An Ethical Question on Medical Oncology Research

October 25, 2011

oncology question

An Ethical Question on Clinical Trials

GxP Perspectives receives some excellent questions and comments about best practices. Here a regular reader asks a very pertinent question on Oncology Research. I don’t have the answer but I am hoping that the GxP Perspectives Community has some people that can help answer this for George. I hope so because I can learn a few things as well. Please comment if you have ideas for George and others to pursue.

An Ethical Question on Medical Oncology Research:

I am not sure the best place to post this question: I work in Medical Oncology Research and I have been noticing what I feel to be a distubing trend in manditory tumor tissue submission. In the past, studies required tissue samples if they were needed to determine eligibility or randomization to a treatment arm (Essentially something that was a potential benefit to the patient or needed to deterimne if study endpoints were met). Those studies usually gave patients the option to allow the sponsor to keep archived tissue for “future testing” that had no benefit to the patient or current study. Recently, some sponsors have been requiring this “archived tissue” as part of the inclusion / exclusion criteria – “If you don’t give us the tissue, you can’t go on our study.” Do you know if anyone is discussing this issue or is concerned how this may impact patient rights?


Three Comments. The first is from Abby: If the intended use of the archival tissue sample is to send to a central reader to show that the subject indeed has the pathological diagnosis intended for the study, I believe this is a legitimate and important request by the researchers. In the case of a more nebulous use (e.g. “general exploratory pharmacodynamic studies” or “future use”), I do think it is good if the Sponsor can try to provide more specifics, such as “future use in cancer research” or something even better.

It has been my experience that the Informed Consent wording related to these samples must be very clear, and address the short-term and long-term storage of the samples, as well as information on how the subject may revoke that consent and have the samples returned. Clinical sites often request return of the archival samples on behalf of the subject, and sponsors often return the samples–especially if the subject is moving onto another study that also likely requires tissue. Interesting question–and I look forward to hearing other responses!

And the second is from Kevin: As far as the patient’s rights, they aren’t affected at all. As you state, it is clearly in the Inclusion criteria that if you want to participate, the Sponsor requires this sample. This should be included in the consent form as well. The patient, at this point, has the right say “no” to the study.

Sponsors routinely collect these samples as a way to further their research and hopefully capitalize on a novel therapy. I guess you can look at this in one of two ways: 1) Big Pharma is trying to make a dollar (…obviously, which is how/why they exist in the first place) or 2) since they have the ability to take the research beyond the confines of the current protocol, they may just find a cure or improved therapy, which in turn, benefits the patient.

It would be unethical only if the Sponsor took the sample and archived it without the patient’s consent.

My suggestion would to be to discuss your feelings with the Sponsor or to start with, perhaps your IRB.

And Eleanor: There is currently a significant shift in the approach to cancer treatment. In many cancers, there is not a universal response to treatment but some sub-populations respond much more effectively to treatment than the general population. In many cases this response to treatment relates to expression of certain genes by the tumour that do not occur in all patients with the disease. If it is possible to identify the gene and which patients express that gene then treatment is much more effective both in terms of success and in terms of cost.

This may be one of the reasons that sponsors are moving towards mandatory collection of samples. If they identify that a particular sub-population has responded more effectively they can go back and examine stored samples to try and identify the reasons that the sub-population responded more effectively. Thus, there may be the possibility of developing diagnostic tools to identify the sub-population and only treat that population. If there are only limited samples available then it may not be possible to do so. Just a thought…..

Please leave a comment on this question. Thanks!

There are THREE Weeks left to comment on the Draft FDA Guidance Document on Risk-based Monitoring
Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring

How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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Informed Consent & Research Ethics Discussed at WIRB Annual Training Seminar

October 2, 2011

Seminar on Informed Consent and Research Ethics

WIRB Training Seminar was Held in Seattle, WA

“Obtaining consent does not make an unethical study ethical,” Dr. Marjorie Speers told the Annual Training Seminar of the Western Institutional Review Board (WIRB). Speers is the President and CEO of AAHRPP (Association for the Accreditation of Human Research Protection Program). She pointed out that, although many IRBs focus on the informed consent process, protocol design is an equally important ethical consideration. The focus of this year’s seminar was informed consent and the speakers’ presentations led to some lively discussion on consent forms, protocol design, research in the developing world, and financial disclosure.

