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


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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:

Click to access UCM171256.pdf

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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