October 13, 2010.

Who should attend
[x] Monitors.
[x] Clinical research associates.
[x] Managers and directors of clinical research.
[x] Start-up companies planning their first clinical trial.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop will be presented on Wednesday, 20 October 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Or you can take the event later by CD or OnDemand. Sign up at here or phone us at 773-489-5706.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

A Plan for EU Clinical Evaluation Reports

What Do Notified Bodies Want?

A Whitepaper by Nancy J Stark, PhD.

We've come a long way in our understanding of what Europe expects in a Clinical Evaluation Report. Where you start depends on where you are: 1) writing a CE Report for a new, pre-approval device, or 2) writing a CE report for a commercial device. In the first case, you are asking the question, "Do I need new clinical data for certification?" In the second case, you are bringing your documentation up-to-date.

Clinical evaluation reports for pre-certification devices
If you're still in the stage of designing your device, you begin by identifying its intended uses. Then you evaluate the existing clinical data to determine if it is sufficient to support safety and performance per the Essential Requirements of the MDD or AIMD, or if you need additional clinical data. If additional clinical data are needed you have the choice of revising the intended use or performing a clinical trial.

Once you believe the data are sufficient, you convince top management to grant a CE Mark and sign the Declaration of Conformity to your quality management system. Finally, you will discover the truth when the Notified Body comes to call.

Clinical evaluation reports for commercial devices
The more common situation is that your device is already on the market in Europe, and the Notified Body has informed you that its clinical evaluation report was due last March. He will give you a grace period, but you are expected to conform. You follow the same process of evaluating the existing data to determine if it is sufficient to support safety and performance for the intended uses. Should the report conclude that the existing data are insufficient you are in a difficult situation: you'll need to suspend sales until additional data are acquired.

Because the consequences of determining the data are not sufficient are so financially significant for your firm, and the consequences of determining the data are satisfactory are so financially favorable, it is wise if the report writers are as far removed from the device designers as possible.

Resources
To write the report you need a team of at least three people: 1) a medical writer, 2) an information specialist, and 3) a statistician.

In addition you need a written procedure for how to proceed, a report template (useful, but not required), and access to literature databases such as Medline and Embase. Medline is easy, it is operated by the US National Library of Medicine and is available to anyone with a browser. Medline provides access to 5400 worldwide journals in 39 languages dating from 1947 to the present. And it is free.

Embase, on the other hand, is not free. It provides access to an additional 2000 European medical journals, and so, is indispensable since you want to sell in Europe. But it is owned by Elsevier Publishing. You should be prepared to pay a hefty access fee ($7000 and up per year) or sub-contract the time from a third-party source.

A Three-Legged Stool
First leg
The first leg of a Clinical Evaluation Report is an evaluation of the existing literature data. The Global Harmonization Task Force (GHTF) Study Group 5 document "Clinical Evaluation" coupled with MEDDEV 2.7.1 Rev 3, which is slightly easier to read, are the guidances that tell us how to do the literature evaluation.

Here's what the medical writer—working together with you—will do:
[1] Define the key questions.
[2] Identify the databases to search (Medline, Embase, MAUDE, Cochrane).
[3] Define scope of search and search strategies using a qualified information specialist.
[4] Scan the abstracts to identify articles for review.
[5] Acquire full-texts of articles.
[6] Weight the articles for technical significance, discard anything with a low weight.
[7] Have a statistician weight the articles for statistical significance, discard anything with a low weight.
[8] Review only those articles with the highest weightings; maybe 5-25 articles per intended use.

The literature data are evaluated to determine if they support safety and performance of the device for its intended use. I like to prepare a separate literature review and attach it to the main CE Report as an annex. The literature review annex has several required elements including the search strings used by the information specialist, a list of abstracts scanned, the articles reviewed, their weights and justification for those weights, and full-text copies of the articles.

Second Leg
The second leg of the CE Report is a review any existing clinical investigation that your firm may have sponsored. These data are reviewed separately from the literature because you have closer access to the details. The writer asks questions such as: "Was the Declaration of Helsinki followed?" or "Were adverse events resolved?" If not, those facts are noted in the report but the data are not used.

Once the writer is satisfied that ethical and administrative requirements were correct, he/she reviews the study results to see if they support safety and performance of the device for its intended use. I like to prepare a separate sponsored study review and attach it to the main CE Report as an annex.

Third leg
In the third leg, the medical writer comes to the most sensitive step of all; examining the complaint file against the risk management system. They review the file to see if complaint handling, as dictated by the risk management system, supports the safety and performance of the device for its intended use. I like to prepare a separate risk management review and attach it to the main CE Report as an annex.

The CE Report
Finally, the medical writer takes the literature review, sponsored study review, and risk management review altogether and reaches an overall conclusion of whether the existing data support the device's safety and performance for the intended use, or if additional clinical data are needed newly. You know what happens if new clinical data are needed.

The Technical File
If the data are sufficient, the CE Report is filed away in the Technical File, a written procedure describing the writer's strategy is incorporated into your quality management system, and you wait with baited breath until the inspector comes.

How long, how much
There are only two questions in top management's mind: 1) how long will it take, and 2) how much will it cost. The answers are simple: "It depends." Let's say you have a very nice ultrasonic toothbrush and you intend to use it for cleaning roadside burns—the kind of burn you get when your motorcycle crashes and your skin scrapes against the pavement. The toothbrush is used to remove the dirt, grit, and tarmac from the wound. It's an unusual intended use and raises all kinds of questions about potential damage from the bristles, safety features to prevent over-brushing, effects of ultrasound on open wounds, comparing gum tissue to wound tissue, instructions for use, and so on. A clinical evaluation report for cleaning wounds will take longer and cost more than a report for brushing teeth with the same device.

CDG can help
Clinical Device Group is poised and ready to help you with writing your reports. We have medical writers, information specialists, experienced statisticians, access to Embase, a written procedure, a standard template, and a proven process. CE Reports written by our specialists have been reviewed by at least three different Notified Bodies and all have been accepted. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way.

Buffet approach
But perhaps you'd like to do your own medical writing in order to keep down costs, but don't have access to an information specialist, an experienced statistician, or Embase. Call us anyway, we like to work flexibly to meet your needs.

Contact us
Phone or email us at 773-489-5721 or [email protected].

A Standard Development Tale: ISO/FDIS 14155 (2010)

ISO/FDIS 14155 "Clinical investigation of medical devices in human subjects—
good clinical practices" (2010) 
A Whitepaper by Nancy J Stark, PhD 

ISO 14155 (2011) to become good clinical practice for medical devices
In this opinion-editorial I'd like to give some background on how the revisions to the 2003 ISO 14155 standards came about, why it took so long, what the economic implications may be, and what it's like to serve on a Working Group. These are my personal opinions and experiences, so please keep that in mind.

The medical device clinical investigation standard has had a varied and difficult past. To emphasize the point, here is the publication history as near as I can piece it together:
(1993) EN-540 "Clinical investigation of medical devices"
(1996) ISO 10993 "Biological testing of medical and dental materials and devices - Part 8: Clinical investigation".
(2003) ISO 14155 "Clinical investigation of medical devices for human subjects—Part 1: General requirements" and "Clinical investigation of medical devices for human subjects—Part 2: Clinical investigation plans."
(2011?) ISO 14155 "Clinical investigation of medical devices for human subjects—good clinical practices."

In 2003, the US voted yes to the revisions of the ISO 14155 (1996) standard. The yes vote did not come lightly. The 1996 standard was fluff, even for those days, and the 2003 standards were not a substantial improvement. The ICH-GCPs were adopted in 2000, FDA expectations were already higher than the 2003 standards, and even large firms such as 3M Company or Hollister Incorporated set higher expectations for themselves than the 2003 standards. Japan abstained from voting for ISO 14155-1 and voted against ISO 14155-2. The US reluctantly agreed to the 2003 standards with the idea of moving the action forward and on the condition that revisions begin immediately.

In January of 2003 the US began work on the contents of a New Work Item Proposal. The most important consideration was to harmonize the 2003 standards with the ICH-GCPs. But by April of that year the US backed away. There were competing political sensitivities between ISO (International Standards Organization), who had taken the lead for Part 1 with a Swiss convener; and CEN (Center for European Normalization), who had taken the lead for Part 2 with a British convener. The relationship between ISO and CEN had only recently been formalized in 2001 with the Vienna Agreement. A new Japanese law had passed, adopting the ICH-GCPs as their standard for medical device investigations in outright rejection of the ISO 14155 (2003) standards. And the US had declared war on Iraq, irritating much of Europe and weakening our international status in leadership roles.

Finally, the standard was originally a European initiative, pre-dating the 2001 Vienna Agreement between CEN and ISO. The original members of the CEN working group have always seemed a little surprised at the American and Asian interest in the standard and usually interpreted "international" to mean "pan-European"; eventually we started using the word "global" to make it clear that the standard would have world-wide consequences.

Possible changes to 2003 standards
Work resumed on a New Work Item Proposal (NWIP) in late 2004 with a list of 42 potential changes. Among the most important points proposed were:
[1] Merge Part 1 and Part 2 to avoid overlap and improve document flow.
[2] Harmonize the ISO standard with the ICH-GCPs.
[3] Harmonize the standard with MedDev guidances on clinical trials.
[4] Expand the principles of the standard.
[5] Clarify the responsibilities of investigator, sponsor, monitor, and IRB/EC more thoroughly and consistently.
[6] Clarify risk and risk assessment with regard to the subject rather then device design.
[7] Update the literature review section to match MedDev and any developing GHTF documents.
[8] Clarify the responsibilities of sponsors, monitors, investigators, institutions, IRBs/ECs, DSMB, auditors, and other parties.
[9] Clarify details of the investigator brochures, final report, adverse event handling, case report forms, and data management.
[10] Distinguish between adverse events and deviations.

NWIP approved, 2006
A New Item Proposal was finally introduced for voting in August 2006; it passed in December 2006 saying only that the ICH guidelines should be considered. Only the United Kingdom voted against revisions, leaving one to ask the question why they would oppose an improvement to the standard: there is always something to be gained from a position taken.

One part or two parts?
Work began in earnest in February 2005 in Berlin. The first item of discourse was whether to retain the standard in two parts or combine it into one; the consensus of the group was to combine the standard into one. By this time CEN had abandoned its working group and couldn't allocate funds to support development of a new standard so the question of who was to take the leadership role was easily resolved: ISO would take the lead and the British convener would step aside. The British did not attend another working group meeting until September 2009.

Project management approach
The working group began by dividing into sub-groups, each sub-group took on a major section of the standard and rewrote it to harmonize with ICH-GCPs and their own experiences of best practices. The result, when we met again in December 2005, was several well-written sections which lacked flow and integration. Someone complained that just looking at responsibilities didn't give a new firm a feel for how to go about getting started, and then someone else suggested modeling the standard after any project management approach: preparation, initiation, implementation, maintenance, and close-out; and then there could be sections on who is responsible for what.

Some countries argued that standards should not be teaching documents, but after much heated debate we agreed that teaching was important if we were to going to elevate the quality of device clinical investigations and gain respect for the standard itself. Whether teaching is a proper purpose of a standard or not would have to take second place to the more important goal of subject protection and data integrity.

Regulatory Authorities
Every country has it's own regulations and we needed to find a way to fit standard into a global structure. Many paragraphs are qualified with variations of the phrase "when requested by regulatory authority" as a way of building in flexibility. The phrase gets a little old, but its importance is indisputable.

Time or no time
The next debate was quickly resolved: should we mention time frames for reporting, say, adverse events. Our unanimous answer was no, because each country had it's own time frames and we didn't want to contradict them.

The same held true for EC/IRB responsibilities. We agreed to leave their job descriptions up to individual regulatory authorities.

Adverse event & effect definitions
Defining adverse events and effects turned out to be a fairly easy affair; we turned to the ICH-GCPs whenever we struggled and adapted the language to work for a medical device scenario. But there were wrinkles. The Japanese needed a definition for an "unanticipated, serious adverse effect". We Americans are so accustomed to having it left out that we didn't care, but certainly the standard meshes better with Part 812 by having a definition included.

Work stalls
By January 2006 we had a fairly complete standard. Then work stalled for reasons known only to the convener, the Secretariat, and ISO top management. No one with authority would call a meeting and from December of 2005 to July of 2008—18 months—there was no Working Group 4 meeting. The meeting in Chicago in July of 2008 was unproductive.

Unbeknownst to most Americans, Europe was in disarray. The admission of a number of Eastern European countries into the European Union left the New Approach in question. With 27 member states, reporting of adverse events, device deficiencies, and other post-market surveillance issues became unmanageable. Regulation of the medical device industry came within weeks of being under the control of the European Medicines Agency. It is my belief that the difficulties in Europe affected the progress of the standard.

First ISO/DIS issued in Sep08
In September 2008, despite the nearly unanimous recommendation of the Working Group, an ISO/DIS draft international standard was issued by the ISO Secretrariat. Most of the changes requested by the working group had been overlooked and the draft standard was eventually voted down by the Member States. 

New leadership—second ISO/DIS issued Sep09
No matter what the circumstances may be, when progress stalls it is the leadership that takes the hit. Working Group 4 is no different, and in September 2009 the group elected a new convener. The new convener, also Swiss, worked us hard for three days, not dismissing the meetings until 7 pm or until we had reached consensus. The work culminated in a second ISO/DIS being issued that same month.

Risk management and device deficiencies
The British rejoined the group for the first time since 2005. They brought with them a background in ISO 14971 "Application of risk management to medical devices" and were quite firm about including risk management language in the standard.

We also owe the reporting requirements for device deficiencies to the British members. This is one example of how the ISO standard differs from the ICH-GCPs; the standard needed to bring in the concept of devices that malfunction, deploy improperly, are misused, subject to use errors, and the like.

Adverse event categorization chart
One issue was not resolved: that of developing an adverse event categorization chart. A sub-committee, known as the Editing Committee, worked from January 2008 on to develop a chart, going through at least 15 different versions and never reaching consensus. Two versions of the chart, one from the British and another from the Japanese, were finally included in the final draft. It's interesting that we agreed on the definitions of the terms, we didn't agree on their relationship or if there was a hierarchy. The long discussions revealed basic differences in our understanding of how adverse events and effects are related to each other, and explain why definitions have always been do difficult.

The publication plan
FDIS stands for 'final draft international standard'. While the document is in the final draft stage it is being translated into French. Once this is complete the FDIS will be presented to the ISO members (Standards Bodies from each member country) for a final vote, but the only changes allowed at this stage will be spelling, punctuation, or grammar. After publication by ISO in 2011, each ISO member will be free to adopt the standard at the national level and publish it as a national adoption; so in the US the standard may be adopted as an ANSI/AAMI/ISO standard of the same number (ANSI is the American National Standards Institute, AAMI is the Association for the Advancement of Instrumentation.)

Oddly enough, an ISO member is free to modify the standard, within limits, before issuing it under its own designation. So buyer beware, the national adoption published in France may be different from the national adoption published in the UK, or the one published in the US!

If you were bored with the whitepaper, take the workshop anyway
If you were bored with this whitepaper, try the previous one on ISO 14155; and then take the workshop. The learning objective of this five-hour workshop is to review the changes from the old, 2003 standards to the new, 2010 FDIS. The recording is available by OnDemand or CD at http://www.clinicaldevice.com/mall/Workshops.aspx. 

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 5 hour presentation.
[x] Hints for writing Clinical Evaluation Reports and their role in clinical investigations.
[x] Hints for writing Risk Analysis Reports and their role in clinical investigations.
[x] The required contents of clinical investigation plans (i.e. protocols).
[x] The required contents of investigator's brochures.
[x] Steps in planning clinical investigations.
[x] Steps in implementing clinical investigations.
[x] Steps in closing-out clinical investigations.
[x] The monitor's role in clinical investigations.
[x] Responsibilities of sponsors and investigators.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who estimate study costs.
[x] Project managers who want better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark has been a member of Working Group 4 since 2001 and was an active participant in shaping the coming ISO 14155 standard. She is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop will be presented on Wednesday, 22 September 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

ISO/FDIS 14155 "Clinical Investigations of Medical Devices in human subjects—good clinical practices" (2010)

New Rules for International Device Trials
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 22 September 2010, 11 AM Central; or OnDemand soon after. 

Sweeping changes to ISO 14155
The international standard for medical device clinical research is about to undergo sweeping changes. The first and most evident change is the change in title; the standard is now known as ISO/FDIS 14155 " Clinical investigations of medical devices in human subjects—good clinical practices". Harmonized with the ICH-GCPs, 'Good clinical practices' was added to the title to signal to the world the Working Group's intention that this is now the standard to be followed for international medical device investigations.

There are other significant changes as well. The mechanical, physical, and engineering nature of devices are taken into account with the integration of the normative reference ISO 14971 "Application of Risk Management to Medical Devices". The contents of Investigator's Brochures looks like a document that reflects a mechanical device rather than a chemical drug, while the requirements for recording and reporting device deficiencies alongside adverse events complements the essential requirements of the MDD and AIMD.

All studies are created equal
Possibly the hardest thing for Americans to grasp is that there is no risk-based categorization of clinical trials in the standard. The concept of non-significant risk studies versus significant risk studies does not exist—all the rules apply equally to all clinical investigations.

An international standard written by international experts
The new standard was written by a team of experts from the US, Europe, and Japan. The team consisted of industry representatives, consultants, and regulators to assure that it was achievable, consistent with country regulations, and in keeping with accepted ethical and organizational practices. It did not come easily; the working group and editing committee met fourteen times, with a dozen or so teleconferences sprinkled in between the meetings.

One result is a standard that will be an an economic leveler—it will be neither easier nor more difficult to conduct a trial in one country over another. Another result is a standard that will be an ethical leveler—it will be neither easier nor more difficult to conduct trials in developing countries than developed countries.

Format and approach
The Part 1 and Part 2 standards from 2003 are now combined into single, comprehensive, 65-page document. The strategy was to approach clinical investigations from a project management perspective. A look at the layout gives an idea of the breadth and depth of the standard.

First, there are four administrative sections:
[1] Scope.
[2] Normative references.
[3] Terms and definitions.
[4] Ethical considerations.
The scope tells us that "the principles ...apply to all other clinical investigations...." The statement has no legal precedence but was clearly important to the Europeans. The scope also makes it clear that the standard does not apply to in vitro diagnostic devices.

"Normative" is ISO-speak for required. It is the one, small sentence under normative references that elevates ISO 14971 to importance. Being listed as a normative reference means that the sponsor is, de facto, non-compliant with ISO 14155 if they are not compliant with ISO 14971. Scattered throughout the document are the many ways in which Risk Analysis Reports are integrated into clinical investigations.

These are followed by three project planning sections:
[5] Clinical investigation planning.
[6] Clinical investigation conduct.
[7] Suspension, termination, and close-out.
It is not that there is anything new in the project management sections, but there is so much more detail and instructive language. If you have never done a clinical study before, you will find these sections to be a welcome reference.

The need for a Clinical Evaluation Report performed according to the principles of GHTF Study Group 5 to justify the design of the clinical protocol is another example of a requirement included to meet the essential requirements of EU Directive 93/42/EEC on medical devices (MDD) and EU Directive 90/385/EEC on active implantable medical devices (AIMD).

These are followed by two responsibilities sections:
[8] Responsibilities of the sponsor.
[9] Responsibilities of the principal investigator.
Sponsor and principal investigator responsibilities follow closely with FDA's new guidance "Investigator Responsibilities—Protecting the Rights, Safety, and Welfare of Study Subjects" and the ICH-GCPs. Principal investigators (aka "investigators" in the States) are still required to sign final reports under ISO, but investigators (aka "co-investigators" or "sub-investigators" in the States) are off the hook.

While much of the detail is laid out in five annexes:
Annex A (normative)—Clinical investigation plan.
Annex B (normative)—Investigator's Brochure.
Annex C (informative)—Case report forms.
Annex D (informative)—Clinical investigation report.
Annex E (informative)—Essential clinical investigation documents.
Annex F (informative)—Adverse event classification decision tree.
Annexes A and B on Clinical Investigation Plans (i.e. protocols) and Investigator's Brochures are required for compliance, the remaining annexes are for the reader's information. They contain extremely valuable information on organizing case report forms, writing a final report, and understanding the relationships between adverse events and effects.

