CDG e Conferences & Workshops

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