The seminar, which WIRB opens to research professionals in the Puget Sound, features national experts on bioethics and the regulation of IRBs. Among the speakers were Dr. Speers; Dr. Jerry Menikoff, Director of the Office of Human Research Protections (OHRP); Dr. Vincent Ahonkhai, Senior Regulatory Office, Bill and Melinda Gates Foundation; and, Dr. Jeremy Sugarman, Professor of Bioethics and Medicine, Johns Hopkins University. The University of Washington and the Fred Hutchinson Cancer Research Center co-sponsored the seminar with WIRB.

informed consent and research ethics

Simplifying the Informed Consent Process

A recurring theme was the need to shorten consent forms to make them more accessible to research subjects. Dr. Speers referred to most of the required elements of informed consent a “required disclosures,” stating that “disclosures” was a preferrable term. During discussion periods there were several comments that the disclosures had more to do with legal concerns than with involving the research subject in an informed consent process. Dr. Speers stressed that, “too much information is no information.”

Dr. Speers spoke of the need to involve communities as well as the individual research participants. “Communities can be harmed and benefitted by the research,” maintained Speers. “Generally, the public does not understand the drug development process,” Speers said, the aim of gaining new knowledge.

The seminar discussed some humorous examples of researchers not understanding sensibilities in the developing world. For example, informed consent forms frequently use units of measure such as a teaspoon or quarter cup of blood taken for laboratory analysis. However, when the research was in sub-Saharan Africa, because researchers were using units of measurement most common in cooking, potential subjects assumed that the blood was going to be cooked, not analyzed. This led to worries about witchcraft, which was clearly not the intent of the researchers.

WIRB invited a research participant, Debbbie, to address the seminar. Debbie had participated in many cystic fibrosis studies in the past 20 years. She talked about how access to healthcare and money were her primary motivations for participating in a clinical trial. She had lost her health insurance a few months before enrolling in the study. Then she developed pneumonia. During the run-in phase of the study there was a “cleanout” using antibiotics, a common practice in CF studies. Participating in the clinical trial directly benefitted her healthcare. One of the reasons she enjoyed research participation was the access to healthcare and cutting edge developments in the treatment of cystic fibrosis.

The Influence of Money on Research Ethics

Money was a major topic of conversation, as always at a meeting discussing bioethics. Debbie was asked, “how much of a factor is it?” Quite a lot, she replied. Speakers discussed the question from the perspective of financial disclosure. Dr. Speers said that any financial interest by a member of the research team should be an expected disclosure. Others pointed out that the only type of financial relationship that significantly affected potential research participants was when the researchers had an equity interest in the research drug. But not always in ways you might expect. One potential subject said that when learning the PI owned stock in the company sponsoring the research, they thought, “the drug must work,” and wanted to participate.

There was one embarrassing moment for quality assurance professionals during a talk by Dr. Maria Greenwald, a researcher from California. She had recently been audited by a sponsor QA auditor who cited her for failing to report “protocol violations” to the IRB. The protocol required periodic laboratory tests for calcium levels, which were a concern for the investigational product.

Research Ethics and Audit Findings on Calcium Levels

Elevated Calcium Levels

When blood tests revealed significantly increased calcium levels for one research subject, Dr. Greenwald ordered laboratory tests at every study visit, more frequently than the protocol required. She considered this necessary for patient safety using her medical judgment, as required by the Form FDA 1572. The auditor disagreed and insisted that she had violated the protocol.

I remember my own inspection training in the FDA Bioresearch Monitoring program. “Never argue the practice of medicine with an MD,” I was told. When Dr. Greenwald said that she ordered the lab tests for patient safety according to her medical judgment, the auditor should have accepted it and merely noted it in her report.

The public seminar concluded with David Forster, the Chief Compliance Officer for WIRB pointing out a three-page informed consent form approved by WIRB during the first year of its existence. It had all of the required elements, or disclosures, and was simple and to the point. He challenged WIRB board members to see if it was possible to return to a clear, simple consent form. Most appeared up to the challenge.