Other extensive changes
Each section was expanded to include sufficient narrative to teach a new sponsor how to conduct a clinical investigation. This controversial move is meant to educate as well as to set a performance bar. Some notable examples of additions or changes include:
[1] Clearer definitions of adverse events, adverse device effects, and unanticipated device effects.
[2] A new definition, recording, and reporting requirements for device deficiencies.
[3] Requirements for recording and reporting adverse device effects in persons other than subjects.
[4] Implied requirement for a clinical research quality management system.
[5] Requirement for Risk Analysis Report.
[6] Requirement for a Clinical Evaluation Report to justify the study design.
[7] Required content for a protocol (clinical investigation plan).
[8] Required content for an Investigator's Brochure.
[9] Suggested content and organization for case report forms.
[10] Discussion of data monitoring committees.
[11] Requirements for document and data control.
[12] Requirements for electronic data systems.
[13] Auditing recommendations.
[14] Procedures for suspension or premature termination of a trial.
[15] Procedures for working with vulnerable populations.
[17] An extensive list of the documents essential for a clinical trial.
[18] Omission of the annex discussing how to do a literature review.
[19] And, very importantly, two differing attempts at adverse event classification.

The publication plan
FDIS stands for 'final draft international standard'. While the document is in the final draft stage it is being translated into French and German. Once this is complete the FDIS will be presented to the ISO members (Standards Bodies from each member country) for a final vote, but the only changes allowed at this stage will be spelling, punctuation, or grammar. After publication by ISO in 2011, each member Standards Body will adopt the standard into its own system; so in the US the standard will be re-issued as an ANSI (American National Standards Institute) standard of the same number.

Oddly enough, a member Standards Body is free to modify the standard, before issuing it under its own name if it wishes. So buyer beware, the French version may be different from the British version or from the US version!

If you liked the whitepaper, take the workshop
The learning objective of this five-hour workshop is to review the changes from the old, 2003 standards to the new, 2010 FDIS. The recording is available by OnDemand or CD at http://www.clinicaldevice.com/mall/Workshops.aspx.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 5 hour presentation.
[x] Hints for writing Clinical Evaluation Reports and their role in clinical investigations.
[x] Hints for writing Risk Analysis Reports and their role in clinical investigations.
[x] The required contents of clinical investigation plans (i.e. protocols).
[x] The required contents of investigator's brochures.
[x] Steps in planning clinical investigations.
[x] Steps in implementing clinical investigations.
[x] Steps in closing-out clinical investigations.
[x] The monitor's role in clinical investigations.
[x] Responsibilities of sponsors and investigators.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who estimate study costs.
[x] Project managers who want better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark has been a member of Working Group 4 since 2001 and was an active participant in shaping the coming ISO 14155 standard. She is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop will be presented on Wednesday, 22 September 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Keeping Study Costs under Control

Building and Managing A Realistic Budget Plan A Whitepaper and Workshop by Nancy J Stark, PhD Wednesday, 1 September 2010, 11 AM Central; or OnDemand soon after. Reading someone else's copy? Opt-in for whitepapers to get your own. A modest device study for a million dollars A modest device study costs $1M and a major study $10M or more, big bucks for a start-up venture, not insignificant for big firms. The total costs are divided between investigative sites, centers such as CROs or consultants, and internal costs such as your salary and benefits. In this whitepaper we'll discuss common mistakes made in estimating study costs and steps you can take to keep spending under control. It starts with the protocol  Consider the following study plan: 100 subjects will be implanted with a vascular access port; they will use the port for the duration of their primary treatment, and then have the port removed. Let's say the protocol requires still photographs from a final fluoroscopy and radiologist's report at the time of implant to confirm catheter and port position; and still photographs from a final fluoroscopy and radiologist's report at the time of explant to determine possible migration. These are procedures that are outside the normal standard of care. Mistake [1] The first mistake sponsors make is to ask for too much information; information that is unnecessary to investigating the study objective. Don't ask for nice-to-have procedures, lab tests, or information; limit your requests to information that is essential to analyze your primary hypothesis. The 2010 CRA Handbook is Finally Here The 2010 CRA Handbook is finally here! We delayed production until we were sure that the ISO/FDIS 14155 "Clinical investigations for medical devices—good clinical practices" (2010) was definite. So here you have it: the best and the original field guide to medical device clinical trials, brought to you from Clinical Device Group. If you have used our handbook before, you'll be pleased to know that we are offering it again as either a spiral-bound paper edition (designed to lie flat, fit compactly in your briefcase, and lend itself to field notes) OR the electronic version (designed to load to your laptop, be fully searchable as a pdf document, and annotatable if you have Acrobat Writer). Full descriptions, table of contents, and ordering information are here. Know your investigator's costs Begin by building an investigative site budget on your own. Sophisticated sites expect that the sponsor will provide a study overview and model budget for them to work from. The study overview summarizes the study in a paragraph or two, describes the subject selection criteria, and that includes a list of every task the site must do to fulfill the study requirements. Think in terms of verbs or action items for the site, organized by the site's prestudy, study, and post-study tasks. Mistake [2] The Site's Task List is more than just a procedure list for the subjects, it includes every activity the site must perform in order to implement the study. Such tasks as 'review the protocol', 'prepare the IRB application', 'screen patient medical records', 'meet with monitor', 'enter data onto case report forms', and other administrative duties are included in the list. The Site's Task List might look like this: Site Prestudy Tasks (Study Start-Up): [1] Submit protocol and consent to IRB [2] IRB review fee [3] IRB amendment fee [4] Meet with monitor for study training [5] Set up regulatory binder [6] Set up subject binders x number of subjects [7] Administrative fee Mistake [3] Our human tendency is to under-estimate the time required to perform a task; however long you think it will take, multiply by a correction factor characteristic of you. I usually underestimate the actual time by half. It's hard to get firm numbers because investigative sites don't invoice sponsors by the hour. Site Study Tasks: [1] Screen patient records [2] Offer study to patient [3] Obtain informed consent [x] Implant vascular access port—procedure not paid by sponsor [4] Take implant fluoroscopy and still image, write radiology report [x] Treat subject—procedures not paid by sponsor [5] Investigate adverse event [6] Take explant fluoroscopy and still image, write radiology report Mistake [4] Under-estimating the cost of study-procedures; accurate estimations are hard to find. Practice Management Information Corporation (PMIC) reminds us that third party payers rarely disclose their fee databases, and professional medical associations are prevented by Federal antitrust legislation from disclosing fee survey results. You can obtain Medicare fee schedules from the CMS site if you can find them, and a variety of medical fee schedule databases are available for sale. You can use MEDFEES from PMIC or EncoderPro.com from Ingenix, for example. Site Post-study Tasks: [1] Transcribe/enter data from source files to case report forms/EDC screens [2] Be available to monitor for monitoring visit [3] Answer data queries [4] Notify IRB of study close-out Other: [1] Overhead, ~30% of total site budget Mistake [5] No-one like to pay overhead. My own Clients argue over a 10% overhead. A quick search in Google showed that Vanderbilt charges 29%, Memorial University of Newfoundland charges 30%, the Center for Cancer Care and Research in St. Louis, MO wants 20%, UCLA wants 16% of total direct costs, and NYU wants 30%. Overhead costs are higher if calculated on procedure fees only, lower of based on total direct costs. You should plan on a 25-30% overhead charge against the total site budget. THE TASK TABLE Put the task list into a spreadsheet and create a Task Table by assigning hours, hourly rates, and amounts to each task. For tasks that require time, like preparing the IRB submission, imagine in your own mind how long it would take you to perform the task, this will help you estimate the number of hours associated with the task. Then you'll decide if the investigator can perform this duty (high complexity duty or patient-contact duty) or if a trained member of the study staff can perform it. This will help you determine "fair market value" for the hourly rate. Fair market value for a physician/surgeon will be around $250-$350 and for a study nurse around $70-$90. Finally, sites like to discuss study costs in terms of costs per subject and some sites have a minimum per subject. Northwestern Memorial Hospital in Chicago considers any study that pays less than ~$2000 per subject as a money-loser and will not participate. Center budgets A 'center' is a business that pays its own taxes. First you need to identify all the centers that will contribute to your study. Possible centers are central IRBs, central laboratories, contract research organizations, independent monitors, independent professionals, contract research organizations, data management centers, and anyone else whose time you will charge against the study. You begin in the same way. Center budgets are built around the protocol, so you'll make a task list of all the activities you need each center to perform in order to fulfill their part of the study. Mistake [6] Bring a competent clinical research professional into the project early on. Too many sponsors wait until after they have designed the protocol and contracted with the sites to discuss study issues. CROs can often save you money by suggesting better regulatory strategies, study designs, or sample size calculations. Once you have a protocol you'll go through it page-by-page, as before, and make a table of tasks you want to sub-contract and which center you want to do the task. Mistake [7] Don't chose your center by cost alone. Look at references, experience in the device world, reputation, sub-contractor network, and size. Time and again I see centers hired because their estimates were lowest; and then cost over-runs come in when it is too late to switch vendors. Mistake [8] Don't hire a big firm for a small job, or a small firm for a big job. In the first scenario your study will be lost in the daily shuffle; in the latter scenario the center will not have the resources to implement the project. Then, you estimate a budget for each center. Some centers have fixed fees, such as central IRBs; others charge a fixed fee per subject, such as central laboratories; data management centers charge by the number of data fields; and other centers charge an hourly rate, such as professional consultants. As before, you divide the center's activities up into prestudy, study, and post-study tasks; and then assign a number of hours and hourly rate (or fixed fee) to each task. Mistake [10] Don't cut corners by not monitoring poorly performing sites. Clinical studies are market-driven, and there is always a reason for poor performance. If enrollment is slow there is a good chance a competing study is paying more than you per subject, but you won't know until you monitor face-to-face. Sponsor budgets As the sponsor, your own budget fits into the equation too. Sponsor costs aren't just the clinical trial department's costs, they are costs spread throughout the company but that rightfully should charge back to the clinical trial project. Statistical functions, data management functions, quality design costs, costs for comparator devices, and even manufacturing costs for building investigational devices, are all charges that should be included in the sponsor budget. And, of course, don't forget the salaries and benefits of in-house employees. As before, you organize the activities that in-house personnel are expected to do by prestudy, study, and post-study tasks. Here I like to include a separate category of data management tasks, because these tasks span the study project in time from before study initiation to after study close-out. Mistake [11] Task lists, line items, and budgets are tricky to make. A 'splitter' personality will easily find a couple of hundred things for people to do, a 'lumper' personality may whittle a study down to 30-40 tasks. When splitter personnel work for lumper bosses, or vice versa, sparks fly. Learn the personality preferences of your workmates and accommodate them with sub-lists and super-lists. Total study budget Finally, you will add the budgets for each investigative site, each center, and yourself (the sponsor) to make a total study budget. By getting a good estimate ahead of time you can assess the scale of the study, re-evaluate the cost of a hypothesis, plan for expenditures, give realistic information to top management, and scope back when necessary. Mistake [12] First-time sponsors are always surprised that as much as 50% of the study budget may be spent before the first subject enters the study. Good budget planning, organized by study timing, prepares top management for what lies ahead and helps keep middle-managers out of the 'you didn't tell me' hot-seat. If you liked the whitepaper, take the workshop The objective of the workshop is to learn how to plan and manage clinical study costs. Sign up at registration. You will receive, we will discuss [x] PowerPoint slides. [x] A 4-5 hour presentation. [x] How to build a task list. [x] How to relate task to line items. [x] How to craft a budget. [x] How to estimate the cost-at-completion midway through a study. [x] Examples of site budgets, center budgets, study budgets. [x] A 30-minute quiz to reinforce your learning experience. [x] CEUs and certificate of attendance. Who should attend [x] Clinical research professionals who estimate study costs. [x] Project managers who want better planning and reporting from their group. [x] CROs who want to improve their proposal skills. [x] Executives who are planning the future of their company. Presenter Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The 4-5 hour workshop will be presented on Wednesday, 1 September 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc

Risk Analysis Reports and EU Clinical Trials

A Whitepaper by Nancy J Stark 
An e-Conference by Barry Sands
Wednesday, 4 August 2010; available OnDemand soon after.

If you are planning a clinical trial in Europe, now is the time to learn about risk management in clinical trials. Risk management plays a critical new role in ISO/FDIS 14155 "Investigation of medical devices in human subjects—good clinical practices". The standard is expected to be published in late 2010 or early 2011 and will be incorporated into the AIMD and MDD immediately; there will be no phase in period.

Compliance with risk management is required
The ISO 14971, "Medical devices—Application of risk management to medical devices" standard is a normative reference for ISO/FDIS 14155; meaning its implementation is indispensable for the conduct of clinical trials. In other words, in order to be compliant with ISO/FDIS 14155, the entire clinical trial process must also be compliant with ISO 14971.

Hazards, harms, and risks in clinical trials
It's simple: in risk management terms a hazard is a situation that could cause harm, a harm is an adverse event, a risk is the likelihood that the harm will occur. For example, a lose connection is a hazard, an unwanted electrical shock is a harm, the risk is the mathematical probability that the harm will occur. In a clinical trial you focus on subject-centric risks: what happens to the subject if the device's handle falls off? What happens to the subject if the procedure takes too long? Then you consider the probability that the adverse event will occur and the severity to the subject if it does occur.

Risk and its application to clinical trials
Applying risk management to making sound/informed decisions on clinical study initiation, suspension, modification, reinitiation and stoppage are among the most intense decisions your organization will make. These decisions affect patient safety, clinician/surgeon reputation/relationships, company reputations and product liability.

As clinical research professionals responsible for these studies you aren't unfamiliar with risk concepts, but you will have to learn a new language. For example, what is the difference between risk estimation, risk analysis, risk assessment, risk evaluation, risk control, residual risk, a risk analysis report, risk management, and a risk management file? Here is a partial list of some of the issues you will face with regard to risk management.

Clinical evaluation report
The ISO/FDIS 14155 (2010) takes a whole new strategy toward initiating a clinical trial. Before you start writing the protocol you review the scientific data to prepare a clinical evaluation report consistent with the principles of GHTF Study Group 5. CDG has written several whitepapers on how to prepare clinical evaluation reports and scientific literature reviews. One outcome of the clinical evaluation report is a justification for the design of your clinical study.

Risk analysis report
Another outcome of the clinical evaluation report is a Risk Analysis Report. "What's that?" you ask? It is a table of potential adverse events (i.e. harms) that may occur to the subject as a result of participation in the trial. The list includes all the adverse events that might occur from use error (say, perforating the bowel during a colonoscopy), device malfunction (a laser that over-delivers energy), or the procedure itself (tooth loss following radiation for head and neck cancer). Then the next columns of the table identify the frequency with which the event will occur, the severity of the event if it does occur, the risk (likelihood) that the event will occur, how you will mitigate the event (protect against occurrence or treat should it occur), and finally any residual risks left after mitigation. The table might look like this:

RISK ANALYSIS REPORT
POSSIBLE ADVERSE EVENT | FREQUENCY | SEVERITY | RISK | MITIGATION | RESIDUAL RISK

The standard is serious about risk management; any serious adverse event that occurs and is not identified in the Risk Analysis Report is considered unanticipated and is subject to expedited reporting.

There is a skill to writing Risk Analysis Reports. One colleague prepared a three page report on the risks of removing medical tape from your skin. Don't include so many minor harms that you obfuscate the important ones. Don't omit serious harms, even when they have only a slight chance of occuring. Update the Report and the Investigator's Brochure whenever there is a change in perceived risks.

Informed consent
It isn't enough to prepare a Risk Analysis Report; you have to share it with the subject as part of the informed consent.

Resulting decisions
You will decide whether or not to establish a data monitoring committee based on the findings in the Risk Analysis Report. You will decide whether or not to audit the study based on the Risk Analysis Report. You will determine the follow-up period based on the Report, the follow-up period should be long enough to asses whether or not a harm occurs. And the decision to suspend or terminate a study due to unacceptable risk to subjects will follow naturally from the Risk Analysis Report.

Final report
The conclusion section of the final report shall assess the risks and benefits of the investigational device and identify any groups of persons that are at particular risk.

Expertise in ISO/EN 14971
I've asked Barry Sands to walk us through ISO/FDIS 14155 and ISO/EN 14971 and examine all the ways in which risk and risk concepts are to be applied to clinical trials. Barry is experienced in both clinical research and risk management and we are lucky to have him. He will provide examples on how this process was and was not effectively applied to actual medical device clinical trials.

If you liked this whitepaper, take the e-conference
In this e-conference you will learn how to apply risk management concepts to the clinical research process. You will learn how risk management allows a manufacturer to make more objective and informed decisions about when to initiate, suspend, restart, modify or stop a clinical study. And you will learn how specific risk management tools can assist in these clinical study decisions. 

You will receive
[x] PowerPoint slides.
[x] An expert speaker who has worked for industry and FDA.
[x] Knowledge essential for ISO/FDIS 14155 compliance.
[x] Chance for Q&A.
[x] CEUs and certificate of attendance.
[x] Please purchase your own copy of ISO/DIS 14155 from DIN and ISO/EN 14971 at www.iso.org.

Who should attend?
[x] Anyone who's considering a device trial outside the United States.
[x] Anyone who monitors clinical trials outside the United States.
[x] Regulatory professionals who prepare documents for CE certification and marking.
[x] Regulatory professionals submitting foreign data to FDA.
[x] FDA personnel who review data from foreign trials.
[x] FDA inspectors who inspect foreign sites or sponsors.

Instructor
Mr. Barry Sands is a biomedical engineer with a chemical engineering concentration. He has seven years experience as a Biomedical Engineer and Sr. Scientific Reviewer at FDA/CDRH/ODE and FDA’s Boston District. This government experience was followed with seventeen (17) years in midlevel and executive regulatory/clinical/quality affairs management positions in small start-up and large multinational medical device companies. His firm provides support in the areas of regulatory submissions (510k, IDE, PMA, HUD/HDE, Design Dossiers), Clinical Study Design/Management, Risk Management, Quality System Design/Audits (FDA QSR and ISO 13485) and FDA Negotiation and Communication (QSR Audits, 483s, Warning Letters, Bioresearch Monitoring, Medical Device Reports, Recalls). He can be reached at [email protected].

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 90-minute e-conference will be presented on Wednesday, 4 August 2010, at 11:00 am Central Time. Event materials will be distributed the day before the event. Sign up at registration.

==============================
Be Trained or Be Left Behind

It's a fact in today's fast-paced world: you are never fully trained or up-to-speed. The regulations, standards, and current thinking about the clinical research process are constantly changing. You need access to think-tankers, thought-leaders, insiders, and researchers in order to maintain your knowledgability.

Happily, you can get the full spectrum of current thought from Clinical Device Group, available on CD or OnDemand, at our website.
============================

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

CRO Capabilities from Clinical Device Group

An Advertisement from Nancy J Stark, PhD

Reading someone else's copy? Opt-in for whitepapers to get your own.

It starts with a technology
You know your technology works, now it's time for a clinical trial. CDG is here to help. We have a unique business model: all professional work is sub-contracted to our spider-web of expert Network Staff Associates. Click here for an Acrobat pdf copy of our brochure and business model.

Marketing needs determine indications for use
Meet Judi Bednarz
Next comes deciding which indication(s) you should pursue. CDG suggest's "easy claims first" but our marketing specialist, Judi Bednarz, can help you phrase your indications and claims to get the best play in the marketplace with the least burdensome requirements from FDA. "Work with the words", says Judi. We often ask her to assist in investigative site recruitment. With her knowledge of how to find people who know things, she is ideal for finding investigators with unusual skill-sets or hard-to-find subjects.

Biological Safety Assessments
Meet Dr. Dan McLain—Toxicologist
Investigational device safety is of primary consideration before any human exposure to a device. The animal biological safety tests and animal preclinical safety and performance experiments can be reviewed in the Investigator's Brochure or Report of Prior Investigations by device toxicologist Dr. Dan McLain. Dan's PhD in toxicology, status as a convener for ISO 10993-8, and years of experience in the medical device field give him high credentials for assessing the biocompatibility of a new technology or device, for preparing expert reports to include in regulatory submissions, or in answering questions you have received from FDA.

Clinical Evaluation Reports, Investigator's Brochures, Medical Writing
A Clinical Evaluation Report is a review of existing clinical and safety data to: a) determine there is already sufficient data to support your technology's safety and performance for its intended use, or b) justify the design of a clinical trial. We have a team of medical writers and information specialists who can prepare these essential reports for you.

Meet MEDIcept Inc—Medical Writers
F. David Rothkopf, founder and President of MEDIcept, has more than 20 years of professional strategic experience in the development, quality and regulatory control of medical devices. They offer engineering, quality, and regulatory consulting assistance to the medical device and blood plasma industry. MEDIcept's Todd Rhode and Joanne Fides have engineering and quality system backgrounds that give them an edge in technical writing for high-technology devices.

