CDG e Conferences & Workshops

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.

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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.
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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