Carl Anderson
GxP Perspectives
02 October 2011


Good Documentation Practice: Thanks to Jerry Chapman at IPQ Publications for this useful resource list for GDP Guidance Canon

Information about IPQ Publications


Next Week: Veteran GCP educator, David Montgomery opines on the
FDA Draft Guidance on Risk-Based Monitoring

Six Weeks Left to Comment on Risk-Based Monitoring!

How to comment to FDA? Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

The Federal Register Docket Number is FDA-2011-D-0597


Just released– FDA Draft Guidance for Medical Devices: De Novo Classification Process (Evaluation of Automatic Class III Designation)
Read the Federal Register Announcement


You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).

clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training

FDA & OHRP Hold Regulatory Forum at ACRP Meeting in Seattle

May 1, 2011

FDA OHRP regulatory forum

Jerry Menikoff of OHRP & Jean Toth-Allen of FDA

FDA and OHRP both presented at a Regulatory Affairs Public Forum at the ACRP Global Conference on Sunday, May 1st.Speaking for FDA were Leslie Ball, MD, Director of the Division of Scientific Investigations (DSI) which initiates the majority of Bioresearch Monitoring inspections at FDA. Also from FDA was Jean Toth-Allen, PhD, Biophysicist, Office of Special Medical Programs. Jerry Menikoff, MD, JD, spoke on the panel as the Director of the US Office for Human Research Protection. The Association of Clinical Research Professionals hosted the forum in a setting more reminiscent of a TV game show than a professional panel that was complete with theme music and multi-colored columns highlighting the stage. However the questions posed were the ones on everyone’s minds and the speakers gave some good answers.

Please note that the Plenary Session on the Regulatory Affairs Public Forum was recorded and is available on the ACRP website for free.

One question brought up the issue of sponsor oversight of outsourced clinical trial responsibilities. Toth-Allen said that the sponsor is ultimately responsible for all of the clinical trial responsibilities and only CROs are specifically mentioned in the regulations. She emphasized the need to have SOPs in place covering how they are going to oversee contracts of vendors and what the contracts should cover. Leslie Ball said that DSI had an increased focus on sponsor and CRO inspections.

Dr. Ball said that she thinks sponsors should look at three qualities when selecting vendors:

1. The overall capability of the organization and staff.

2. That contracts clearly point out who is responsible for specific responsibilities.

3. That the sponsor oversees the vendor’s activities while the trial is ongoing.

OHRP FDA regulatory forum in Seattle

When Does FDA Inspect?

Another area of interest was when and where FDA would inspect. Both Leslie Ball and Jean Toth-Allen said that FDA was focusing more on inspections during the actual conduct of the study and not just when a sponsor makes an application to the agency.

Dr. Ball said that with the shift to more sponsor/CRO inspections that FDA inspections were looking at sponsor oversight of ongoing trials. She also said that DSI was developing a risk-based site selection tool that looked at three different levels. First, at the application level, did the application pose certain risks that FDA needed to consider. Then at the trial level, tending to focus on pivotal trials. Then at the site level, were there complaints or a history of non-compliance. She also said that they were looking at data from the application such as the rate of subjects dropping out or very high or very low rates of adverse events.

FDA OHRP regulatory forum

Dr. Leslie Ball, FDA

Dr. Ball also emphasized that FDA looked at what they considered important, specifically data integrity for primary efficacy endpoints or key safety indicators, and oversight by the sponsor. She noted that many things that are routinely listed on a Form FDA 483, Inspectional Observations, such as study drug accountability sometimes didn’t find their way to a Warning Letter that focused on items of significance to the approval of the application.

Another interesting discussion was on the topic of online informed consent forms, which are beginning to appear. Jerry Menikoff said it depended on the nature of the study when an online consent might be appropriate. Jean Toth-Allen spoke of the need for a verification process, that the online consent was given by a real person.