Meet Dr. Charles Hurwitz—Medical Writer
American-born and educated, Dr. Charles Hurwitz has a PhD in microbiology. He earns his living as a medical writer, writing instruction manuals, manuscripts, and clinical evaluation reports. Living in Israel gives him an advantage; he is closer to "Euro-think" than most Americans.

Meet Sunny Worel—Information Specialist
Sunny Worel was a former medical librarian. She has a background in Biochemistry and Microbiology (from the University of Minnesota). Sunny worked on the laboratory side of clinical trials and made immunodiagnostic kits before getting her Master in Library Science. She has been in independent information specialist with skills in Embase searches for many years.

Meet Brian Hartman—Information Specialist
Mr Hartman holds a Masters Degree in Library Service, is proficient in Embase searches, and is highly comfortable in Access, Excel, HTML, and Visual Basic development. He brings a unique background in information management to his responsibilities as Information Specialist at CDG.

Clinical Evaluation Reports: Procedure and Templates If you'd prefer to write your own clinical evaluation report to protect your confidential and proprietary information, we understand. You can get a jumpstart with CDG's Standard Procedure and Templates for Clinical Evaluation Reports. The procedure says who will do what and how it will be done. The Article Grade Template, in Excel, provides a convenient way to organize the articles you purchase and keep your grading system in order. The Report Template, in Word, provides a convenient drop-in format that will allow you to utilize content you have already for other purposes. Click here for more information.

Regulatory professionals
Meet Kathleen Johnson—Pre-IDE meetings and regulatory strategies for devices
The number of pre-IDE meetings in FY 2007 increased to 484 "due primarily to increasing awareness of the existence and usefulness of the program", its positive effect on successful first-cycle IDE review, and value for posing other issues to FDA. CDG's regulatory expert Kathleen Johnson, RN, can organize and facilitate a pre-IDE meeting for you. At this meeting we'll cross-check the study design against the proposed indications to be sure FDA is in agreement.

Meet Dr. Gail Radcliff—Strategies for IVD start-ups
Gail loves a challenge and limits her practice to new and interesting technologies. Her education in molecular biology and virology give her strong credentials for helping diagnostic companies with complex new products. Gail has written numerous 510(k)s for diagnostic and biological devices, assessed market opportunities for new technologies, developed business models for cancer biomarkers, and worked on numerous projects for investor and university technical transfer.

Meet Fabio De Pasquale
Living in British Columbia, Canada, Fabio De Pasquale has worked with several local and US companies helping them to bring their devices to the US, Canadian and European markets. His experience in quality assurance allows him to advise small companies on how to set up quality management systems. His expertise in regulatory affairs allows him to bring fresh ideas to wording indications for use so that the best regulatory pathway is an option.

Protocol development and study design
Meet Patsy Trisler
Patsy is one of those multi-talented people that can do anything regulatory or clinical. She is listed here under protocol development and study design, but could be listed under IDE approvals or regulatory submissions. To give you an idea of her breadth, here is a list of technologies for which she has provided strategic guidance: allograft tissue applications, blood processing technology, dental products, drug delivery devices, dura substitutes, interventional cardiovascular therapies, orthopedics (including bone replacements/substitutes, bone growth stimulators, growth factors & spinal technologies), pain therapy technologies, plastic & reconstructive cosmetic & rehabilitative products, soft-tissue reinforcement implants, software (medical), weight-loss products, and wound care therapies. 

Meet Cheryl Hayden
Dr. Hayden is educated as a microbiologist, has research experience in cancer epidemiology and biostatistics, and has hands-on experience in clinical research. She has prepared over thirty clinical evaluation reports on the performance of different kinds of medical devices. Although she has a broad range of expertise, her specialty is diagnostic devices and biomarkers.

Meet Barry Sands
Barry is a biomedical engineer with a chemical engineering concentration. He has seven years experience as a Biomedical Engineer and Sr. Scientific Reviewer at FDA/CDRH/ODE and FDA’s Boston District. This government experience was followed with seventeen (17) years in midlevel and executive regulatory/clinical/quality affairs management positions in small start-up and large multinational medical device companies. His firm provides support in the areas of regulatory submissions (510k, IDE, PMA, HUD/HDE, Design Dossiers), Clinical Study Design/Management, Risk Management, Quality System Design/Audits (FDA QSR and ISO 13485) and FDA Negotiation and Communication (QSR Audits, 483s, Warning Letters, Bioresearch Monitoring, Medical Device Reports, Recalls).

Sample size calculations and statistical development plan
Meet Michelle Secic—biostastician
Michelle Secic, MS has worked on hundreds of protocols and the full range of devices, biologics, and drugs in her years as Manager of Statistical Analysis at Cleveland Clinic. She knows a protocol's sample size must be based on defensible estimates. She will work with you to design a study that gets you the indications you need with the least number of subjects. "Work with the words" she agrees. Michelle knows from experience that measuring the time to heal a wound versus the number wounds healed at a given time will lead to very different sample sizes. She will work with the performance estimates you provide to give you a table of possible sample sizes.

Meet Dr. Robert Thiel—Bayesian and IVD specialist
Dr. Robert P. Thiel has degrees in physics and psychometrics. He is an expert in the analysis of IVD data for the Medical Device Industry with more than seventy-five 510K and five PMA approvals. He has published papers in the areas of free PSA, breast cancer, ovarian cancer, liver disease and multivariate analyses. His current interests lie in the area of bootstrap and permutation test methodology and the application of these methods to small sample trials and Bayesian analysis as applied to diagnostic clinical trials.

Project Management
Meet Lynette Chiapperino—Monitor and Clinical Project Manager
The Clinical Trial Project Manager is the person who plans the study and provides forward motion to the clinical trial. Lynette Chiapperino, AAS in medical technology and BS in management, is a born clinical trial project manager. She can estimate time, cost, and human resources needed for a trial. She understands both the sponsor's and investigator's responsibilities and works both sides of the aisle when monitoring a study so that everyone's records are in order.

Case report forms and other study documents
Meet Dr. Nancy Stark
Dr. Stark has some pretty good skills with MS Visio and often works with the protocol designer, statistician, and data manager, to layout the case report forms. The goal is to make the forms easy for the form-filler and easy for the data-enterer, while following the protocol exactly. Three-part paper forms are still the best way to collect data for small studies or small companies.

Study implementation
Meet Kathleen and Lynette-monitors
Yes, these are the same Kathleen Johnson and Lynette Chiapperino you met above. Multi-talented, Kathleen, Lynette, and Sue (below) are CDG's go-to people for day-to-day monitoring.

Meet Sue Lesly
Sue Lesly is educated with a BS in English and psychology, which explains her diverse clinical research experience. She has been involved in all aspects of clinical trial performance
including: monitoring, site recruitment, site management, CRA & CRO management, protocol development, CRF & source document design, development of study specific procedures & internal clinical SOPs, and preparing reports for FDA & regulatory submissions. 

Data Safety Monitoring Boards and Clinical Events Committees
Meet Steven Schurr, Esquire
More complex products or those with new technologies often require a Data Safety Monitoring Board or Clinical Events Committee to adjudicate adverse events; i.e., make the final call as to whether an adverse event is device related or not. CDG's Steve Schurr, Esquire has the clinical, legal, and DSMB experience to manage this external board of independent experts.

Data management
Meet Wessam Sonbol
Wessam Sonbol has a BS in computer science and business management, and he uses these skills effectively to design databases to receive clinical data (Wessam is proficient in Access, Excel, Clindex and other applications), validate the database, import data, and verify the data. He is comfortable with Part 11 controls and able to advise you as to how and when controls should be implemented. Wessam has over 11 years of experience in Clinical Data Management.

 

We can help you; hire us as your CRO
Clinical Device Group has the capabilities to perform all of these tasks for you—we are a full-service CRO. But if you prefer, hire us to perform specific tasks or act as an advisor to your staff.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc
773-489-5706
[email protected]

The Medical Device Clinical Trial Process

From Vision to Market
A Whitepaper by Nancy J Stark, PhD

Reading someone else's copy? Opt-in for whitepapers to get your own.

It starts with a technology
Time and again, companies develop a new technology, and then go on a clinical trial Easter egg hunt to find a claim they can make for it.They know the technology works, but aren't sure how to design a trial to give them the most efficient regulatory pathway (significant risk or non-significant risk, 510k or premarket approval) and whose outcomes will maximize their chances for FDA approval and third-party reimbursement.

Let's say you have a technology and you are confident that it works. You are at the stage of designing the clinical trial, but are struggling with where to start. It starts with the claims: well really it starts with the intended use and indications for use you want to make for the technology.

Intended use
The first decision is to decide on the intended use you will pursue. When considering intended use, think in terms of verbs acting on the body: stimulates nerves, measures impedance, or measures biomarker concentrations.

Perhaps you have a neurostimulation technology; you might intend to use it for transcutaneous electrical nerve stimulation (TENS), functional electrically stimulation (FES), muscle stimulation, neural stimulation arrays to act as cochlear or retinal prostheses, or deep brain stimulation. Perhaps you have a biomedical impedance technology and you want to measure lean body mass, daily calorie expenditure, or tomography imaging. Or perhaps you have identified a family of biomarkers characteristic of a medical condition. Do you intend to diagnose a symptomatic patient for the condition, screen large populations for the condition, or act as an adjunct diagnostic tool?

Indications for use
Indications for use are more specific than an intended use, here we are talking about a disease or condition to treat, cure, mitigate, prevent or diagnose. There may be many indications for a single intended use. Your deep brain stimulator might be indicated to mitigate epileptic seizures, prevent depression, and treat headache.

And then the claim, i.e. the study outcome
A claim is an assertion of truth. There is no regulatory definition for a claim. Claims result from the outcome of the clinical study. So in essence, the marketing department writes copy for the glossy brochure first, and the clinical department designs the study to match it.

Clinical Evaluation Report
Next you need a thorough clinical evaluation report. What's this, you ask? There is no such thing in the FDA regulations or guidances. The requirements comes from ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010), which coordinate with Europe's Medical Device Directive and Active Implantable Medical Device Directive.

The process involves an evaluation of published clinical data (a literature review), sponsored clinical data, and the manufacturers risk management system (complaint history) to determine if sufficient clinical data already exist to support safety and performance for the indications or if new clinical data are needed. If a new study is needed, the report is necessary to justify the study's design.

Do You Need A Clinical Research Quality Management System? CDG's Clinical Research Quality Management System is a comprehensive collection of statements, policies, procedures, templates, and supporting documents that contains everything you need to set up a clinical research function. Each procedure is designed to tell you 'how to' do something and results in a work product such as a document or report. The procedures are organized chronologically, the way you would organize a project schedule, to walk you step-by-step through the process of running a clinical trial and a clinical department.The manual is divided in sections that follow the major activities of a clinical project. For more information click here.

Protocol Development
The next big step is designing the protocol, i.e. the plan for the study. It's an interactive process and you and the product development team will change your minds many times along the way.

Study design
You'll need to choose a study design, such as single arm, superiority to a comparator, equivalence to a comparator, non-inferiority to a comparator, or registry.

Objectives, hypotheses, endpoints, outcomes
There are endless arguments over what is meant by study objectives, but in my view of the world it refers to why you are doing the study: [1] research, [2] feasibility to prove a concept, develop a hypothesis, refine a design, or obtain data for sample size calculations, [3] manufacturability, [4] pivotal—this is the study on which the success or failure of the 510k or PMA pivots, [5] new claim substantiation, [6] consumer preference, [7] market positioning, [8] marketing support, [9] reimbursement, [10] post-market approval.

Hypotheses are testable statements of safety, efficacy, or performance. The 'null' hypothesis is usually the statement we want to to be false (my product is worse than yours), and the 'alternate' hypothesis is the statement we want to be true (my product is better than yours). In most protocols we only write the alternate hypothesis and we let the statistician make the translation in the Statistical Analysis Plan (SAP). But for non-inferiority studies we want to prove the null hypothesis (my product is no worse than yours); a technique devised by FDA statisticians to help device manufacturers demonstrate substantial equivalence. A study may have a primary hypothesis and several secondary hypotheses.

An endpoint is a method for measuring device success or failure. The word used to signal the end of treatment, but end of treatment is not a meaningful concept for devices that mitigate or manage diseases or conditions. Remember the endpoint as a measurement method and you will be fine. A study must have a primary endpoint to measure the primary hypothesis, and will have secondary endpoints for other hypotheses.

The outcomes are the result—did the device work or not? You'll need to decide now what value will be required to declare success. Here are some possibilities: [1] time to a distinct event, such as range of motion or death, [2] number of events by a certain time, such as number of adverse events within the first month, [3] correlation of observations to a diagnosis from another test, or [4] correlation of observations to a distinct event, such as disease or death

Design considerations
In designing the study, you'll make choices about screening procedures, stratification, blinding (difficult to do), randomization, washout periods, baseline measurements, follow-up schedules, and exposure assignments. Exposure assignments refer to whether you'll do a single group (aka single arm), parallel group, crossover group, Latin square, matched pair, a factorial design, or some other variation of these basics.

Sample size—how many subjects
Here's the deal, every choice you've made so far has influenced the sample size of the study. That's why you'll go through these steps many times before reaching a firm design. Most of the time, top management worries that a study is too expensive and will take too long. The only solution is to adjust the design elements to reach a lower sample size.

Project Management
You must think like a project manager to successfully implement a clinical trial. Begin by working backwards from the intended use, diseases or conditions, and claims the marketing department wants to make. Use these to develop the hypotheses, endpoints, and outcomes measures for the study. These critical parameters will dictate the size, duration, and resource requirements for the trial. From here we can build a Gantt chart and study budget.

Clinical Research Quality Management System
The clinical research quality management system has procedures for who does what by when, provides template forms and checklists, and assures efficiency and inter-departmental effectiveness through top management endorsement. ISO/FDIS 14155 (2010) falls just short of an outright requirement for a Clinical Research Quality Management System, but compliance with the coming standard will be difficult without one.

Clinical Trial Project Manager
The Clinical Trial Project Manager is the person who provides forward motion to the clinical trial; the job is often performed by a Clinical Research Associate. Much more than monitoring a trial and reporting back to management, serving as project manager means analyzing problems, offering solutions, and knowing the regulations well enough to offer meaningful work-arounds.

A project manager can also build you a Gantt Chart, a cost estimate, and a resource schedule, and provide ongoing reports on the cost and resource consumption of the trial.

Investigator's Brochure
The next big-ticket documentation item is the Investigator's Brochure. Often double or triple the length of the protocol, this document is meant to give investigators all the information they need in order to make informed decisions about device safety. The Investigator's Brochure contains the following sections: [1] device description including a description of the mechanism of action, instructions for use, storage, handling, preparation, or pre-use checks, [2] preclinical testing including design calculations, in vitro tests, mechanical and electrical tests, reliability tests, software validation, performance tests, ex vivo tests, biological safety tests, [3] existing clinical data, [4] risk management, and [5] regulatory references.

You'll use the Investigator's Brochure over and over again, for every clinical trial you do on the new technology. So write it with thoroughness and be sure to keep it under version control.

Other study documents
Case report forms and informed consent are prepared next. The case report form should follow exactly from the protocol, asking for no more and no less information than the protocol requires. The informed consent should follow from the risk analysis, but with a subject-centric approach.

You'll also need a signed Investigator Agreement, investigator's and key study staff's CVs (signed and dated), log of key study staff, IRB approval, IDE clearance for significant risk studies, financial agreements with the site, and a host of other documentation forms.

Study implementation
Prestudy visits
Pre-study visits are like job interviews; these are the visits the Clinical Research Associate (CRA) makes to the potential investigative site to assess physical capabilities and investigator credentials. Not every company lets a CRA do this; site selection is so important it is frequently done by management.

Initiation visits
Initiation visits are the process in which the study is implemented at each site. The process can be complex, consisting of several steps. For example, here is the process for one device: [1] presentation of technology background, [2] presentation of biological safety and warnings, [3] on-hands device use in a mechanical dummy, [4] on-hands device use in an animal, and finally [5] on-hands device use under direct supervision of the coordinating investigator. In addition there was training to regulatory expectations, study staff training, and documentation in a log with original signatures. The technology associated with this company's process has been on the market for several years now.

Routine monitoring visits
Routine monitoring visits are the bread and butter of study implementation. This is the process where the sponsor's agent (employee, CRO, or independent contractor) travel to the study site to inspect the progress of the study. Disliked intensely by investigators when first introduced by FDA in 1976, it was FDA's way of telling manufacturers that they are responsible for how their investigational devices are used!

Data collection
Perhaps the most important part of monitoring is source verification of the data collected. Data transcribed onto case report forms by the study staff are compared to entries made in the subject's original medical records. The opposite is true too, entries in the medical records are compared to data logs (such as concomitant medications) to ensure that all data have been captured.

Adverse event review is another critical part of routine monitoring visits. Have all adverse device effects been recorded and reported? Have other adverse events, as required by FDA or the IRB, been recorded and reported?

Close-out visits
The study close-out visit will be a time for celebration, if the investigator has done a good job of record-keeping along the way. It is like your taxes. You can file in one day if you have kept good records all year.

Data management
Data management is a ongoing process that begins while the protocol and case report forms are being designed. If consulted early on, a good data manager can save you thousands of dollars in wasted effort by advising in question construction and layout. Data management consists of: [1] designing a database in Excel, Access, SAS, or other application to receive the data, [2] entering faux data and validating the database calculations, queries, and reports, [3] entering the actual data, [4] verifying the actual data, usually with a sampling plan, and [5] upon agreement, locking the database so no changes can be made.

Statistical analysis and final report
Now it is time to close the circle. In statistical analysis, a qualified biostatistician tests the hypothesis using the outcomes data from the related endpoint. The product is successful if it has reached the pre-determined value.

The final report should contain the following elements per FDA: [1] product identification, [2] study progress including number of devices shipped, subjects enrolled, subject exposure to device, disposition of devices, brief summary of results, summary of anticipated and unanticipated adverse effects, and description of deviations from the protocol, [3] risk analysis, [4] any changes in manufacturing practices or quality control; or per ISO/FDIS 14155 (2010): [1] cover page administrative information, [2] table of contents, [3] executive summary, [4] introduction, [5] description of device and methods, [6] protocol summary, [7] statistical results including analysis of outcomes data and adverse event data, [8] discussion and overall conclusions, [9] terms and definitions, [10] ethics confirmation, [11] investigators and administrative structure, [12] signature page, and [13] list of annexes.

If you liked this whitepaper, hire us as your CRO
Clinical Device Group has the capabilities to perform all of these tasks for you—we are a full-service CRO. Or, if you prefer, hire us to perform specific tasks or act as an advisor to your staff.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc
773-489-5706
[email protected]

CRO Capabilities from Clinical Device Group

CRO Services from Clinical Device Group -- Click for Help
Clinical trials are not designed by one person, they take a team. Consider the big-ticket items you need:
[1] Project Management,
[2] Investigator's Brochure or Report of Prior Investigations,
[3] Study documents,
[4] Pre-IDE meeting with FDA (optional but recommended),
[5] Approvals,
[6] Study conduct.

On average, a new clinical trial takes 6-9 months to initiate; as much as 75% of your clinical trial labor will be spent on study start-up. You'll need people from toxicology, regulatory, clinical research, manufacturing, marketing, and R&D to pull this all together.

Good Monitoring Practices: FDA versus ISO

ISO/FDIS 14155 (2010) to Change Your Life
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 10 February 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

Learning Objective
The objective of this workshop is to learn the responsibilities of monitors throughout the four stages of study implementation.

The New ISO Standard and the Old FDA Guidance
Long, long ago in 1988 FDA issued the Guideline for the Monitoring of Clinical Investigations. This guideline has remained the standard of practice in the United States ever since then. Sometime within the next year ISO, the International Standards Organization, will publish a new standard for medical device clinical trials with the intention that it will become good clinical practice for medical devices. It is possible that FDA may recognize the standard when it is published, giving it powerful international standing.

The fundamentals of monitoring have not changed between the 1988 FDA guidance and the 2010 ISO/DIS standard, but the depth and breadth of monitoring responsibilities have. The biggest changes are that the ISO standard frames study implementation within a project management context, there is heavy emphasis on quality management of trials (ISO 13485), and there is a devout commitment to risk management (ISO 14971). Monitoring responsibilities follow along naturally with these new requirements.

It should be stated that, technically, monitors have no legal responsibilities. Monitoring is a "non-delegatable duty" of the sponsor. While the sponsor may hire an employee or CRO to conduct various monitoring tasks, the responsibility for those tasks remains with the sponsor. The ISO/DIS standard speaks about sponsor responsibilities and monitoring tasks, acknowledging that it is the sponsor who is responsible for these activities.

Project Management Approach
FDA's guidance document discusses: [A] the selection of monitors (trained and qualified individuals), [B] the need for written monitoring procedures, [C] the need for preinvestigation visits, [D] the need for periodic monitoring visits, [E] how to review subject records, and [F] maintaining a record of on-site visits. But it is only six pages long (five if we discount the cover page) and it's economy of words does not offer a lot of detail.

The new ISO/DIS 2009 standard can be thought of as being presented in three parts. The first part, aside from scope and definitions, presents the concepts of monitoring within the classic context of project management: formulate, plan, implement, manage, and report. The second part presents the specific duties of the parties. The third part consists of several annexes with detailed how-to information. Sometimes the standard may seem redundant, but it achieves its goal of a teaching document for start-up firms as well as a standard of practice.

Prestudy Process
Pre-investigation or assessment visits to select investigators and prepare sites for the study are much too complex to be accomplished in a single visit. It is better perceived as a process in which the capabilities and business relationship of the sponsor and investigator are established.

Both FDA and ISO envision this as a time for sponsors to assure that investigators understand the investigational nature of the device, the requirement to wait for IRB approval, the need for informed consent, agreement that records will be created and made available for monitoring, and that contractual obligations are mutually understood and agreed to. This period of time may take several months, visits, phone calls, and email messages and can be thought of as spanning from project conception to first subject consented. In the workshop you'll learn how to evaluate sites and prepare them for study initiation.

Initiation Process
The primary focus of the initiation process is getting the device on the subject. Exposure to the investigational device isn't necessarily automatic or immediate just because a subject is consented. In many studies, subsequent screening procedures may disqualify the subject from study participation. FDA feels strongly that consent and enrollment are the same thing. Whether you agree or not, what is important is that every patient who is consented must be accounted for in the final report.

The supporting focus of the initiation process is investigator and study staff training. Training may begin with an investigator's meeting if there are many investigators involved in the study. Or investigative sites may be trained one at a time. As protocols and data collection become more complex, more and more time is dedicated to reviewing the study steps and special IRB and FDA requirements. The importance of training the investigator to device use cannot be over-emphasized. Even investigators familiar with your type of device will need to review special features, materials, software, hardware, or instructions for use. Misuse of an investigational device by an investigator may come back on the sponsor as a failure to adequately train the user and may be considered an adverse event.

In the workshop you'll learn how to set up study record-keeping by building Investigator Regulatory Binders, Coordinator's Study Manuals, Subject Binders, and Source Document Verification Logs.

Routine Monitoring Visits
A routine monitoring visit is an on-site visit in which the monitor observes the progress of the study, compliance to protocol, compliance to regulations, completeness of documentation, and verifies accuracy of data on the case report forms against source information. You should monitor on a periodic basis, but I suggest you allow no more than 2-3 days of work to accumulate at a site.

Monitoring requires an extensive skill set: a knowledge of regulations, a knowledge of company practices, and a knowledge of the special requirements of the study at hand. In this workshop you'll learn tricks for email management, action item control, the cost of database queries and how to prevent them, and many other valuable techniques in order to implement "well-controlled" clinical studies.

Monitoring also requires a special kind of personality. Monitors should be people who love data, people who can sift through pieces of information and fit them together, people who do not leave details unaddressed, and people who cannot tolerate an unbalanced checkbook.

Close-out Visits
A close-out visit deals with ending issues and has the goal of making the site inspection-ready. Close-out visits are like filing income taxes, if you've done a good job of record-keeping the close-out visit will go quickly; if not, it could take days. You'll learn the requirements of close-out visits in the workshop.

A quiz, of course
The five-hour workshop is following by a half-hour online quiz, taken on your own time within the following two weeks. The quiz is designed to test your learning of the concepts discussed in the lecture and your ability to apply those concepts to real-life issues.

Course level
This is an intermediate level course. Participants are expected to have a basic knowledge of clinical research and device regulations.

You will receive
[x] One computer connection for one learner (each learner must log-in individually).
[x] Printable PowerPoint slides.
[x] Clear example distinguishing intended use, indications, claims and warning.
[x] Monitoring procedures and templates.
[x] Recent monitoring warning letters.
[x] A graded quiz with immediate test results.
[x] Certificate of Attendance and 0.55 CEUs.

Who should attend
[x] Monitors.
[x] Clinical research associates.
[x] Managers and directors of clinical research.
[x] Anyone needing to learn about ISO/DIS 14155.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop was presented on Wednesday, 10 February 2010 and is available today OnDemand. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Project Management of Medical Device Trials

Taking Control of the Process
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 21 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

You can only expect what you inspect
As a manager, you know its true. As a monitor, you know its true. A clinical study can be doomed from the start due to poor design, or it can evaporate into a cloud of non-enrollment and no data without watchful nurturing while it matures.

Recently a couple of clients asked me to review their protocols after they had IRB approval. Here are some of the problems I found: the least trained people were recording critical data (patients and home-healthcare providers); subjects received permanent implants with no provision for long-term follow-up; no provisions for documenting patients who were screened but not enrolled; and big-name investigators who only did difficult cases, not the everyday cases required by the study. All of these design problems are fixable, but it's embarrassing, time-consuming, and expensive in lost opportunity costs, to go back to the IRB for changes.

Plans are useless, but planning is essential [Eisenhower]
Everyone manages projects, whether you're planning a trip to China or changing the spark plugs. You know its a project if it has a beginning, middle, and end. You are managing the project if you take specific, planned steps on a defined schedule and within limited costs to achieve a distinct, pre-determined goal.The six steps of project management are as old as the hills and as familiar as a summer day; but it isn't always obvious how to apply the steps to clinical trials.

...[1] Define the clinical project
The first step is to define the project. Why are you conducting the study? Is it an early developmental (feasibility, first-in-man, proof-of-concept) study? Is it to gain 510k or PMA or other regulatory approval? Is it to add a new indication for use? Is it a post-approval study to gain visibility, exposure, or additional clinical history? Is it to show non-inferiority to your biggest competitor?

I insist that my project development team request a clinical trial in writing, and that they answer the following questions: [1] what is the device being tested, [2] what is the business objective of the product development project, [3] who is the target market, i.e. who makes the buying decision, [4] what are the intended use and indications for use, [5] what are the features, functions, benefits, or outcomes you hope to make claims about, and [6] who are the major competitors, including competitive procedures.

Tricky me, I have just gotten the team to design the clinical study for me: number one is the device being studied, two tells me if I should look for a big-name or a first-time investigator, three tells me the medical profession of the investigator, four identifies the subject population, five describes the primary endpoints, and six tells me who or what to use as a comparator.

Do You Need A Clinical Research Quality Management System? CDG's Clinical Research Quality Management System is a comprehensive collection of statements, policies, procedures, templates, and supporting documents that contains everything you need to set up a clinical research function. Each procedure is designed to tell you 'how to' do something and results in a work product such as a document or report. The procedures are organized chronologically, the way you would organize a project schedule, to walk you step-by-step through the process of running a clinical trial and a clinical department.The manual is divided in sections that follow the major activities of a clinical project. For more information click here.

...[2] Clinical project schedules
Next comes the task list and Gantt chart. You make a list of every task to be done. If you're a "lumper" you might see a clinical trial as five easy steps, if you're a "splitter" you might see it as several hundred. I cannot wrap my mind around more than 20-30 tasks, so I prefer to work with tasks and sub-tasks in order to keep things manageable. You want to have enough tasks so the project team understands what comes next, but not so much as to confuse them.

Then you organize the tasks in chronological order. Some tasks will overlap in time, others will be in sequence. For other tasks, what is important is that they end at the same time. I have never thought of a good clinical study example for this, but think of your supper tonight. You hope the chef will have the meat and potatoes done at the same time.

Next you estimate how long it will take to do each task. Writing a new protocol without a prior example to work from takes about 30 working days. Designing the content and layout for case report forms takes about four hours per page. You should look backwards into your company's history to get numbers that are realistic for your product area.

Finally, you link the tasks to make a Gantt chart. The most popular application for this is Microsoft Project, but there are other affordable applications as well. Gantt charts really are important: without them the team doesn't understand why even simple trials on non-significant risk devices take an average of six months from conception to first product on first subject.

...[3] Resource allocation
Subjects, investigators, and monitors are the three most important human resources to allocate. The statistician will tell you how many subjects are required and the protocol will dictate the number of case report form pages that will be generated and over what time frame. Using that information you can estimate the number of investigators (investigative sites) you'll need and the number of monitoring hours and monitors you'll need. The fewer the better.

You may need to allocate some physical resources, too. One company I worked for required the clinical research function to order and 'buy' investigational devices from the manufacturing function. The financial department actually moved money from one function's budget to another.

... [4] Clinical project estimates, why do studies cost so much?
For each task item you'll assign a cost. The cost may be fixed (such as a one-time IRB fee), per unit of work-hour (such as internal or contracted labor), or per unit of material (such as forms or devices.) The most accurate way to do a budget is to look at the actual costs for a similar study and add 5%, but you'll need to do a zero-based budget if you don't have a past one to work from.

As much as 50% of the entire budget may be spent before the first device goes on the first subject! A task-related (line item) budget really is important. It communicates to the the team and to management where the money will go, and why so much will be spent before there is any data. As a clinical researcher, you should talk about this a lot—keep it in front of the team's face—get them used to the idea of spending money first in order to get good data later.

...[5] Site support, study management, and reporting
During the implementation process is when most studies fail. Once study start-up is completed there is a tendency to coast while the site does the work. Keep active contact with the site with emails or phone calls every week, a good study coordinator both expects this and appreciates the attention. Provide the site with updates on the trial as a whole, everyone is part of the team and needs to be included.

Study management means following the events and progress of a study; adding or moving resources as needed to get the job done; advising, coaching, or even intervening if personnel are floundering.

Reporting means making certain that top management, other sites, and regulatory authorities are informed as required.

...[6] Study close-out
Finally the fun—a celebration for study completion. But some work, too, as you assure the site is inspection ready. Study close-out is like doing your income taxes. If you have done a good job of record-keeping all study long the close-out process will be simple. If you have been careless in ongoing record-keeping the close-out process can be expensive and complex.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn how to plan and manage a clinical study. Sign up at registration.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 4-5 hour presentation.
[x] How to craft a Clinical Development Plan.
[x] How to craft a Gantt chart.
[x] How to calculate monitoring time (labor).
[x] How to estimate the number of monitors needed.
[x] How to prepare a clinical study budget.
[x] How to estimate the cost-at-completion midway through a study.
[x] A checklist of documents to be retained in the sponsor's study file.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who want to improve their study management skills.
[x] Clinical research managers who need better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 4-5 hour workshop will be presented on Wednesday, 21 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Clinical Research Quality Management Systems

Another new requirement from ISO/DIS 14155 (2009) Workshop presented by Dr. Nancy J Stark, available OnDemand The revisions to ISO 14155 "Clinical investigation of medical devices in human subjects—good clinical practices" will bring sweeping changes to device clinical research everywhere. One of the new challenges for sponsors will be determining how to meet the requirements for clinical quality assurance and quality control. Here is an excerpt from ISO/DIS revisions published in September 2009. Implement and maintain clinical quality procedures, maintain records, ensure auditing requirements, justify and document exceptions, integrate into the sponsor's overall quality system, and see ISO 13485 for more information? These are requirements for clinical research (CR) that do not exist today! Crafting a Quality Management System for Clinical Research A useful approach to get you started is to view the clinical research function as a "contractor" for the sponsor. Your "customers" are top management, product development, marketing, regulatory, FDA and foreign regulators. Your "suppliers" are investigators, investigative sites, central laboratories, central IRBs, CROs, and other outsourced services. Your "products" are data, reports about data, and publications about data. Now you have the foundation for building a workable quality management system (QMS) for clinical research, because you can identify CR's relationship to other functions and parties in the system. Parts of a Quality Management System It's all how you like to slice and dice things, but I organize my QMS into nine parts: [1] Content description of the quality manual (i.e., the physical binder that houses CR's QMS) including: ...[a] Table of Contents. ...[b] A statement—composed, signed, and dated by top management—of their commitment to assure training and compliance to good clinical practices and the procedures it contains. ...[c] Statements of top management's vision and mission for the clinical research function. ...[d] An operations manual describing how clinical trials fit into the overall product development cycle. ...[e] Cross-functional flowcharts for inter-departmental and within-department operations. ...[f] Job descriptions. ...[g] Procedure "style manual". ...[h] Documentation matrix—(a cross-check to regulations and other functions) to assure that there are procedures in place for every regulatory, ethical, and business activity the CR function is expected to fulfill. ...[i] Communications procedure. ...[j] List of procedures and procedure numbers. [2] Procedures for Prestudy Tasks [3] Procedures for Study Tasks [4] Procedures for Close-Out Tasks [5] Procedures for Data Management Tasks: Database Design [6] Procedures for Data Management Tasks: Data Entry & Analysis [7] Procedures for Other Tasks, including: ...[a] Studies on Healthy, Employee Volunteers. ...[b] Label Copy Review. ...[c] QMS Maintenance. ...[d] Training. [8] Bibliography. [9] Glossary. ISO 13485 Quality management systems, Part 820 Quality system regulation The standard, ISO 13485 "Medical devices—Quality management systems—Requirements for regulatory purposes" (2003) was written to assist medical device manufacturers in understanding how to apply ISO 9000 to the medical device development process. In a nutshell, the idea is to ensure a quality product by maintaining a quality process using a system of quality: i.e., the organizational structure, procedures, processes and resources needed to implement quality control, quality assurance, and quality improvement. The corollary in the US system is the quality system regulation, 21 CFR Part 820; also known as the "QSR". The QSR views clinical trials as simply one more tool in the toolbox of tests to verify a device's design. In a little bit of circularity, Part 820.30 Design Controls is applicable to investigational devices. The Clinical Research Quality Management System from CDG CDG's Clinical Research Quality Management System is a comprehensive collection of statements, policies, procedures, templates, and supporting documents that contains everything you need to set up a clinical research function. Each procedure is designed to tell you 'how to' do something and results in a work product such as a document or report. The procedures are organized chronologically, the way you would organize a project schedule, to walk you step-by-step through the process of running a clinical trial and a clinical department.The manual is divided in sections that follow the major activities of a clinical project. For more information click here. Monitoring compliance and performance You cannot expect what you do not inspect, so monitoring CR's compliance to good clinical practices and performance against procedures is part and parcel of the system. Most device clinical research functions fall woefully short of measuring either. Monitoring compliance Compliance is best monitored by an audit. Most large firms have corporate auditing departments. If you are smaller, you can outsource an audit to an independent expert. An entire study, or a single site, or even a few subjects may be selected. Then follow the data starting from the moment the data were recorded in the source files. Was their transfer to case report forms complete and accurate? Was their input into the database complete and accurate? Does a statistical reanalysis give the same results? And do those results support the label copy? In one firm the label copy claimed that "fifty leading cardiologists" used the device. Corporate auditing made marketing change the copy because it could not be shown that all fifty cardiologists were leading. Monitoring performance Performance should be monitored ongoingly. When the clinical research staff turn in their monthly time-sheets, they should assign their hours and costs to primary study tasks. You may need to establish a baseline newly. Start by making a list of important tasks and items for a study. [1]Task duration and labor Next, record the start-date and completion-date for each task. The completion-date minus the start-date gives you the duration for the task. I have actually had to pull this information from old email messages! Then, estimate the number of person-hours for the task as best you can, this gives you the hours of labor for the task. [2] Count the number of items As you work, record the number of investigative sites per study, the number of monitoring visits per study, the number of monitoring visit-days per study, the number of data queries per study, the enrollment rate of subjects, and any other item that can be counted. [3] Assign costs to tasks or items As you work, assign the costs that were charged to the study to the tasks involved in implementing the study or to the items accumulated during the study. Now, when staff turn in their monthly time sheets you can use the information to monitor department performance against a historical reference. Is the number of days to IRB approval longer at one site than another? Is the number of data queries higher for one site than another? Is it higher than one monitor than for another? Is the subject enrollment rate faster or slower? Such department metrics are used ongoingly to monitor performance and prospectively to plan schedules and estimates for future studies. Procedures and work instructions A good set of procedures is so much more than simply a set of plans, it is the set of proprietary business operations for the clinical research function and is protected as part of your company's proprietary business information. Procedures can be written broad and shallow, where one procedure covers a whole collection of tasks. Or they can be written narrow and deep, where one procedure is written around one task and results in one work product. A procedure that describes an important task, one who's poor implementation could jeopardize subject safety or data integrity, should be signed by department management or higher. But procedures that are routine, like how to FedEx case report forms to the data center, can be signed off by lower management and are often called work instructions. If you don't write a procedure that CR needs, they will do it for you. You will find them on Post-It Notes, little binders by their desks, scraps of paper taped to the copying machine, or shared by email. Benefits of a quality management system There are many benefits to having a quality management system for clinical research: 1) managers have better control over their staff and the work product they produce, 2) professional staff have a better understanding of what is expected of them, and 3) the rest of your company has a clearer expectation of what they will receive, what it will cost, and how long it will take to get it. Perhaps the biggest benefit of a quality management system is that you'll gain some control over study costs by learning how to plan a study. You'll understand where the money goes and be able to make realistic trade-offs between cost and quality. Learning objective of the workshop The learning objective for the workshop is to learn how to develop a quality management system for clinical research and how to apply it to achieve quality trials. You will receive [x] PowerPoint slides. [x] A five-hour presentation, informal, and incorporating a variety of learning methods. [x] A 30-minute quiz. [x] An expert speaker (to her chagrin, Dr. Stark has nearly 30 years experience.) [x] Selected procedures. [x] An example documentation matrix. [x] An example of a performance time sheet. [x] A chance for Q&A. [x] 0.55 CEUs and Certificate of Attendance for registered learners who: ...[x] complete 90% attendance, ...[x] are 70% attentive (workshop is the active screen), ...[x] ask one meaningful question, ...[x] take the quiz, and ...[x] provide course feedback. [x] One computer connection to the event. [x] The opportunity for colleagues to audit the event. Please note: CDG's model Clinical Research Quality System may be purchased separately and is not required for the workshop. Who should attend [x] People who manage clinical research functions. [x] Clinical research professionals who want a better understanding of their roles. [x] Quality system managers who want to apply quality theory to specific functions. [x] Anyone who will audit a clinical research function. [x] Top management. Instructor The workshop will be presented by Dr. Nancy J Stark. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Registration The five-hour workshop is available OnDemand. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc

Project Management of Medical Device Trials

Project Management of Medical Device Trials
Taking Control of the Process
A Whitepaper and Workshop by Nancy J Stark, PhD
Wednesday, 21 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

You can only expect what you inspect
As a manager, you know its true. As a monitor, you know its true. A clinical study can be doomed from the start due to poor design, or it can evaporate into a cloud of non-enrollment and no data without watchful nurturing while it matures.

Recently a couple of clients asked me to review their protocols after they had IRB approval. Here are some of the problems I found: the least trained people were recording critical data (patients and home-healthcare providers); subjects received permanent implants with no provision for long-term follow-up; no provisions for documenting patients who were screened but not enrolled; and big-name investigators who only did difficult cases, not the everyday cases required by the study. All of these design problems are fixable, but it's embarrassing, time-consuming, and expensive in lost opportunity costs, to go back to the IRB for changes.

Plans are useless, but planning is essential [Eisenhower]
Everyone manages projects, whether you're planning a trip to China or changing the spark plugs. You know its a project if it has a beginning, middle, and end. You are managing the project if you take specific, planned steps on a defined schedule and within limited costs to achieve a distinct, pre-determined goal.The six steps of project management are as old as the hills and as familiar as a summer day; but it isn't always obvious how to apply the steps to clinical trials.

...[1] Define the clinical project
The first step is to define the project. Why are you conducting the study? Is it an early developmental (feasibility, first-in-man, proof-of-concept) study? Is it to gain 510k or PMA or other regulatory approval? Is it to add a new indication for use? Is it a post-approval study to gain visibility, exposure, or additional clinical history? Is it to show non-inferiority to your biggest competitor?