FDA regulatory forum Seattle

Discussion on Electronic Medical Records in
Clinical Trials

Finally the panel discussed electronic medical records (EMRs). All three panelists supported the use of EMRs. Toth-Allen said that if an EMR is used in a clinical trial then the institution needs to provide access to verify the record, that it was not acceptable to for monitors to be told that you can’t see it, which elicited a hearty round of applause from the many monitors in attendance. Dr. Ball noted that there were a lot of advantages to EMRS. “You can actually read them,” she said. She also emphasized that EMRs should have the same criteria for clinical trials, that they should be ALCOA– Attributable, Legible, Contemporaneous, Original and Accurate. She also said that although they may not need to be Part 11 compliant, they did need to have an audit trail so that all changes to the record could be traced.

To view the Regulatory Forum visit the
ACRP Website on the Plenary Sessions


On the Blogroll: RegBlog on all things regulatory from the University of Pennsylvania Law School. Covers much more than FDA


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On The Blogroll: Applied Clinical Trials Blog discusses,
“It Takes a Village: Recruiting Latino and Hispanic Patients.”

ACRP Meets in Seattle for 2011 Global Conference

April 29, 2011

ACRP Seattle

ACRP Meets in Seattle for 2011 Global Conference

Seattle, WA plays host to the Association of Clinical Research Professionals’ (ACRP) annual Global Conference. ACRP is one of the larger professional organizations focusing on clinical trials and expects 2,000 participants. It will be the first time I have attended their Global Conference and I am looking forward to it. There will be sessions on “Introduction to Imaging in Clinical Trials” and on “Distance-Based Learning for Foreign Study Coordinators.” GxP Perspectives will be there for the entire conference (the pre-conference workshops have already begun) and among the sessions I look forward to is “Comparative Effectiveness Trials.” I am going to try to blog at least twice during the conference on issues I think are of concern to GxP Perspectives readers. If I am super industrious maybe I will blog from the ACRP Global Conference every day.

Here is a new feature that ACRP is offering:ACRP is pleased to announce that for the first time ever, two live-feed Plenary Sessions from the ACRP Global Conference & Exhibition will be broadcast FREE of charge. Join us May 1 for the Regulatory Affairs Public Forum featuring representatives from global regulatory agencies addressing issues facing clinical trials. Join us May 2 for Innovation & Global Health, a discussion by Tachi Yamada, MD, President, Global Health Program, Bill and Melinda Gates Foundation.

For more information visit the ACRP Website on the Plenary Sessions

ACRP clinical trials

Do You Have a Guest Commentary for
GxP Perspectives?

Another highlight will be the May 1st session on “Your Site Doesn’t Need 60 SOPs, But How Many Does It Need?” The speakers are Christine Pierre, RN and Steven Steinbreuck, MPH and the author of a Guest Commentary on GxP Perspectives on Informed Consent Requirements. Remember, I am always looking for a good Guest Commentary. Send me a note and ask me how-

Leave a Comment to Submit a Guest Commentary!

On the Blogroll: Top 40 Websites (and Tweeters) on the FDA, by FDAZilla (Yes, we made the list.)

Moriah Consultant’s Blog – Commentary by Michael Hamrell, one of the conference speakers

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Conferences: Pharma/Bio Boot Camp on the eTMF on 20-21 May 2011 in Philadelphia

Medical Research & Drug Prices: One Patient’s Perspective

March 26, 2011

a patient perspective on medical research

Medical Research:
A Patient Perspective

Do patients always benefit from clinical trials and medical research? Are patients consumers? There is an assumption that medical research automatically correlates into improved outcomes for patients, particularly those with chronic medical conditions, such as diabetes, or with life-threatening conditions, such as many forms of cancer. However, their are different viewpoints. After the recent anger over drug price hikes for pregnancy and MS drugs GxP Perspectives requested a Guest Commentary by Marc Stecker, who has multiple sclerosis, and is the author of the blog, Wheelchair Kamikaze: “The Rants, Ruminations, and Reflections of a Mad MS Patient.” He is also an outstanding photographer and his photo, “rail-shadow” is featured above left. Because Marc’s commentary is different than most on this blog I am going to start with his concluding comment. I think it will help put things into perspective:

“I’ll let my final words on the subject be these: As responsible members of a just and honorable society, please, view me first as a patient, not as a consumer. Human suffering should never be treated as a commodity, regardless of the considerable economic incentives to do so.”