I insist that my project development team request a clinical trial in writing, and that they answer the following questions: [1] what is the device being tested, [2] what is the business objective of the product development project, [3] who is the target market, i.e. who makes the buying decision, [4] what are the intended use and indications for use, [5] what are the features, functions, benefits, or outcomes you hope to make claims about, and [6] who are the major competitors, including competitive procedures.

Tricky me, I have just gotten the team to design the clinical study for me: number one is the device being studied, two tells me if I should look for a big-name or a first-time investigator, three tells me the medical profession of the investigator, four identifies the subject population, five describes the primary endpoints, and six tells me who or what to use as a comparator.

Do You Need A Clinical Research Quality Management System? CDG's Clinical Research Quality Management System is a comprehensive collection of statements, policies, procedures, templates, and supporting documents that contains everything you need to set up a clinical research function. Each procedure is designed to tell you 'how to' do something and results in a work product such as a document or report. The procedures are organized chronologically, the way you would organize a project schedule, to walk you step-by-step through the process of running a clinical trial and a clinical department.The manual is divided in sections that follow the major activities of a clinical project. For more information click here.

...[2] Clinical project schedules
Next comes the task list and Gantt chart. You make a list of every task to be done. If you're a "lumper" you might see a clinical trial as five easy steps, if you're a "splitter" you might see it as several hundred. I cannot wrap my mind around more than 20-30 tasks, so I prefer to work with tasks and sub-tasks in order to keep things manageable. You want to have enough tasks so the project team understands what comes next, but not so much as to confuse them.

Then you organize the tasks in chronological order. Some tasks will overlap in time, others will be in sequence. For other tasks, what is important is that they end at the same time. I have never thought of a good clinical study example for this, but think of your supper tonight. You hope the chef will have the meat and potatoes done at the same time.

Next you estimate how long it will take to do each task. Writing a new protocol without a prior example to work from takes about 30 working days. Designing the content and layout for case report forms takes about four hours per page. You should look backwards into your company's history to get numbers that are realistic for your product area.

Finally, you link the tasks to make a Gantt chart. The most popular application for this is Microsoft Project, but there are other affordable applications as well. Gantt charts really are important: without them the team doesn't understand why even simple trials on non-significant risk devices take an average of six months from conception to first product on first subject.

...[3] Resource allocation
Subjects, investigators, and monitors are the three most important human resources to allocate. The statistician will tell you how many subjects are required and the protocol will dictate the number of case report form pages that will be generated and over what time frame. Using that information you can estimate the number of investigators (investigative sites) you'll need and the number of monitoring hours and monitors you'll need. The fewer the better.

You may need to allocate some physical resources, too. One company I worked for required the clinical research function to order and 'buy' investigational devices from the manufacturing function. The financial department actually moved money from one function's budget to another.

... [4] Clinical project estimates, why do studies cost so much?
For each task item you'll assign a cost. The cost may be fixed (such as a one-time IRB fee), per unit of work-hour (such as internal or contracted labor), or per unit of material (such as forms or devices.) The most accurate way to do a budget is to look at the actual costs for a similar study and add 5%, but you'll need to do a zero-based budget if you don't have a past one to work from.

As much as 50% of the entire budget may be spent before the first device goes on the first subject! A task-related (line item) budget really is important. It communicates to the the team and to management where the money will go, and why so much will be spent before there is any data. As a clinical researcher, you should talk about this a lot—keep it in front of the team's face—get them used to the idea of spending money first in order to get good data later.

...[5] Site support, study management, and reporting
During the implementation process is when most studies fail. Once study start-up is completed there is a tendency to coast while the site does the work. Keep active contact with the site with emails or phone calls every week, a good study coordinator both expects this and appreciates the attention. Provide the site with updates on the trial as a whole, everyone is part of the team and needs to be included.

Study management means following the events and progress of a study; adding or moving resources as needed to get the job done; advising, coaching, or even intervening if personnel are floundering.

Reporting means making certain that top management, other sites, and regulatory authorities are informed as required.

...[6] Study close-out
Finally the fun—a celebration for study completion. But some work, too, as you assure the site is inspection ready. Study close-out is like doing your income taxes. If you have done a good job of record-keeping all study long the close-out process will be simple. If you have been careless in ongoing record-keeping the close-out process can be expensive and complex.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn how to plan and manage a clinical study. Sign up at registration.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A 4-5 hour presentation.
[x] How to craft a Clinical Development Plan.
[x] How to craft a Gantt chart.
[x] How to calculate monitoring time (labor).
[x] How to estimate the number of monitors needed.
[x] How to prepare a clinical study budget.
[x] How to estimate the cost-at-completion midway through a study.
[x] A checklist of documents to be retained in the sponsor's study file.
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Clinical research professionals who want to improve their study management skills.
[x] Clinical research managers who need better planning and reporting from their group.
[x] CROs who want to improve their proposal skills.
[x] Executives who are planning the future of their company.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 4-5 hour workshop will be presented on Wednesday, 21 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

European Medical Device Regulations Tighter than US

Introduction to Medical Device Regulations: EU

A Whitepaper and Workshop by Nancy J Stark, PhD
Thursday, 1 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

The fundamentals of EU regulations are evolving rapidly....
In this whitepaper I want to discuss the fundamentals of medical device regulations in the European Union with the goal of determining whether or not a clinical study is necessary in order to obtain certification and CE Mark. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the United States are discussed in a companion whitepaper and workshop. The companion US workshop is available Wednesday, 30 June 2010, 11 AM Central and on OnDemand soon after.

Regulation by European Medicines Agency?
In 2008, medical device regulation in Europe was fragmented, disorganized, and hard to understand. All 27 States has imposed their own unique positions on the law, making regulation an impossible puzzle.

The 2008 system of regulation left the following issues wanting:
[1] 80 Notified Bodies from 27 Member States resulted in variable enforcement and inspection.
[2] Three main Directives and six implementing or modifying Directives were hard to follow.
[3] IVDs were not risk-based classified.
[4] 'Quasi' devices such as lip fillers and wrinkle fillers were not regulated.
[5] Notified Bodies were not transparent, did not share information with each other.
[6] Notified Bodies didn't communicate the Competent Authorities.
[7] Manufacturers openly shopped for Notified Bodies that would give easy inspections (forum shopping.)
[8] There was wide variation in vigilance reporting from State to State.
[9] The incidence of vigilance reports was considerably lower than in the US or Japan.
[10] There was no centralized registration system for devices; even Competent Authorities don't know what is being sold.
[11] NBs do not inspect foreign manufacturers with same rigor as EU manufacturers.
[12] Devices for export were not regulated.

Intrigue at the European Commission
But while the European device industry was dragging its feet, resisting changes to ISO 14155 (2003), and generally working to maintain the status quo, a coup was cooking in the kitchen. Suddenly one day, the European Commission proposed creation of a Medical Device Committee within the European Medicines Agency (EMEA). The proposal would have given the EMEA, as possibilities, the following powers:
[1] Consolidation of all existing nine Directives into one.
[2] Regulation of medical devices made up wholly of non-viable human cells or tissues or derivatives.
[3] Imposition of sanctions and penalties on Notified Bodies who failed to act properly.
[4] Create an automatic link between invoking the Safeguard Clause and withdrawal of certification.
[5] Accreditation system for Notified Bodies.
[6] Public input into approval of high-risk devices.
[7] Mandate institution and caregiver vigilance reporting.
[8] Exchange vigilance report globally.
[9] Strengthen Commission's authority for post-market surveillance.
[10] Medical Device Committee to provide opinions on classification of borderline devices.
[11] Incorporate GHTF guidances as much as possible into new regulatory framework.

Quick action by device industry
The device industry suddenly woke up and was quick to act. This ISO 14155 Working Group resumed activity and is finally getting a new standard out—a standard harmonized with the Medical Device Directive as much as the intended International Conference on Harmonization Good Clinical Practice. The Notified Bodies have begun to coordinate their activities and are diligently inspecting technical files for the presence of clinical evaluation reports. The existing regulatory framework was not changed.

If you are new to Europe
If you are new to European regulations, the story above probably sounded like a soap opera. But read on, and take the workshop, and it will all make sense to you.

The European Union
Europe was not always a union, and most would argue that it isn't one yet today. It is a collection of individual states (countries) whose integration is driven by economic aims, not political ones. The upshot is that industry and regulators are often at odds with each other: industry pushing for a common regulatory system across the union while regulators strive to retain opacity and independence.

An economic union is a collection of peoples and geographic areas that share a common market through the free movement of goods, services, jobs, and people; and who present a common economic face to the world: they share a common currency, have common import and export tariffs, a common tax rate, and common fiscal and economic policies. If you've shopped in Europe you know that they are not quite there yet. The price tag on a sweater lists the price in Euros, true, but there is a different price for France, Germany, Italy, and every other country.

In 1992 there were 15 member states in the union, consisting of Western, economically developed countries. Today there are 27 member states. In 2004, the EU saw its biggest single enlargement when Malta, Cyprus, Slovenia, Estonia, Latvia, Lithuania, Poland, the Czech Republic, Slovak Republic, and Hungary were admitted as members.

The government, located in Brussels, consists of a Parliament, Council, and Commission. The Council sets the general direction and priorities of the Union. The Commission proposes laws (i.e. directives) consistent with the priorities set by the Council. The Parliament and Council jointly approve the directives, which are then issued as law by the Council.

 
The New Approach
When Europe sought to set up a review and approval system for medical devices, they wanted to take advantage of existing governmental institutions. Since the 'old' way to set up a government was to create a entirely new infrastructure, the idea of using what was already there was called the New Approach.

In the New Approach, the European Council issues directives (laws) to govern the sale of medical devices. There are three directives of particular concern to us:
[1] Active Implantable Medical Device Directive (AIMD) 1990-385-EEC.
[2] Medical Device Directive (MDD) 1993-42-EEC.
[3] In Vitro Diagnostic Directive (IVD) 1998-79-EC.

The Standards Body (ISO or CEN), using a committee of experts from industry, investigative sites, and regulators, publishes new standards that are incorporated into directives and become de facto regulation. The standard of concern for medical device trials is ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) and it will be incorporated into Annex 7 and Annex X of the AIMD and MDD, respectively. The standard does not apply to in vitro diagnostic devices.

The Regulatory Body or Competent Authority, usually the department of health and welfare for that country, is responsible to implement directives, regulate clinical research, appoint Ethics Committees and Notified Bodies, and approve the initiation of medical device trials. Most countries have only one Competent Authority, but Germany has more than 40, one from each county.

The various Ethics Committees located within a member state are often appointed regionally and may be structured in a tiered approach. Some Ethics Committees give only opinions, but not approval, regarding a clinical trial. The Ethics Committees in Germany have a close association with the professional medical society.

Finally, the Notified Body, an independent accredited body of experts, is authorized by the Regulatory Body to enforce regulations, review clinical trial results, and inspect a manufacturer's quality management system in application for certification, CE Marking, and approval for sale of a medical device. A country may have as many Notified Bodies as it wants; Germany has sixteen.

Device classification
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In Europe, devices are AIMD, MDD Class I, MDD Class IIa, MDD Class IIb, MDD Class III, or IVD.

[1] Active implantable medical devices: are both implanted and energy requiring.
[2] MDD Class I: non-invasive devices that do not contact blood or body tissues.
[3] MDD Class IIa: short-term use devices that channel blood or body liquids or connect to higher-class devices, also dental devices.
[4] MDD Class IIb: long-term use devices which contact breached skin, supply energy, deliver drugs, monitor vital processes, contraceptives, disinfectants, or blood bags.
[5] MDD Class III: long-term invasive devices which are heart or central circulatory system contacting, central nervous system contacting, biodegradable, drug-device combinations, implantables, or based on animal tissues.

You can consult the European Commission medical devices guidance document MEDDEV 2.4/1 Rev.8 July 2001 for details of classification. Europe is fundamentally different than the States in its classification strategy: there are a series of eighteen rules to follow, which allow you to determine the classification by process of elimination. It is a tidier and simpler approach than the States, but then Europe had the benefit of studying the strengths and weaknesses of our system before developing their own.

CE Mark now, review later
The question we are trying to answer with all of this is whether or not you need to do a clinical trial in order to get Notified Body certification of your quality management system, which gives you authority to affix a CE Mark to our device. But you have a few more variables to work out first, before you can be sure.

Conformity Assessment
The next step is to determine which of eight possible pathways you want to follow in order to assess conformity of your manufacturing process to the specifications set forth in your quality management system. Putting it simply, you: [1] select a Notified Body, [2] have the Notified Body inspect your quality management system and issue you a certificate, [3] design a device and complete a technical file, [4] give yourself a CE Mark, sign your Declaration of Conformity, and start selling, and then [5] the Notified Body reviews your Technical Files at their next visit to see if they agree with your decision.

Do you need a new clinical trial?
Finally, for every medical device you prepare a clinical evaluation report. The evaluation of clinical data consists of three modules and a summary report:
[1] review of published literature to assess safety and performance.
[2] review of any related clinical studies you may have sponsored to assess safety and performance.
[3] review of any related complaints to determine if the quality management system is adequate to support an argument of safety and performance.
[4] summary report to present conclusions.

The results of the clinical evaluation report should lead you to a decision as to whether existing data are sufficient to support an argument of safety and performance for the device's intended use, or if new, additional clinical data are necessary. I discussed the details of how to perform a clinical evaluation report in a whitepaper published last April.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of European regulations and how to determine if you need a clinical study in order to get market your device. Sign up at registration.

This is an introductory workshop and focuses on European regulations. A complimentary workshop focusing on US regulations is also available.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A two-hour presentation.
[x] Discussion of the Directives.
[x] Meaning of Essential Requirements.
[x] Medical device classification in Europe.
[x] Relationship between standards and regulations.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The two-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Introduction to Medical Device Regulation in the US

The fundamentals of US Regulations are unlikely to change...

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday, 06 July 2010, 10 am Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

In this whitepaper I want to discuss the fundamentals of medical device regulations in the United States with the goal of determining whether or not a clinical study is necessary in order to obtain FDA clearance. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the European Union are discussed in a companion whitepaper and workshop. The companion EU workshop is available Thursday, 1 July 2010, 11 AM Central and on OnDemand soon after.

Food, Drug and Cosmetic Act
In the States, medical devices are regulated by the Food, Drug and Cosmetic Act. Then called the Food and Drug Act, it was the first piece of legislation to result from investigative journalism, namely a novel titled "The Jungle" by Upton Sinclair. Sinclair described the filthy conditions of pre-WWI Chicago stockyards and the contamination of our food supply. You can still buy the book, a heart-wrenching, stomach-punching period piece, for $5.95. Sinclair published The Jungle in 1906, and the Food and Drug Act was passed in 1923. In 1933, as part of the 'New Deal', legislation was introduced to expand the Act to cover medical devices; the expansion passed in 1938.

Adulteration and Misbranding
The Food and Drug Act set forth two simple concepts that still govern medical devices today—adulteration and misbranding. Adulteration speaks to the issue of filth, contamination, or toxins being present in or on a medical device. For example, some devices use water during the manufacturing process. The water must be pyrogen free or the finished device will probably be contaminated with pyrogenic material. Pyrogens cause an intense fever spike when they get into the body—an unwanted medical occurrence for any device.

Misbranding speaks to the issue of making false or misleading statements. For example, if I say the device can be used to reduce an HIV viral load, but it not cleared for this indication, it is misbranded. If I say it is sharp enough for a surgical cut and it isn't, it is misbranded.

If I say the knife is sterile, and it isn't, it is both adulterated and misbranded.

Chapter V: Drugs and Devices
Chapter V of the Act deals with drugs and devices. This is where you find the relevant sections of the Act, itself. Follow the link to Chapter V if you want to read more about any of the topics.

Regulations
If you look at the Act, you'll see that it is general; written to last over time and lacking in the specifics that enable day-to-day implementation. The specifics are left to the regulations, which are promulgated by the Food and Drug Agency (FDA). Regulations are rules which have the force of law. They are first published as proposed rules and are open to public comment. Some comments are accepted, other rejected. When the regulation is first published as a final rule it appears in the Federal Register along with a summary of the comments and FDA's responses and explanations, called the preamble. Preamble's have legal standing and are worth your while to read and understand.

Once a year the regulations and associated amendments, but not the preambles, are published in the Code of Federal Regulations, Title 21. 21 CFR, Parts 1-99 are regulations that apply to devices, drugs, and biologics. Parts 800-1299 are regulations that apply only to devices. If you work in clinical research, you should become intimate with Parts 50, 54, 56, 812, and 814.

Device Classification—point of entry
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In the States, devices are classified as Class I—General Controls, Class II—Special Controls, and Class III—Premarket Approval.

Class I devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices. Approximately 74% of the Class I devices are exempt from the premarket notification process (i.e., 510k clearance). These exemptions are listed in the classification regulations of 21 CFR and have been collected together in the Medical Device Exemptions document.

Class II devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices and whatever special controls deemed necessary by FDA, such as performance standards, postmarket surveillance, patient registries, guidance documents, or evidence of efficacy from a well-controlled clinical study.

Class III devices are devices purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and there is not sufficient information to establish a performance standard for reasonable assurance of safety and effectiveness.

Intended Use, Indications for Use
Let's say you are developing a device that is new to your company. Your first concern is to identify its classification, because all other regulatory requirements will stem from there. But the classification will depend on a few more variables you'll have to fix before you can make that determination.

Intended Use
The first decision is to decide on the intended use for the device. In a market-driven company we probably have an indication (customer need) looking for a device, but in technology-driven companies it is common to have a device looking for an intended use. Think in terms of an active verb: do you intend to ablate tissue, vibrate cells, stimulate neurons, fix body parts, take images, or measure impedance? Deciding on your intended use for a device is the first step in determining its classification.

Indication for use
The next step is to decide on the disease or condition you plan to diagnose, cure, mitigate, treat, or prevent. Think in terms of diseases and conditions to which the intended use can be applied. You might ablate tissue in order to prevent tumor growth, you might vibrate cells in order to intercept a seizure, you might fix the spine in order to prevent curvature or treat scoliosis, and so on. The intended use may have many applications in medicine, i.e., there may be many diseases or conditions to which it can be applied.

Some indications will cause your device to be classified higher than other indications. For example, if you say your device will diagnose breast cancer it is going to be a Class III device, but if you say it is a adjunct test for the diagnosis of breast cancer it will be a Class II device. If you indicate a device that exposes to body to magnetic waves as a treatment for HIV it is going to be a Class III device, but if you indicate that magnetic waves help activate the immune system to viral load, it may be a Class II de novo.

Think of your device as consisting of two parts: 1) the physical device, and 2) its indications for use. If you are a start-up firm, choose an indication for use for which it is easy and inexpensive to get FDA clearance. Go after the harder, and more profitable, indications for use after you have experience and cash flow.

How to determine classification
Go to FDA's product classification database and search for a part of the device name or, if you know the device panel (medical specialty) to which your device belongs, go directly to the listing for that panel and identify your device and the corresponding regulation.

It may sound simple to find your device, but it isn't. The classification database does not have a fuzzy search engine; you will find only what you ask for. Suppose you have a radio-frequency ablation device. A search for "radio frequency ablation" turns up nothing, a search for "RF ablation" turns up nothing, finally a search for "ablation" brings up twelve records: one is a mapping instrument to plan the ablation, four are for cardiac atrial flutter, one is for endometrial ablation, one for urological ablation, one—for treatment of varicose veins—is grandfathered in as a pre-amendment device, two are low-energy devices for general soft tissue ablation, one uses ultrasound as a high energy source, and one uses liquid nitrogen for cosmetic surgery (like removing moles).

It is useful to note is that the primary tissue (think disease or condition) being ablated dictates which device panel reviews the device, and the energy intensity (high or low) as well as the newness of the technology dictates its classification. Unfortunately, we still don't know how our RF-ablation device is classified.

Device classification panels
FDA has classified and described over 1,700 distinct types of devices and organized them in the CFR into 16 medical specialty "panels". For each of the devices classified by the FDA the CFR gives a general description including the intended use, the class to which the device belongs (i.e., Class I, II, or III), and information about marketing requirements. Your device will presumably meet the definition in a classification regulation contained in 21 CFR 862-892.

A search for "RF" in the product classification database is more useful. We find seven devices, one is a Class III device for RF/microwave hyperthermia for cancer treatment—sounds like a good match and finally we know the class and regulatory status of our device and indication.

Let's discuss the product code. The product code, together with the product name, uniquely identifies a category of devices for FDA and is a useful way to find related products. If you go to the PMA database and search on the product code LOC, you will find 27 PMA submissions or amendments. Here you will find some useful information, such as the manufacturer of the devices, when they received clearance, location of the manufacturing facilities, which advisory panel reviewed the PMA, and more.

Notice the absence of a Regulation Number? While FDA may say: "Your device should meet the definition in a classification regulation contained in 21 CFR 862-892," the truth is that it can take years before FDA assigns a regulation number to a new product category.

510(k) or PMA
The point of classification is to determine the pathway to FDA clearance. You don't have a choice in the matter, unless you want to revise the indications for use. To summarize it simply:
[ ] Class I—74% are exempt from requiring FDA clearance, the remainder need a 510(k).
[ ] Class II—requires a 510(k), which is a type of FDA submission in which you argue that your device is substantially equivalent to another device which was on the market prior to May 28, 1976.
[ ] Class II de novo 510(k)—a Class III device that is a new technology of low risk; for example exposing the hands to a magnetic field for immune system stimulation. New technologies are automatically Class III devices, but the manufacturer can petition FDA for a down-classification to Class II. The difference is the 510(k) requires de novo (from the beginning) evidence of safety and effectiveness, rather than evidence of substantial equivalence, because there is nothing to be equivalent to.
[ ] Class III—requires pre-market approval (PMA).

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not we need to do a clinical trial in order to get FDA clearance. The answer is:
[ ] No, if you have a Class I device.
[ ] Maybe, if you have a Class II device. About 10% of 510(k)s require clinical trials in order to support the argument of substantial equivalence.
[ ] Yes, if you have a Class II de novo device.
[ ] Yes, if you have a Class III, PMA device.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of FDA device regulations and how to determine if you need a clinical study in order to get FDA clearance. Sign up at registration.

This is an introductory workshop and focuses on US regulations. A complimentary workshop focusing on European regulations is also available.

You will receive, we wil discuss
[x] PowerPoint slides.
[x] A three-hour presentation.
[x] Discussion of the types of 510(k).
[x] Difference between 510(k)s and PMAs.
[x] How to take advantage of the Mohan memorandum.
[x] Distinction between guidance documents and standards.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Tuesday, 6 July 2010, at 10:00 am Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The three-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Introduction to Medical Device Regulations: EU

A Whitepaper and Workshop by Nancy J Stark, PhD
Thursday, 1 July 2010, 11 AM Central; or OnDemand soon after.
Reading someone else's copy? Opt-in for whitepapers to get your own.

The fundamentals of EU regulations are evolving rapidly....
In this whitepaper I want to discuss the fundamentals of medical device regulations in the European Union with the goal of determining whether or not a clinical study is necessary in order to obtain certification and CE Mark. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the United States are discussed in a companion whitepaper and workshop. The companion US workshop is available Wednesday, 30 June 2010, 11 AM Central and on OnDemand soon after.

The European Union
Europe was not always a union, and most would argue that it isn't one yet today. It is a collection of individual states (countries) whose integration is driven by economic aims, not political ones. The upshot is that industry and regulators are often at odds with each other: industry pushing for a common regulatory system across the union while regulators strive to retain opacity and independence.

An economic union is a collection of peoples and geographic areas that share a common market through the free movement of goods, services, jobs, and people; and who present a common economic face to the world: they share a common currency, have common import and export tariffs, a common tax rate, and common fiscal and economic policies. If you've shopped in Europe you know that they are not quite there yet. The price tag on a sweater lists the price in Euros, true, but there is a different price for France, Germany, Italy, and every other country.

In 1992 there were 15 member states in the union, consisting of Western, economically developed countries. Today there are 27 member states. In 2004, the EU saw its biggest single enlargement when Malta, Cyprus, Slovenia, Estonia, Latvia, Lithuania, Poland, the Czech Republic, Slovak Republic, and Hungary were admitted as members.

The government, located in Brussels, consists of a Parliament, Council, and Commission. The Council sets the general direction and priorities of the Union. The Commission proposes laws (i.e. directives) consistent with the priorities set by the Council. The Parliament and Council jointly approve the directives, which are then issued as law by the Council.

 

The New Approach
When Europe sought to set up a review and approval system for medical devices, they wanted to take advantage of existing governmental institutions. Since the 'old' way to set up a government was to create a entirely new infrastructure, the idea of using what was already there was called the New Approach.

In the New Approach, the European Council issues directives (laws) to govern the sale of medical devices. There are three directives of particular concern to us:
[1] Active Implantable Medical Device Directive (AIMD) 1990-385-EEC.
[2] Medical Device Directive (MDD) 1993-42-EEC.
[3] In Vitro Diagnostic Directive (IVD) 1998-79-EC.

The Standards Body (ISO or CEN), using a committee of experts from industry, investigative sites, and regulators, publishes new standards that are incorporated into directives and become de facto regulation. The standard of concern for medical device trials is ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) and it will be incorporated into Annex 7 and Annex X of the AIMD and MDD, respectively. The standard does not apply to in vitro diagnostic devices.

The Regulatory Body or Competent Authority, usually the department of health and welfare for that country, is responsible to implement directives, regulate clinical research, appoint Ethics Committees and Notified Bodies, and approve the initiation of medical device trials. Most countries have only one Competent Authority, but Germany has more than 40, one from each county.

The various Ethics Committees located within a member state are often appointed regionally and may be structured in a tiered approach. Some Ethics Committees give only opinions, but not approval, regarding a clinical trial. The Ethics Committees in Germany have a close association with the professional medical society.

Finally, the Notified Body, an independent accredited body of experts, is authorized by the Regulatory Body to enforce regulations, review clinical trial results, and inspect a manufacturer's quality management system in application for certification, CE Marking, and approval for sale of a medical device. A country may have as many Notified Bodies as it wants; Germany has sixteen.

Device classification
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In Europe, devices are AIMD, MDD Class I, MDD Class IIa, MDD Class IIb, MDD Class III, or IVD.

[1] Active implantable medical devices: are both implanted and energy requiring.
[2] MDD Class I: non-invasive devices that do not contact blood or body tissues.
[3] MDD Class IIa: short-term use devices that channel blood or body liquids or connect to higher-class devices, also dental devices.
[4] MDD Class IIb: long-term use devices which contact breached skin, supply energy, deliver drugs, monitor vital processes, contraceptives, disinfectants, or blood bags.
[5] MDD Class III: long-term invasive devices which are heart or central circulatory system contacting, central nervous system contacting, biodegradable, drug-device combinations, implantables, or based on animal tissues.

You can consult the European Commission medical devices guidance document MEDDEV 2.4/1 Rev.8 July 2001 for details of classification. Europe is fundamentally different than the States in its classification strategy: there are a series of eighteen rules to follow, which allow you to determine the classification by process of elimination. It is a tidier and simpler approach than the States, but then Europe had the benefit of studying the strengths and weaknesses of our system before developing their own.

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not you need to do a clinical trial in order to get Notified Body certification of your quality management system, which gives you authority to affix a CE Mark to our device. But you have a few more variables to work out first, before you can be sure.

 

Conformity Assessment
The next step is to determine which of eight possible pathways you want to follow in order to assess conformity of your manufacturing process to the specifications set forth in your quality management system. Putting it simply, you: [1] select a Notified Body, [2] have the Notified Body inspect your quality management system and issue you a certificate, [3] design a device and complete a technical file, [4] give yourself a CE Mark, sign your Declaration of Conformity, and start selling, and then [5] the Notified Body reviews your Technical Files at their next visit to see if they agree with your decision.

Clinical Evaluation Reports have the answer
Finally, you prepare a clinical evaluation report for the device. The clinical evaluation report consists of three modules:
[1] review of published literature to assess safety and performance.
[2] review of any related clinical studies you may have sponsored to assess safety and performance.
[3] review of any related complaints to determine if the quality management system is adequate to support an argument of safety and performance.

The results of the clinical evaluation report should lead you to a decision as to whether existing data are sufficient to support an argument of safety and performance for the device's intended use, or if new, additional clinical data are necessary. I discussed the details of how to perform a clinical evaluation report in a whitepaper published last April.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of European regulations and how to determine if you need a clinical study in order to get market your device. Sign up at registration.

This is an introductory workshop and focuses on European regulations. A complimentary workshop focusing on US regulations is also available.

You will receive, we will discuss
[x] PowerPoint slides.
[x] A two-hour presentation.
[x] Discussion of the Directives.
[x] Meaning of Essential Requirements.
[x] Medical device classification in Europe.
[x] Relationship between standards and regulations.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The two-hour workshop will be presented on Wednesday, 1 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

ISO/FDIS 14155 (2010) and Clinical Evaluations

Clinical evaluations justify design of clinical investigations A Whitepaper by Nancy J Stark, PhD.

Today I want to discuss the role that clinical evaluations will play in justifying the implementation and design of device clinical trials once the 2010 ISO/DIS 14155 "Clinical investigations for medical devices in human subjects--good clinical practices" becomes a published standard. Over the past several months I've written extensively about clinical evaluation reports, but always within the context of obtaining or maintaining a CE Mark and quality system certification. What does the standard say? The ISO/DIS 14155 (2010) standard states: Clinical evaluations may be indication specific The intent of the standard is that a clinical evaluation report be prepared before any clinical trial begins. The results of the clinical evaluation report--performed with selected indications in mind--should lead naturally to the decision as to whether or not new clinical data are needed to confirm the safety and performance of the device, or that existing data are sufficient in and of themselves. Shades of the American system The idea of using existing data to support an argument of safety and performance (i.e., safety and efficacy) is not new to Americans. Although there is no literature review requirement for non-significant risk studies under the abbreviated IDE system, an extensive Report of Prior Investigations is required for every full IDE before FDA will grant approval to conduct a significant risk clinical trial. Part 812.20(b)(2) states: A sponsor shall submit "...a complete report of prior investigations of the device..." as part of the IDE application. GHTF SG5 is the guiding document The Global Harmonization Task Force (GHTF) Study Group 5 document "Clinical Evaluation" is the guiding light for preparing clinical evaluation reports. While you may choose to follow MEDDEV 2.7.1 Rev 3, the European (region specific) document couldn't be referenced in an international standard. The steps for preparing clinical evaluation reports to justify a clinical trial are the same as those for a clinical evaluation report for maintaining certification and CE Marking except that pre-clinical testing becomes an important part of the review. Briefly, the steps are: [1] Define the key questions. [2] Identify the databases to search (usually MedLine, Embase, MAUDE, and Cochrane). [3] Define scope of search and search strategies using a qualified information specialist. [4] Assess abstracts to identify articles for weighting. [5] Acquire full-texts of articles. [6] Read and weight the articles for relevance. [7] Weight the articles for statistical significance using a qualified biostatistician. [8] Review only those articles with the highest weightings; typically 6-8 articles per indication. [9] Review existing sponsored clinical investigations. [10] Review the risk management system. And additionally, [11] Review the pre-clinical and biocompatibility data. [12] Finalize the report, taking into account the four elements of: ----[b] existing clinical data from the literature, ----[c] data from existing clinical investigations sponsored by the manufacturer, ----[d] the risk management system, and ----[a] pre-clinical testing including bench, animal, and biocompatibility data. The clinical evaluation should lead you naturally to a decision as to whether a new clinical investigation is necessary and, if so, to its design. A shift in thinking The thinking is a little bit different than what I was trained to do. Perhaps erroneously, the default position was always to do a clinical investigation to demonstrate safety and efficacy in humans unless you could justify not doing one. But so many trials are being done today there is a critical shortage of subjects. The new (European) thinking is that a clinical investigation is only performed if existing literature data, existing clinical data, the risk management system, and pre-clinical data--taken together--cannot confirm the safety and performance of your device for a selected indication. Rephrase the indication As the manufacturer, you will have some choices in situations where new clinical trials are deemed necessary. If a study is too expensive for your corporate budget, you can probably rephrase the indication. For example, an indication for the prevention of epileptic seizures by early neurological intervention might require a different level of data than the abatement of epileptic seizures by neurological intervention triggered by the seizure itself. Or the relief of cancer pain might require a different level of data than the management of physical discomfort. Or a wrist support to heal carpal tunnel syndrome might require more data than a wrist support to stabilize the joint. Return on investment If the indication represents a large enough market size, the cost of the clinical trial may be justifiable. It's a simple enough exercise: estimate the cost of the clinical trial, estimate the profits from the new indication, and determine profit/loss over the next six months. Return on investment (ROI) = (estimated new profits - cost of trial)/(cost of trial); for example, the ROI for pediatric clinical trials ranged from -$8.9 million to +$507.9 million over six months. Many companies consider their estimated daily sales for a new indication and view every day the trial is delayed as a lost opportunity cost. Once the decision to implement the clinical trial is made by top management the pressure is on to get the trial underway and completed. CDG can help Clinical Device Group is poised to help you work through the process of evaluating existing data and justifying the design of a clinical trial. We have a vast network of professionals who are experts in biocompatibility, information technology, medical writing, clinical research, biostatistics, data management, market size estimation, cost estimation, scheduling and Gantt chart preparation, and regulatory submissions. Our experts are ready to: [1] Assess your pre-clinical and biocompatibility data, [2] Prepare a clinical evaluation report, [3] Suggest design variations for a clinical trial with larger or smaller sample sizes, depending the indication's wording, [4] Write or review your protocol, [5] Estimate the market size and profitability of the indication, [6] Estimate the cost of the clinical trial, [7] Calculate the return on investment, [8] Implement and monitor the trial, [9] Enter and manage the data, [10] Analyze the data to support or refute the indication, [11] Prepare the final trial report, [12] Prepare the regulatory submissions for product commercialization. Contact us Phone or email us at 773-489-5706 or [email protected].

Introduction to Medical Device Regulation: US

The fundamentals of US Regulations are unlikely to change...

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday 6 July 2010, 10:00 AM Central; or on CD.

In this whitepaper I want to discuss the fundamentals of medical device regulations in the United States with the goal of determining whether or not a clinical study is necessary in order to obtain FDA clearance. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the European Union are discussed in a companion whitepaper and workshop. The companion EU workshop is available Thursday, 1 July 2010, 11 AM Central and on CD.

Food, Drug and Cosmetic Act
In the States, medical devices are regulated by the Food, Drug and Cosmetic Act. Then called the Food and Drug Act, it was the first piece of legislation to result from investigative journalism, namely a novel titled "The Jungle" by Upton Sinclair. Sinclair described the filthy conditions of pre-WWI Chicago stockyards and the contamination of our food supply. You can still buy the book, a heart-wrenching, stomach-punching period piece, for $5.95. Sinclair published The Jungle in 1906, and the Food and Drug Act was passed in 1923. In 1933, as part of the 'New Deal', legislation was introduced to expand the Act to cover medical devices; the expansion passed in 1938.

Adulteration and Misbranding
The Food and Drug Act set forth two simple concepts that still govern medical devices today—adulteration and misbranding. Adulteration speaks to the issue of filth, contamination, or toxins being present in or on a medical device. For example, some devices use water during the manufacturing process. The water must be pyrogen free or the finished device will probably be contaminated with pyrogenic material. Pyrogens cause an intense fever spike when they get into the body—an unwanted medical occurrence for any device.

Misbranding speaks to the issue of making false or misleading statements. For example, if I say the device can be used to reduce an HIV viral load, but it not cleared for this indication, it is misbranded. If I say it is sharp enough for a surgical cut and it isn't, it is misbranded.

If I say the knife is sterile, and it isn't, it is both adulterated and misbranded.

Chapter V: Drugs and Devices
Chapter V of the Act deals with drugs and devices. This is where you find the relevant sections of the Act, itself. Follow the link to Chapter V if you want to read more about any of the topics.

Regulations
If you look at the Act, you'll see that it is general; written to last over time and lacking in the specifics that enable day-to-day implementation. The specifics are left to the regulations, which are promulgated by the Food and Drug Agency (FDA). Regulations are rules which have the force of law. They are first published as proposed rules and are open to public comment. Some comments are accepted, other rejected. When the regulation is first published as a final rule it appears in the Federal Register along with a summary of the comments and FDA's responses and explanations, called the preamble. Preamble's have legal standing and are worth your while to read and understand.

Once a year the regulations and associated amendments, but not the preambles, are published in the Code of Federal Regulations, Title 21. 21 CFR, Parts 1-99 are regulations that apply to devices, drugs, and biologics. Parts 800-1299 are regulations that apply only to devices. If you work in clinical research, you should become intimate with Parts 50, 54, 56, 812, and 814.

Device Classification—point of entry
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In the States, devices are classified as Class I—General Controls, Class II—Special Controls, and Class III—Premarket Approval.

Class I devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices. Approximately 74% of the Class I devices are exempt from the premarket notification process (i.e., 510k clearance). These exemptions are listed in the classification regulations of 21 CFR and have been collected together in the Medical Device Exemptions document.

Class II devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices and whatever special controls deemed necessary by FDA, such as performance standards, postmarket surveillance, patient registries, guidance documents, or evidence of efficacy from a well-controlled clinical study.

Class III devices are devices purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and there is not sufficient information to establish a performance standard for reasonable assurance of safety and effectiveness.

Intended Use, Indications for Use
Let's say you are developing a device that is new to your company. Your first concern is to identify its classification, because all other regulatory requirements will stem from there. But the classification will depend on a few more variables you'll have to fix before you can make that determination.

Intended Use
The first decision is to decide on the intended use for the device. In a market-driven company we probably have an indication (customer need) looking for a device, but in technology-driven companies it is common to have a device looking for an intended use. Think in terms of an active verb: do you intend to ablate tissue, vibrate cells, stimulate neurons, fix body parts, take images, or measure impedance? Deciding on your intended use for a device is the first step in determining its classification.

Indication for use
The next step is to decide on the disease or condition you plan to diagnose, cure, mitigate, treat, or prevent. Think in terms of diseases and conditions to which the intended use can be applied. You might ablate tissue in order to prevent tumor growth, you might vibrate cells in order to intercept a seizure, you might fix the spine in order to prevent curvature or treat scoliosis, and so on. The intended use may have many applications in medicine, i.e., there may be many diseases or conditions to which it can be applied.

Some indications will cause your device to be classified higher than other indications. For example, if you say your device will diagnose breast cancer it is going to be a Class III device, but if you say it is a adjunct test for the diagnosis of breast cancer it will be a Class II device. If you indicate a device that exposes to body to magnetic waves as a treatment for HIV it is going to be a Class III device, but if you indicate that magnetic waves help activate the immune system to viral load, it may be a Class II de novo.

Think of your device as consisting of two parts: 1) the physical device, and 2) its indications for use. If you are a start-up firm, choose an indication for use for which it is easy and inexpensive to get FDA clearance. Go after the harder, and more profitable, indications for use after you have experience and cash flow.

How to determine classification
Go to FDA's product classification database and search for a part of the device name or, if you know the device panel (medical specialty) to which your device belongs, go directly to the listing for that panel and identify your device and the corresponding regulation.

It may sound simple to find your device, but it isn't. The classification database does not have a fuzzy search engine; you will find only what you ask for. Suppose you have a radio-frequency ablation device. A search for "radio frequency ablation" turns up nothing, a search for "RF ablation" turns up nothing, finally a search for "ablation" brings up twelve records: one is a mapping instrument to plan the ablation, four are for cardiac atrial flutter, one is for endometrial ablation, one for urological ablation, one—for treatment of varicose veins—is grandfathered in as a pre-amendment device, two are low-energy devices for general soft tissue ablation, one uses ultrasound as a high energy source, and one uses liquid nitrogen for cosmetic surgery (like removing moles).

It is useful to note is that the primary tissue (think disease or condition) being ablated dictates which device panel reviews the device, and the energy intensity (high or low) as well as the newness of the technology dictates its classification. Unfortunately, we still don't know how our RF-ablation device is classified.

Device classification panels
FDA has classified and described over 1,700 distinct types of devices and organized them in the CFR into 16 medical specialty "panels". For each of the devices classified by the FDA the CFR gives a general description including the intended use, the class to which the device belongs (i.e., Class I, II, or III), and information about marketing requirements. Your device will presumably meet the definition in a classification regulation contained in 21 CFR 862-892.

A search for "RF" in the product classification database is more useful. We find seven devices, one is a Class III device for RF/microwave hyperthermia for cancer treatment—sounds like a good match and finally we know the class and regulatory status of our device and indication.

Let's discuss the product code. The product code, together with the product name, uniquely identifies a category of devices for FDA and is a useful way to find related products. If you go to the PMA database and search on the product code LOC, you will find 27 PMA submissions or amendments. Here you will find some useful information, such as the manufacturer of the devices, when they received clearance, location of the manufacturing facilities, which advisory panel reviewed the PMA, and more.