There will be differing reactions to the viewpoints expressed in Marc’s Guest Commentary. Please feel free to comment with your own views.

Guest Commentary

A Patient Perspective on the Mechanics of Medical Research
by Marc Stecker

Although there have been some incredible advances made in our efforts to heal sick humans over the last 50 years, there are still vast swathes of patient populations whose illnesses remain poorly understood, insufficiently and ineffectively treated, and ultimately incurable. Problematically, many of these patient populations generate billions and billions of dollars for the modern medical hierarchy, a situation that sets up a paradox within our profit driven medical establishment. Cure these patients, and vast sums of money and an elaborate infrastructure would simply evaporate; keep them perpetually reliant on hyper expensive medicines and medical procedures, and reap the fruits of an unending money machine.

Before I am accused of being a conspiracy nut, let me state outright that I do not believe that there is a cabal of evil, mustache twisting, demonic connivers assembled around a huge flaming conference table, snacking on deep-fried baby’s arms while plotting to keep cures and remedies hidden and out of reach from the desperately ill. If this were the case, the solution would be fairly straightforward; simply “out” the conspirators, and the walls come tumbling down. Rather, the problem has become incorporated into the system itself, insidious and inherent, the logical outcome of the evolution of a medical industrial establishment that has come to view sick people as consumers and horrendous illnesses as opportunities for tremendous financial gain. This system does not require people with malicious intent to keep it functioning; it only needs decent people doing their appointed jobs to the best of their abilities to keep the gears turning.

The job of a publicly traded pharmaceutical company CEO is to constantly drive up the price of his company’s stock, not to facilitate the creation of drugs that would be of the most benefit to the patients taking them. This isn’t a question of morality, but of economics. The drug companies, and those who manage them, are merely doing what every other business endeavors to do in our free-market capitalist system, constantly increase profit. I’m all for free-market capitalism; in recorded history there has been no better economic driver and creator of wealth. Unfortunately, when applied to healthcare, in many cases good economics has led to very bad medicine.

medical research patient perspectiveGiven that the mission of pharmaceutical companies is to generate the most bang for their research bucks, their research dollars are directed to projects that have the best possibility of leading to substantial profit. This, in turn, influences the behavior of even the most well-meaning medical researchers, who, just like everybody else, need to feed their families, pay their bills, and naturally seek to advance their careers. Thus, they are drawn to investigations that will most likely win hotly contested research dollars. That funding, the vast majority of which comes from the big pharmaceutical companies, goes almost exclusively into researching novel compounds that can be patented and remain the sole property of the company that discovers them for many profitable years.

I’ll let my final words on the subject be these: As responsible members of a just and honorable society, please, view me first as a patient, not as a consumer. Human suffering should never be treated as a commodity, regardless of the considerable economic incentives to do so.


Please see Marc’s Blog, Wheelchair Kamikaze where you can read more of his viewpoints and see his photographs .and videos. Here is one of his videos which is quite funny.

The Wheelchair Kamikaze in Central Park

Read the blog FDA Matters, on Drug Pricing

Time Magazine on Drug Price Anger

31 March 2011: MedPage Today: FDA allows compounding of pre-labor drug

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Foreign Clinical Trials: Cause for Concern?

June 25, 2010

Foreign clinical trials

What are the Concerns for Foreign Clinical Trials?

Are there ethical or data integrity concerns for foreign clinical trials used for FDA drug approvals? Are the research standards as high as in the United States? What are the challenges facing developing countries in conducting clinical trials? Two recent reports discuss the issue. One report is by the Inspector General of the U.S. Department of Health and Human Services on “Challenges to FDA’s Ability to Monitor and Inspect Foreign Clinical Trials.” It was reported on in an article by Gardiner Harris of the New York Times. The report noted that FDA isn’t able to conduct foreign inspections at the same level as at domestic clinical trial sites and that trials were dramatically increasing in places such as Latin America that lack strong regulatory oversight. The report recommends “FDA should continue to explore ways to expand its oversight of foreign clinical trials.”