Notice the absence of a Regulation Number? While FDA may say: "Your device should meet the definition in a classification regulation contained in 21 CFR 862-892," the truth is that it can take years before FDA assigns a regulation number to a new product category.

510(k) or PMA
The point of classification is to determine the pathway to FDA clearance. You don't have a choice in the matter, unless you want to revise the indications for use. To summarize it simply:
[ ] Class I—74% are exempt from requiring FDA clearance, the remainder need a 510(k).
[ ] Class II—requires a 510(k), which is a type of FDA submission in which you argue that your device is substantially equivalent to another device which was on the market prior to May 28, 1976.
[ ] Class II de novo 510(k)—a Class III device that is a new technology of low risk; for example exposing the hands to a magnetic field for immune system stimulation. New technologies are automatically Class III devices, but the manufacturer can petition FDA for a down-classification to Class II. The difference is the 510(k) requires de novo (from the beginning) evidence of safety and effectiveness, rather than evidence of substantial equivalence, because there is nothing to be equivalent to.
[ ] Class III—requires pre-market approval (PMA).

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not we need to do a clinical trial in order to get FDA clearance. The answer is:
[ ] No, if you have a Class I device.
[ ] Maybe, if you have a Class II device. About 10% of 510(k)s require clinical trials in order to support the argument of substantial equivalence.
[ ] Yes, if you have a Class II de novo device.
[ ] Yes, if you have a Class III, PMA device.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of FDA device regulations and how to determine if you need a clinical study in order to get FDA clearance. Sign up at registration.

This is an introductory workshop and focuses on US regulations. A complimentary workshop focusing on European regulations is also available.

You will receive, we wil discuss
[x] PowerPoint slides.
[x] A three-hour presentation.
[x] Discussion of the types of 510(k).
[x] Difference between 510(k)s and PMAs.
[x] How to take advantage of the Mohan memorandum.
[x] Distinction between guidance documents and standards.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Tuesday, 06 July 2010, at 10:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The three-hour workshop will be presented on Wednesday, 1 July 2010, at 1:00 pm Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Reporting Study Deviations: US and ISO

A Whitepaper and Workshop by Nancy J Stark, PhD Wednesday, 30 July 2010, 11 AM Central; or OnDemand soon after. Reading someone else's copy? Opt-in for whitepapers to get your own. In this whitepaper I want to discuss the concepts of study deviations, violations, non-compliances, and amendments; and to compare the US and ISO positions with regard to reporting. When I say ISO, I mean ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010) which may be purchased from the International Standards Organization in Geneva. When I say US, I mean 21 CFR Part 812 plus a collection of FDA guidances and IRB voluntary standards. A poll—how many deviations do your colleagues make? Maybe you'd like to compare your perceptions to your colleague's. Answer poll question 18, "How many total deviations do you think will occur in a typical device study of 100 subjects, 50 case report forms per subject, and 5 investigative sites?" and then see what your colleagues had to say. The one hundredth person to answer the poll will receive an Adverse Event Notepad. Who deviates? Who amends? Investigators deviate, sponsors amend. It is the nature of 'sponsored' research: the firm paying the bills gets to design the study the way they want within the limits of regulatory and ethical boundaries. The difference between an amendment and a deviation is timing: did the investigator get permission prior to making the change, or did they make the change and then go to confession.   Sponsors may, themselves, contribute to deviations. Sponsors do incredible things such as: 1) writing protocols with such tight specifications they cannot be reasonably followed, 2) authorizing changes verbally, but not following up in writing, 3) approving changes they have no authority to approve, 4) inadequately training the study staff, 5) not insisting on IRB or EC approval or notification, 6) not insisting on FDA approval or notification, or 7) changing the device—such as it's configuration, formulation, materials, or software—without prior approval or notification, 8) selling devices without FDA clearance (tantamount to conducting a study without approval), 9) trying an unapproved device on a few patients to see if the design is right, or 10) a host of other things I haven't thought of yet. Regulatory definitions ISO/FDIS 14155 is clear on what it means by a deviation. Section 3.14 defines a deviation as an "instance(s) of failure to follow, intentionally or unintentionally, the requirements of the [protocol]." A violation is not defined. And the only reference to a non-compliance is in regard to subjects not complying with requirements stated in the informed consent (Section 8.2.4.5.q—Routine on-site monitoring visits.) ISO/FDIS 14155 has no definition for amendment, but it can be deduced that it means any intentional change made to the investigator's brochure, protocol, case report forms, informed consent form, or other study documents; that the change must have the approval of the sponsor and investigator, and be noticed to the EC and regulatory authorities. (Section 6.5.1.) Part 812 has no definition of deviation, but it does say that the investigator is responsible to keep a log of deviations from the protocol (Part 812.140(a)(4)). Emergency deviations taken to protect a subject are reportable to the sponsor and reviewing IRB within 5 working days (Part 812.150(a)(4)). All other deviations require prior approval by the sponsor and possibly the IRB and FDA, and we usually consider these to be amendments. The only reference to a noncompliance is in regard to good laboratory practices. The IRB's view It's useful for sponsors to understand the IRB's point of view, because we are so concerned with our investigator's compliance to their requirements. It's mostly that their use of words is different. They think in terms of unanticipated problems, where a problem can be anything from a shortage of test tubes to malfunctioning equipment. In the short term, they want to know about everything that is unanticipated; the anticipated events can go in the annual report.   The IRB doesn't think in terms of deviations so much as unanticipated problems. And they merge the issue of adverse events with problems that are anticipated or unanticipated; in other words an adverse event is one more type of problem. Industry definitions It really isn't that hard. The ultimate goal is that no one gets to act independently, or make changes to the study plan, i.e., the protocol, investigator's brochure, case report forms, informed consent form, and any other critical study documents, without everyone else's approval. Here are definitions the industry has come to use: [ ] Deviation—a failure to follow the study plan. A deviation that occurs repeatedly should probably become an amendment. [ ] Violation—a failure to follow the study plan in such a way that subject safety was in jeopardy. [ ] Non-compliance—a failure to follow a regulation or IRB requirement. [ ] Amendment—a change to the study plan after obtaining the necessary permissions. [ ] Unanticipated—not identified in the study plan.

And what about reporting Only deviations and violations (and adverse device effects) have to be reported, since amendments already have approval. Time frames differ depending on IRB, country, the event's effect on subject safety and data integrity, and what you said in the protocol. The protocol is king, it governs your study. A wise monitor once said to me: "You can do anything, if you put it in the protocol." For ISO: The monitor is expected to identify deviations, discuss them with the investigator, and list them in the monitoring report (Section 7.2.4.5.a.) The sponsor is expected to list the deviations in progress reports as requested by reviewing ECs and regulatory authorities (Section 8.2.3.f). Investigators that cannot be compliant may need to be excused from the study (Section 7.1.1.) For FDA: The US is different from the rest of the world in that we have a risk classification system for clinical studies. The rules are different for non-significant risk and significant risk studies, and this system is unique in the international community. For significant risk studies, the investigator is expected to keep a deviation log (Part 812.140(a)(4) and report deviations to the sponsor (Part 812.150(a)(4)). The sponsor is expected to take steps to bring the investigator into compliance either by withholding shipment of additional devices or by reporting the investigator to FDA. These requirements do not apply to non-significant risk studies. For US IRBs: The rules vary from IRB to IRB, but if the board follows the OHRP guidance, unanticipated problems should be reported in the short term (my phrase) and anticipated problems in the annual progress report. Workshop learning objective The objective of the workshop is to explore the US and ISO definitions and reporting requirements in more detail, using practical examples to apply the rules, and reviewing warning letters to see how we have all gotten into trouble. You will receive [x] PowerPoint slides. [x] By popular demand, a three-hour course. [x] Office of Human Research Protections (OHRP) "Guidance on reviewing and reporting unanticipated problems involving risks to subjects or others and adverse events" (Jan07). [x] FDA "Information sheet guidance for IRBs, clinical investigators, and sponsors; FDA Institutional Review Board Inspections" (Jan06). [x] FDA "Changes or modifications during the conduct of a clinical investigation; final guidance for industry and CDRH staff" (May01). [x] FDA "Deciding when to submit a 510(k) for a change to an existing device" (Jan97). [x] A 30-minute quiz to reinforce your learning experience. [x] CEUs and certificate of attendance. Who should attend [x] Anyone monitoring a device trial. [x] Anyone sponsoring a device trial. [x] Investigators for device trials. [x] Regulatory professionals who prepare submissions to FDA. [x] Managers who sign-off on clinical trials. [x] Executives who are planning the future of their companies. Presenter Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The three-hour workshop will be presented on Wednesday, 30 June 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc

The Difficulties of Good Data Management

A Whitepaper by Dr. Nancy J Stark
Reading someone else's copy? Opt in to whitepapers and get your own.

Let's define a mid-sized device study as 100 subjects, 50 pages of paper case report forms per subject, and an average of 10 fields per page. Device sponsors are always surprised to hear that data management for such a study will require in the neighborhood of 2500+ hours. So what's all the time about?

How it is supposed to work
In a perfect world, data management would happen by the seamless convergence of data collection and database design. I'll discuss a paper-based model first, because that's what most start-ups use and it is easier to understand. Then I'll look at some electronic data capture (EDC) variations.

...Data collection
Data collection begins with defining what data to collect in order to support what you want to show. In other words, start with your envisioned indications for use, then determine how to measure device performance to that indication; the parameters you measure are called the endpoints. 'Endpoint' is an old term that used to mean the end of data collection. Today it means the pivotal data point that demonstrates product success or failure.

You progress to a set of case report forms that are easy for the Form Filler (at the study site) to fill out and error-proof for the Data Enterer (at the data management center) to enter. The case report forms should collect all the data that are necessary to support or refute the indication for use under study.

...Data verification
The case report form data is verified against the source files (medical records) by a monitor who is independent of the Form Filler. When the sponsor and investigator are separate parties, the monitor works for the sponsor and independence of the Form Filler is assumed. When the study is sponsored by the investigator (an investigator-sponsored study), the monitoring function should be outsourced to a third party who has no financial interest in the outcome.

...Handling test reports
Much of the data will be presented in the form of reports from, say, gastroenterologists or interventional radiologists. Statisticians can't work easily with the comment data found in reports. You'll need to develop questions that capture the essential elements of these reports in order to have usable data for analysis. You might have a series of questions, such as: "Is there any sign of cancer: yes, no, unsure." "What is the widest dimension of the cancer (enter 0 for no or 99.9 for unsure): __.__ mm." etc.

...Other data sources
There will likely be other sources of data too. Digital data may be recorded directly from the device. These data might be impedance, frequency, milliseconds, watts, or other parameters of device performance. Or these data might be measurements taken from the subject such as resistance, oxygenation, pH, or blood pressure.

Clinical laboratory data may be recorded on a laboratory information system (LIMS). These data may include analyst concentrations like glucose or potassium or cholesterol levels; or enzymatic levels such as alanine transaminase; or red, white, or plasma cell counts in the blood.

...Data dictionary and map
Next it is time to finalize the data dictionary and data map. The dictionary defines each data element. The definition may be self-evident but sometimes a more lengthy definition is required, perhaps the CT with contrast means a cat scan with barium contrast medium. The definition includes the data type, range of accepted values if any, and maps the data to its source. The dictionary and map aren't just for convenience. They make up part of the meta-data that enables the reconstruction of events at a future time, should that be necessary.

Using the correct data type is very important if you want calculations to run properly downstream. For example, to calculate the subject's age at the time of consent you would subtract the birth date from the consent date. If we erroneously enter the consent date as text, the calculation will return an error. It can be easily fixed, but it will probably cost half a day in labor.

...Database design
Meanwhile, back at the data management center, the Database Designer designs a database uniquely built to receive the data from the various sources of data. The structure of questions on the case report form dictates exactly the structure of the database. If the question says: "How many apples did you eat today?" the database must receive integer data. If the question says: "What was your primary source of protein for lunch? Select one." The database will have a drop-down box that allows the Data Enterer to select one option from a predetermined list. If the question says: "Which of the following vegetables did you eat today? Check all that apply," a related table will be designed that allows several answers to be linked back to a specific subject.

In addition, remember the digital data that is coming in from the device? The database must be designed to accept these data when they are electronically imported and to automatically link the data to the correct subject. The same holds true for any clinical laboratory data that will be directly imported.

Finally, a set of management and outcomes reports will be coded. Management reports will enable managers and sponsor to follow the progress of the study without revealing study outcomes. A typical list of manager's reports includes: [1] Data entered by subject, [2] Data queries by subject, by site, by monitor, [3] Missing data, [4] Adverse events, and [5] Data received but not yet entered. One type of summary report is shown below. Here, each subject is represented by a row, and the case report forms make up the columns. The forms are color-coded to show if the data are entered (blue), missing (gray), outstanding due to queries (red), or received but not entered (yellow).

Outcomes reports might consist of, say, [1] time to an event, [2] number of events at day 14, [3] correlation of diagnosis with gold standard, or [4] any other calculated result.

...Database validation
To validate the database, three or four sets of faux patients are entered into the database. The phony data are entered, reports are run, and the answers are checked against manual calculations. In this way it can be confirmed that all the tables are synchronized, edit checks are firing properly, correct data types are being accepted as specified in the data dictionary and map (below), calculated fields are functioning, and database queries are working.

...Version control
The final touch to the database application is to invoke a version control system. Once the design of the database is validated, the Access or Excel file is 'checked in' to a library such as Microsoft Sharepoint or SourceSafe. Then, whenever someone wants to make a change to the code they check it out of the library, make their changes, and check it in again. The version control software will automatically increment the version number, record who made what changes, and provide a space for notes.

...Convergence: merging data and database application
After the database application is validated it is ready to receive the 5000 pages of case report form data from the mid-sized study described above. This involves entering 50,000 data points! In our perfect world, our easy-to-enter forms are forwarded to the data management center where the Data Enterer enters the data without error. The data may also be re-entered, verified, or reviewed by a second person to improve data quality.

Once all data have been entered and reviewed, edits run, and those very expensive queries resolved (see below), there should be no missing or illegible data and no outstanding data queries. The digital data from the device are forwarded and match exactly with the patient numbers when uploaded. Ditto for the laboratory data.

...Data audit trails and other Part 11 issues
As data are entered into the database an independent, but corresponding, record is kept of what data are entered or changed, when, and by whom. This creates an audit trail of the data (as opposed to version control of the database application). Affordable audit trail/Part 11 add-ons are commercially available for both Access and Excel (still the most popular application for data management). The audit trails will track every entry and every change to data fields, generating a complete history of data entry and data changes.

...Data validation and lock
Earlier we validated the database, confirming the fields were the correct data type, which related tables were properly linked, and reports were accurate. After data entry, we validate the data itself. I like to print a report that 'looks' like a case report form. I print out, say, 10% of the forms and manually compare them to the case report forms used for input. And I print out a report of endpoints. A common level of error acceptance is 0% for pivotal endpoints and 0.5% for other fields. Finally, the data can be locked, imported into SAS, reports can be run, statisticians can analyze, and all is right with the world.

Electronic Data Capture
Viewing it simply, in a paper-based system the data are transcribed onto case report forms by the Form Filler at the study site. After source verification, the data are forwarded to the data management center for data entry by a Data Enterer. In electronic data capture (EDC) the validated database is uploaded to a server and study staff are given access via a password and secure connection. Rather than fill out a paper form, the Form Filler is also the Data Enterer. This is where you'll have a cost savings because the work isn't duplicated and a Form Filler/Data Enterer is entering data directly from the source files.

EDC systems are a worthwhile investment if your company expects to do many trials with similar designs and your investigators are comfortable with computers and applications.

How it usually works
Unfortunately, life is rarely a straight-forward path, and we often begin in the middle. The numbers of things that can go wrong are too many to enumerate. But here are a few likely problem-makers.

...Questions change
It seems so minor, changing a question on the case report form so it makes more sense to the Form Filler. But if you change the data type, it might be hard to merge data for that question from before and after the change. Even worse, you are looking at a couple of hours of database re-design and re-verification.

...Differing subject ID numbers
How can it be? Subjects are numbered 1-100 in the database, but 20100607.1-20100607.100 from the laboratory. As humans, we can see it is a date followed by a number, but our database does not understand. Another half-day is lost learning there is a problem, identifying the problem, and fixing the problem.

...Adverse events
Adverse event data can require a lot of time to manage. The event must be followed until it is resolved or stabilized, and that may not happen for several months. Ongoing adverse events keep the database open and require continuing updates for an indeterminate length of time. Ongoing reports to Database Monitoring Committees or Clinical Events Committees also demand extra time.

...Missing data
Unfortunately, some forms will come in with missing values. When a value is missing, i.e., a question is unanswered, the integrity of the data are compromised. If the missing value is a pivotal endpoint, the Form Filler will be asked by data query to track down the missing data. If the value is no longer available, (let's say you wanted the patient's temperature immediately after the procedure), the statistician may be able to guess at a defensible value for the missing data, but it is still a guess.

...Data queries
Paper case report forms are written in handwriting. In spite of the best monitoring and source verification, some illogical or illegible data will slip through. "Now, let's see", thinks the Data Enterer, "is that a six or a zero?" A data query is sent to the monitor, who sends it to the Form Filler, who looks up the correct answer in the source file and sends it back to the monitor, who sends it to the Data Enterer. This is good for 15 minutes of Data Enterer time, 15-30 minutes of monitoring time, and 30 minutes of Form Filler time. Not counting the Form Filler, we can assume $125 per data query. If there is one data query per subject, that would be $62,500!

Thankfully, in the EDC world, illegible handwriting is not an issue for the data manager as the entry has already been reviewed by the site. Typically, in EDC studies, less time is spent dealing with handwriting and missing value queries and effort can be focused on more complex queries.

...Data arrival
When data are coming in from multiple sources, it doesn't always arrive at the same time. You may have all the device data for subjects 1-37, the paper case report forms for subjects 1-30 except for subjects 3 and 23 which were held back, and no laboratory data. You'll need ongoing management reports to show what data has been received for what subjects, and what data the monitors should be tracking down at the site.

Communication
Throughout all of this, communication will be recorded by email messages. Messages should be written clearly and with detail. All phone conversations are summarized with a list of action items. When referring to a database or spreadsheet, use its name and version number. Communication is not only meant for the immediate reader, it is meant to be meta-data (data about the data) which can serve to reconstruct events at a point in the future. For contractors this is especially important; billing issues are usually resolved based on written communications.

Periodically, all the messages are selected and printed (memo style) to Acrobat Writer. The long pdf file is bookmarked with relevant tables of contents, burned to a CD, and stored as a permanent part of the technical file.

Not just CDG's numbers
I used my own data, of course, but I also called upon the goodwill of several friends to assemble the hours estimate below. A perfectly designed, perfectly executed study will not come with free data management.

How Clinical Design Group can help
Building a database, validating the database, invoking audit trails, rendering the database Part 11 compliant, entering and importing data, validating the data, exporting the data for SAS analysis, and documenting communication are all part of the data management services that CDG offers. Whether you want a paper-based system or an electronic data capture system, CDG has the capabilities and experience to help you.

Do you need all of these services, only part of them, or consulting to help you do it yourself? You can contact Clinical Device Group for help. Here are some of the Network Staff and resources who we have at to help you.

...Meet Wessam Sonbol, Database Designer
Wessam Sonbol is the President of Clinical Systems Consultants Inc. Mr. Sonbol graduated from the University of Minnesota’s Institute of Technology with a degree in computer science. Throughout his career he has held positions at Eminent Research/PPD, American Medical Systems and Sorin Group. He developed a global database with which he gathered data from hospitals all over the world to review cardiovascular diseases and understand the demographics of different causes. Wessam also developed http://www.tctmd.com, an informational website for doctors focusing on Trans Catheter Therapeutics; and Global View, a post-market eRegistry tool used by many organizations such as St. Jude and J&J.  He also developed studies using Oracle clinical, Clindex, ERT and Rave and designed a MS Access 21 CRF 11 compliant database. 

...Meet Michelle Secic, Biostatistician
Michelle Secic is the President of Secic Statistical Consulting, Inc. where she works on a variety of medical research projects.  She aids companies around the world with the statistical aspects of their research from small projects to large clinical trials involving drugs or medical devices. She received her Master of Science degree in applied statistics in 1990.  She worked at the Cleveland Clinic Foundation from 1990 through 2001, when she left to continue expansion of her own consulting company.  She authored a book in 1997 titled "How To Report Statistics in Medicine", published by the American College of Physicians. The book was translated into Chinese and published in China in 2002; the second edition was released in 2006.