MRCT Project

The second report I learned about when I attended a session at the recent meeting of the Drug Information Association (DIA). The session discussed the challenges of international clinical research, particularly in developing countries. In a report of the Multi-Region Clinical Trials (MRCT) project, problems were discussed and practical recommendations suggested for improving the quality of clinical trials in resource-deprived countries.

I was impressed with the panelists who presented to DIA on the MRCT project. The focus was on how clinical trials could be conducted in developing countries with resource challenges. How could the rights, safety, and welfare of research participants be protected? The session was chaired by Mildred Solomon, EdD, Associate Clinical Professor of Medical Ethics at the Harvard Medical School. She discussed the formation of the MRCT project and the report that resulted. Other panelists included Allan Johansen, DVM, Susan D’Amico, and Janet Wittes, PhD. According to the report the MRCT project was:

“Initiated by Pfizer, the Multi-Regional Clinical Trial (“MRCT”) Project began with a Summit Meeting in July 2009 to identify ways to enhance the planning and conduct of multi-regional trials and the integrity of these trials. The Project has involved experts from large and small companies, clinical research organizations (CROs), non-industry sponsors of research (such as participants from the National Institutes of Health), non-industry researchers and bioethicists, and others. The discussions have focused on opportunities to enhance research ethics, ensure respect for study subjects, strengthen fairness and equity in clinical trials, protect subject safety, and identify other opportunities to improve MRCTs involving the developing world.”

The project formed work groups to cover five areas:

1. Efficiency and quality of ethical review
2. Data & safety monitoring
3. Site selection and investigator
4. Monitor performance
5. Transparent contract amendments

Foreign clinical trials

Five Workgroups Formed the MRCT Project

The report discusses the problems in each area and offers some solutions. For example, work group one proposed to “Include an ethics section accompanying each/certain protocols (to help ethics committee review the proposal, as needed).” Work group 4, which focused on monitor performance, proposed to: “Establish a comprehensive set of recognized and expanded core competencies for monitors.”

The report concluded by noting:

“This Report has focused on outcomes that sponsors and CROs have the ability to impact and, thereby, improve research ethics and data integrity in their own operations or through collaboration. Since there is already broad acceptance of foundational ethical principles, the next important step is to ensure operational alignment with those principles.

Predominantly, the MRCT Work Group proposals focus on achieving that alignment through greater professional competence of the many players who must contribute to the global research enterprise. Professionalism is essential to the ethical conduct of clinical research. Just as scientifically unsound research is unethical, so too is research conducted in a manner that cannot ensure the integrity of the science, the quality of the data, and respect for and safety of research participants. Assuring all individuals engaged in research are properly qualified through education and experience is a theme throughout this Report.”

The report also noted that developed countries and the pharmaceutical industry need to assist with resources to achieve this goal. This is certainly an important point. However, the devil is always with the details. Finding a way to finance improvements may prove difficult.

Read the MRCT Report

My own viewpoint is that we should stop referring to “foreign” clinical trials. Clinical research is globalized and we need a strong international component. Not all of the answers are in the United States and we would do well to listen to those from outside our borders, particularly those from the developing world. To me, referring to clinical trials from outside the U.S. as “foreign” infers that they are inferior to trials conducted in the U.S. I don’t think that is always the case. Why don’t we call them “international” or even “multi-regional” trials instead? If we view international research as something that is a shared responsibility then perhaps there would be less concern over “foreign” clinical trials.


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Analysis of Recent FDA Warning Letters to IRBs

January 12, 2010

A clear pattern is emerging from the recent spate of IRB Warning Letters written by FDA. It appears that IRB registration is working. The Food & Drug Administration is learning just who is approving research in the U.S.

IRB FDA warning letter
The addition to the FDA IRB regulations, 21 CFR Part 56.106(a), requires Institutional Review Boards (IRBs) reviewing FDA research to register with FDA. It is an excellent addition to the regulations and is already paying dividends to improve clinical trials. (FDA could update a few more regulations but that’s a different story.) Formerly, FDA would only find out about an IRB’s existence if there was an application for a product approval that listed the IRB or if there was a complaint.