...Meet Dr. Robert Thiel, Biostatistician
Robert Thiel, PhD is the President of Thiel Statistical Consultants. Dr. Thiel has degrees in physics, clinical counseling and psychometrics. He is an expert in the analysis of IVD data for the Medical Device Industry with more than 75 510K and 5 PMA approvals. He has published papers in the areas of free PSA, breast cancer, ovarian cancer, liver disease and multivariate analyses as applied to sports (baseball and basketball).

His current interests lie in the area of Bayesian statistics, bootstrap and permutation test methodology, and the application of these methods to small sample trials.

...Meet Clindex, a web-based EDC system
Clindex (Fortress Medical Systems LLC, MN) offers a Clinical Data Management System, Clinical Trial Management System, and EDC System in one integrated solution. The software is designed for use with medical devices and diagnostic products (and okay, with pharmaceutical trials; but those of you who know me know I don't do drugs....) Clindex is used from start-up firms to Fortune 500 companies. It has been used in hundreds of clinical studies, international studies, and studies that supported FDA marketing applications. The FDA has inspected numerous companies using Clindex with no feedback of any findings or deficiencies.

I look forward to hearing from you!

Best Regards,

Nancy J Stark, PhD
President, Clinical Device Group Inc
773-489-5706
[email protected]

Why Do Non-Inferiority Clinical Studies?

A Whitepaper by NJ Stark and e-Conference by Dr. Robert Thiel Learn more Wednesday, 7 July 2010, 11 AM Central; or here OnDemand soon after. Reading someone's elses copy? Opt-in for whitepapers to get your own. I read an interesting comment in a press release this morning. The CEO of Spectranetics said: "Our physician customers prefer randomized, controlled studies to assist them with their clinical decisions...." and "Our clinical trial program ... demonstrates our commitment to evidence-based medicine." Every book or guidance document I read has a different way of categorizing clinical studies. One obvious categorization for medical devices is by whether or not you are doing a single-group (single-arm) study with no comparator, or whether or not you will compare your device to another. My experience is that most device studies are single-arm designs so I read the Spectranetics press release with a loud hurrah. A poll—what's everybody else doing? What is the most common category of clinical trial your company conducted last year? [a] Single arm. [b] Superiority. [c] Equivalence. [d] Non-inferiority. Answer poll 17 to compare yourself to others. Be the 100th person to answer the poll and win a free Adverse Event note pad. Non-inferiority studies use smaller sample sizes In any comparative study you want to show whether your investigational device is better than, the same as, or no worse than the competitor. If you will be filing a 510k, you might think that you need to be the same as the comparator in order to support the argument of substantial equivalence. It makes sense. The difficulty arises when you calculate the sample size. Sample sizes are calculated based on the difference between the average values of an endpoint. The greater the difference between your device and mine, the fewer the number of subjects you'll need to show it. As the difference between your device and mine gets smaller, the sample size gets larger and larger. As the difference becomes infinitesimally small, i.e., the devices become equivalent, the sample size skyrockets to infinity. Enter non-inferiority. Instead of showing that two devices are the same, a clever FDA statistician named Blackwelder looked at things differently and developed a strategy called "Proving the Null Hypothesis". He figured that if we stopped trying to prove the hypothesis and reject the null, and instead rejected the hypothesis and proved the null, we could accomplish the same thing as an equivalence trial but with a much smaller sample size. Blackwelder's ground-breaking paper was published in 1982. FDA's new guidance document In point of fact, device manufacturers have been doing non-inferiority studies for years; FDA kindly points out the opportunity every time a manufacturer proposes implementing a superiority trial. It is just as unethical to do an unnecessarily large study as it is too do too small a study. Recently, FDA issued a draft guidance document titled "Guidance for Industry - Non-Inferiority Clinical Trials" (Mar2010). The guidance was issued by CDER and CBER because non-inferiority trials require active controls rather than placebos—something new for the drug world. We device people are familiar and comfortable with active controls (who would use a placebo heart valve?), and there is much a good biostatistician like Robert Thiel can teach us with regard to medical devices and diagnostics. What device companies already know The guidance document points out some important "issues" in implementing non-inferiority studies. If you've designed non-inferiority studies before, you have probably already encountered them. [1] You have to know the comparator's performance for your 'pivotal' endpoint. You might learn this from the literature, benchtop data, animal data, or even data gathered at your own expense on the comparator device. [2] You have to judge the investigational device's performance for the 'pivotal' endpoint based on data such as benchtop data, animal data, or data from similar, commercial devices. [3] Non-inferiority really means "not too inferior", and how inferior is too inferior must be determined. You should plan on plenty of pre-protocol discussion over this topic. [4] The study design must be able to detect a difference if there is one. [5] The need to show a lack of difference can lead to a lack of incentive to study excellence, i.e., sloppiness. I personally take issue with this statement, FDA, but I'll let it go.

Motivate Your Study Staff: Give an Adverse Event Note Pad/Mouse Pad The Adverse Event note pad is a graphical way for study site staff to categorize adverse events. Starting at the center, they choose the characteristics in a pie-wedge that best describe the event. The outer ring identifies the event by type. ISO definitions, accepted by FDA, are provided on the right. The tool helps study staff think their way through to the reporting requirements described in the protocol. Read more. Learn more: take the e-conference The objective of the e-conference is to learn more about the historical pitfalls in the design and execution of non-inferiority trials and how to avoid them. Addendum: Brief Comments on Missing Data Let's shift gears and speak for a minute about missing data. The clinical trial has not yet been conducted where there hasn't been at least some missing data: the subject can't remember it, the study staff forgot to record it, the dog ate it, and the statistician is leftout with it. There are three basic kinds of missing data: [1] Data may be 'missing completely at random', meaning the probability that an observation is missing is unrelated to its value. For example, if a subject missed a follow-up visit because of jury duty, the data would be missing at random and we could impute the missing values. [2] Data may be 'missing at random' but not completely at random. For example, people who are depressed might be less inclined to report their income than others. If we can account for the variable depression, we can impute the income value. [3] Data may be 'missing not at random'. For example, if we ask people to report their income, low income people are less likely to respond. The income data is definitely not missing at random, it is missing specifically for a particular group of people. We can't simply impute the value, an algorithm must be developed. A good study design has a plan (called a statistical analysis plan or SAP) that, among other things, determines beforehand how missing data will be identified and handled. Dr. Thiel will take a few final moments to discuss this important, but neglected, issue. Dr. Thiel will discuss [1] What resources are needed to design and execute a non-inferiority trial. [2] What the FDA expects to see for a trial of this type. [3] Design problems with active-control (non-inferiority) clinical trials. [4] Statistical issues associated with non-inferiority clinical trials. [5] How the results of non-inferiority clinical trials are interpreted. [6] The all-important margin of error. [7] An addendum: Handling missing values. You will receive [x] PowerPoint slides. [x] An interpretation of the guidance document. [x] Practical examples to learn from. [x] The expertise of a prominent biostatistician. [x] Chance for Q&A. [x] CEUs and certificate of attendance. Who should attend (no, you do not need to be a statistician) [x] Clinical research professionals who design clinical trials. [x] Regulatory professionals who report clinical data. [x] Statistical professionals who analyze clinical data. [x] Managers who sign-off on clinical trials. [x] Executives who are planning the future of their companies. Presenter Dr. Robert P. Thiel has degrees in physics, clinical counseling and psychometrics. He is an expert in the analysis of IVD data for the Medical Device Industry with more than 75 510K and 5 PMA approvals. He has published papers in the areas of free PSA, breast cancer, ovarian cancer, liver disease and multivariate analyses. His current interests lie in the area of bootstrap and permutation test methodology and the application of these methods to small sample trials and Bayesian analysis as applied to diagnostic clinical trials. Dr. Thiel can be contacted at [email protected]. System requirements [x] Personal computer. [x] Internet Access. [x] Telephone. Date, time, registration The 90-minute e-conference will be presented on Wednesday, 7 July 2010, at 11:00 Central Time. Event materials will be distributed the day before the e-conference. Sign up at registration. Best Regards, Nancy J Stark, PhD President, Clinical Device Group Inc Click here to receive CDG news via our XML/RSS feed Follow us on Twitter

Device AEs Exceed Drug AEs in 2008

 Are You Over-Reporting?
Take the OnDemand Adverse Events Workshop to Find Out

The Government Accounting Office issued a report on Monday, 20 July 09, stating that the number of adverse events reported to FDA for medical devices outnumbered the number of adverse events for drugs for the first time in 2008. The number increased to 588,161 from 189,450 since 2004.

So many adverse event reports go to FDA that their tracking system is overwhelmed; they cannot track which individual reports have been reviewed and which have not. Ask us for a free copy of the GAO Report.

The incredible increase in medical device reports speaks loudly to the increase in medical device use, the increase in device complexity, and the increase in device importance in our healthcare system.

 

Top Twelve Mistakes Monitors Manage

The problems other people cause us...
Many of the problems you'll encounter at a site are the result of other people's actions. But too bad, you have to deal with them anyway. Here's the Top Ten Pick by clinical trial expert Lynette Chiapperino.

1. Trial designer writes impossible protocols.
2. Time, cost, quality--pick any two.
3. Last site visit not reviewed.
4. No action item list.
5. Site isolation.
6. Data points and endpoints don't match.
7. Those boring repetitive entries.
8. Unhappy trends, clues, issues.
9. Undocumented trends, clues, issues.
10. Unkept promises.

Here's another two picks by IVD clinical trial expert Gail Radcliffe.
11. Test results come late from the lab.
12. Out-of-date ranges and test methods not identified.

Learning objective
To be forewarned about common study site problems so you can deal with them creatively.

We will cover
[x] Lynette's Top Ten Pick of study site problems.
[x]How to prevent them.
[x] How to fix, manage, or control them.
[x] Or how to live with them--the problems won't change, so you will have to.

Dig, Dig, Dig
The hallmark of a good monitor is excavation. Every site has problems. You must think to what's behind the obvious to get to a solution. An investigator resigned? What was the motivation? Enrollment is slow? What else is going on in your site's life? Try to look beyond the immediate issue and then try various solutions to see what works.

You will receive
[x] PowerPoint Slides.
[x] Case studies and real examples.
[x] Ideas to try.
[x] An expert speaker.
[x] Certificate & CEUs.

Audience suitability
[x] People who monitor clinical trials.
[x] People who design clinical trials.
[x] People who implement clinical trials.
[x] People who manage clinical trials.
[x] People who work with clinical trial data.

Presenter
The e-conference will be presented by Dr. Nancy J Stark.

The purchase is $425 for OnDemand access and $475 for the CD. Each attendee is eligible for 0.15 CEUs upon completing the course feedback via the link provided with the event materials. Click here to purchase.

 

Part 11 Compliance for Your Access Database

e-Conference
February 18, 2009--Presented by Tyson Mew--Register Here

MS Access is the second most popular application for receiving clinical trial data. Databases in Access are simple to set up and easy to use, but like any other software must be configured to meet the FDA's requirements for 21 CFR Part 11 and Computerized Systems Used in Clinical Trials. Before you can use it, the application you design must be validated, yet hundreds of 483s and warning letters are received each year by companies who fail to validate their software or document changes to its design.



Learning Objective
You will learn how to make your MS Access database Part 11 compliant.

What will be covered
This presentation will provide the instructions, materials, and documentation to ensure full compliance with 21 CFR Part 11 for new or existing Access databases. By streamlining these compliance activities, your organization can make better use of these powerful data collection tools and save money that would have been otherwise spend purchasing commercial products. Specifically we will discuss:

[x] Strategies for how to document and validate Access programs.
[x] How to define requirements quickly.
[x] How to document inputs, code, and security settings.
[x] How to add audit trails to any part of the database.
[x] How to properly secure the data and code.
[x] How to implement security settings for multiple users.
[x] Common settings applied to limit user actions.
[x] Managing change control and common mistakes to avoid.
[x] Details on when and where to use electronic signatures.
[x] Advanced techniques for adding electonic signatures, inactivity timeouts, and controls for users and passwords.
[x] Tips for efficient testing for any type of database.
[x] What the FDA looks for during inspections. 

Download Sample Code
You may download sample code and validation documents for your own use.

You will also receive
[X] PowerPoint slides.
[x] An expert speaker.
[x] A chance for QnA.

Audience Suitability
[x] Clinical research professionals who design clinical trials.
[x] Regulatory professionals who report clinical data.
[x] Quality Assurance professionals.
[x] Managers and staff who are responsible for providing valid data.
[x] Statistical professionals who analyze clinical data.
[x] Managers who sign off on clinical trials.

Presenter
Tyson M Mew is President of Ofni Systems, a software provider and Part 11 consulting firm. He has a strong background in software development and computer system validation, and has spoken at many conferences and workshops on Part 11. 

Date, Time, Registration
This 90-minute event will be presented on February 18, 2009 at 11:00 Central time, and will be available OnDemand after that. Event materials will be distributed the day before the e-conference or will be available for download. You will receive 0.15 CEU and a Certificate of Attendance. You may register here!

System Requirements
[x] Personal computer.
[x] Confirmed access to Adobe Connect (test connection by viewing this cartoon.)
[x] Telephone with speakers for live event.
[x] T1 line for OnDemand presentation.

CDG's Biological Safety Rescue Squad

Medical Device Biological Safety
The biocompatibility of medical devices is approached differently in the States than it is in Europe. FDA prefers a data-based approach. Europe prefers a literature-based defense. In either case, following the ISO 10993 or ISO 10993/G95 matrixes is only a beginning; the data supporting the biological safety of the final device must give ‘reasonable assurance’ of its safety in real use situations. You need to play ‘devil’s advocate’; thinking of all the ways your device might cause a biological reaction with the body and then address each possibility with data, proposed labeling, and a plan for mitigation.

For example, FDA raised the question if an implanted material might have a local oxidative effect. The question required the design of a unique animal test and a focused literature search reviewing the chemistry of the materials. In another example, FDA wanted to know the concentration of unreacted monomers, bimers, and trimers to the ppb level in a plastic, the analytical testing required a unique design. In a third example, reviewers wanted to know the possibility of an implanted material injuring a nerve, the solution required a sub-chronic test in which devices were implanted in dogs.

Clinical Device Group’s Rescue Squad

 

Your first contact with Clinical Device Group will be with Nancy J Stark, PhD. With a doctorate in biochemistry, Dr. Stark will assess your biological safety questions and determine if the firm is able to help you. She will answer your initial questions about the company, its history, services, and rates; will sign a confidentiality agreement and negotiate a service agreement with you. Once the administrative end of the relationship is in place, you’ll be referred to our primary toxicologist, Dr. Daniel McLain.

The Expert Himself

Next you’ll be referred to Dr. Daniel McLain, MS/PhD, Nutritional Toxicology and Preventive Medicine, who will begin immediately to assess your issues and recommend strategies and solutions. He may recommend a literature review, he may provide expert interpretations of laboratory reports, he may recommend additional testing at the test house of your choosing, he may assist in writing unique protocols for sub-chronic or chronic tests, or he may provide expert justifications of safety based on the data you have now. Dan can prepare risk assessments, preclinical strategies, or prepare the biological safety sections of 510(k)s, PMAs, or BLAs.

Dr. McLain is an internationally recognized toxicologist in the medical device industry and currently serves as the Convener for ISO 10993: Biological evaluation of medical devices – Part 11: Systemic toxicity evaluation. It is an extreme honor to serve as a convener, because it is a nomination of your peers, recognizing your expertise in the technical area and ability to work with people to bring them to consensus. He has had extensive interaction with global regulatory bodies as it pertains to product safety submissions and is held in high regard for his development strategies and commitment to product safety.

Now for Some Fun

First, click on the image to the right to solve the puzzle of biological safety.

Second, take Poll du jour 6, a 30-second quiz about FDA's views on biological safety and see how your answers compare to others.

Contact Us
Clinical Device Group Inc
773-489-5721
mailto: [email protected]

Deviations and Amendments

Deviations and Amendments Workshop July 23, 2008

What's a deviation, anyway? What, exactly, is a protocol deviation, and is it different from a violation? Deviations are defined in the regulations, but violations are not. IRBs have many opinions, FDA has yet another. The IRB Regulations are little help here, so we'll turn to the IRB professional associations to learn their views on definitions, distinctions, and reporting requirements. The FDA Deviations and violations are fundamentally different from amendments. In the first, we document the event after the fact; in the second we obtain permission before the fact. We will use the rules for IDE supplements as a guideline for managing trial deviations and violations. Learning Objective: The goal is to be able to identify a deviation when it occurs, properly categorize it, and determine its reportability to the IRB and FDA. The Workshop: Workshops are informal, interactive, and about 3 hours in length—they are not lectures. Each learner is required to logon individually at their own computer to enhance and track their participation during the event.  The material is presented with PowerPoint slides accompanied by extensive notes and reference material; in fact, each learner has the entire presentation in writing. The presentation is followed by an online quiz to be taken within two weeks. You must participate in the presentation, take the quiz, and provide feedback in order to receive CEUs and a Certificate, but the good news is you will receive CEUs for time spent on the quiz and giving feedback.    More information: Presented by Nancy J Stark, Deviations>>

What is FDA's Critical Path Initiative?

The Critical Path Initiative is FDA's effort to modernize the scientific process of medical device regulatory review. According to Janet Woodcock, the private sector (you) has made massive investments in basic biomedical research, but regulators (FDA) have not kept pace with what they call 'regulatory science'. 

We know 'regulatory science' lags behind, what's being done about it?
'Regulatory science', the FDA's ability to review a new technology with expertise and insight, has lagged significantly behind the private sector. Under resourced and understaffed, FDA has struggled to keep pace with evolving technologies. The problem has been compounded by newly emerging applications like new molecular technologies, advanced imaging techniques, nanotechnologies, robotics, and more.

Last year FDA published a list of 76 examples of promising and high-priority projects the initiative will foster. Is your technology among them?
http://www.fda.gov/oc/initiatives/criticalpath/

Inspection Woes, Worries about Safety
Given the Government Accountability Office's report on improvements needed in drug safety, the investigative arm of Congress is calling for more establishment inspections. Last week Congressman John Dingell, D-Mich, held congressional hearings regarding the increase in FDA funding needed to inspect foreign establishments. FDA Commissioner Andrew von Eschenbach said the average inspection cost about $45,000. While the focus was on drugs, I think we can expect increased inspection activity in the device sector as well. http://www.gao.gov/new.items/d06402.pdf
http://money.cnn.com/

Will MDFUMA help?
The re-authorization of MDFUMA means a renewal and expansion the far-reaching changes made by FDAAA:  the new medical device user fee structure will enable BROAD changes to how FDA does business, including inspection of device establishments by third-parties;  a regulation on unique device identification; new requirements concerning pediatric devices and devices with potential for pediatric use; new restrictions of FDA advisory panel member conflicts of interest; new requirements for submission of information concerning clinical trials; the Sentinal Initiative to gather adverse event information from existing medical records, and more.

I want more...
You can listen to this informative e Conference on CD or On Demand.

How Do I Get Reimbursement for my Medical Device?

Real Case Study

A   B

1. Your company makes wrench A.
2. Clever engineers design wrench B.
3. Clinical charged with doing a study to show B is better than A. (This is important clinical research people, so listen up!)
4. Marketing plans big campaign to sell B at twice the cost as A.

BUT, BUT, BUT, hospital won't pay more for B because Medicare will only reimburse for A. Any increase in price comes out of hospital's profit margin.

Take this eConference. Learn how to overcome problems and make your company rich!
---------------------------------------------------------
Objective: To make a better understanding of medical device reimbursement work for you.

Why watch this e Conference? Have you ever wondered why the market uptake of your FDA-approved device was not greater or faster? FDA approval is a necessary, but not sufficient, criterion for payer adoption.

Third-party payers are the ultimate purchasers of medical technologies. They establish various requirements for adoption and set pricing levels. This eConference will help you understand payer requirements and how to meet them and overcome barriers to reimbursement.

You will learn:
An understanding of coverage, coding, and reimbursement for technologies.
- Coverage – What is it? What are payers requirements for coverage?
- Coding – What are the various coding systems and how are they used for reimbursement? How do I know if my technology needs a code and how do I get one?
- Reimbursement – How are various health care providers paid by payers for medical technologies and services? How are rates established? How can I influence or establish rates for my technology?
- An overview of physician, hospital, surgi-center, medical equipment and laboratory services.

Buy Now: The 90-minute e Conference is available on CD or On Demand.