Here is a link to the FDA guidance document for Frequently Asked Questions regarding IRB registration:

The ruling went into effect on 14 July 2009 and came on the heels of the Coast IRB sting where the GAO submitted a fake clinical trial that was unwittingly approved by the now defunct Coast. Since that time some very serious Warning Letters have been written citing some very serious violations of regulations designed to protect human participants in clinical trials. At least two IRBs, the Teneo IRB and the MI Hope Inc. DBA Center for Complex Infectious Disease IRB have been told to stop approving studies and to stop enrolling new subjects in existing studies until FDA approves corrective actions. Is there something seriously wrong with IRBs in this country? Reading the Teneo and MI Hope Warning Letters could lead you to think so. Take a look at MI Hope:

UPDATE: Unfortunately FDA doesn’t appear to keep links to Warning Letters active. The ones inserted into this post no longer work. Thanks FDA. You can find the Warning Letters by going to the FDA Warning Letter Page and searching by company.

And now Teneo IRB:

Although both these Warning Letters are pretty bad I think that they should have been expected. Previously, FDA did not have the authority to require IRBs to register. Although the work of running a good IRB is quite difficult it amazingly easy to start an “IRB.” It takes five people, one of whom is a scientist (they are not required to be a physician), one a non-scientist, and one not affiliated with the institution. Then you toss in some administrative stuff such as a few written procedures and you’re set to go. As a result, organizations such as MI Hope and Burzynski Research Institute could start their own IRBs free from FDA oversight and with serious potential for conflicts of interest. Now that FDA has a list of these IRBs they are conducting inspections and finding a few bad actors. The same thing happened when FDA started inspecting seafood processors and home respiratory care facilities. The first time FDA comes in to conduct inspections, there frequently are problems. FDA isn’t writing Warning Letters to the many established, legitimate IRBs that have been inspected several times in the past


Established institutions, such as the Mayo Clinic, have a long history of IRB regulation

When I was at FDA I inspected over 30 IRBs and found that most IRB members were dedicated, hard working research professionals. Most IRB board members are volunteers, serving for no pay or a small stipend. Few people are getting rich at IRBs. Their purpose is to provide independent review of research to protect clinical trial participants. IRBs are a very good thing. Problems sometimes occur when IRBs become confused between FDA regulations and regulations enforced by the Office of Human Research Protections (OHRP). That is what apparently happened recently when a Warning Letter was written to Florida Atlantic University. They are a small academic IRB that reviews very few protocols under FDA jurisdiction. They are significantly different from Teneo, Burzynski, or MI Hope. Take a look for yourself:

As a result, there is a tendency to heap additional responsibilities onto IRBs. Some in Congress are tempted to do this and some “consumer advocates” are as well. This can lead to a stifling effect on innovative research. One principal investigator I know who conducts non-FDA regulated research, primarily through surveys or questionnaires, described IRBs as the “bane of my existence” because of the overly burdensome administrative procedures. These administrative procedures are frequently enacted because OHRP found problems in the past at some academic research institutions. The American Enterprise Institute, a very conservative policy organization, raised some interesting points last year in an opinion peace published in the NY Times (below). We should give FDA the time to wend their way through the list of newly registered IRBs and not have knee-jerk reactions to the initial results. There will be more Warning Letters in the immediate future but that should just weed out the bad actors. Most IRBs have already been inspected by FDA and are doing their work. We need to make their work easier, not more difficult.

Here is a link to the American Enterprise Institute’s op/ed piece:

The bottom line is we need legitimate IRBs to independently review clinical research in the United States. We also need to understand that we need research vitality. We should resist the impulse to impose too many restrictions on IRBs.

Read about other FDA Warning Letters:
UPDATE: Here is a more recent Warning Letter to an IRB in April 2010. This one appears to be to a smaller IRB that missed a few things. It is different from the ones cited in the story above. Maybe this analysis will need further updating.
This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)
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