PART III: The FDA Speaks on IRB Responsibilities

 

In Part I of this series, we note that some IRBs (Institutional Review Boards) require all investigators, without exception, to submit an Investigational New Drug (IND) application to the FDA. These IRBs claim that this policy will protect the research institution by shifting liability to the FDA in the decision-making process.

 

Even though IRBs are required to make an independent assessment of the risks and potential benefits of a planned clinical study pursuant to 21 CFR §56.111 (Criteria for IRB Approval of Research), IRBs and investigators should be aware that the FDA is apparently more than willing to look the other way, ignore the regulations, and allow IRBs to engage in this questionable practice.

   

An IRB must approve a clinical investigation if all the requirements listed in 21 CFR §56.111 of the FDA regulations are satisfied.  21 CFR §56.111(a)(1) and (2) deal with risk:

(1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies that subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.

Assessing whether a study is exempt from an IND application requires the same assessment of risk and benefit. The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from an IND application with the FDA if all five criteria set forth in 21 CFR §312.2(b)(1) are met:

 

(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;

(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;

(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;

(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and

(v) The investigation is conducted in compliance with the requirements of §312.7. [Dealing with promotion and charging for investigational drugs].

 

Requirements i, ii, iv, and v, relate to administrative requirements that must be met in order to conduct the study, and are not protocol related.  Only criterion iii, related to risks, is protocol-specific. Therefore, only criterion iii is applicable to determining the IND exemption for studies initiated by an investigator.

 

The FDA’s Office of Medical Policy recognizes an IRB’s obligation under 21 CFR §56.111 of the FDA regulations to make an independent assessment of the acceptability of risks and potential benefits when evaluating a planned clinical study. 

 

Reference:

Joe Griffin

Office of Medical Policy

FDA

June 4, 2007

 

 

Some IRBs, in evaluating the risk presented by a proposed study as set forth in 21 CFR §56.111(a)(1) and (2), determine the criteria have been met, yet still require every investigator to submit an IND application to the FDA for the sole stated purpose of forcing the FDA to be the decision-maker, and shifting liability away from the IRB for all studies.  Having already determined a minimal, reasonable and therefore acceptable risk to subjects in the course of approving a study under 21 CFR §56.111(a)(1) and (2) of the FDA regulations for a drug lawfully marketed in the United States, there is no alternative but for the IRB  to apply the same reasoning and conclude an IND exemption under 21 CFR §312.2(b)(1), criterion iii,  is appropriate. 

Criterion iii provides for an IND exemption if the investigation does not significantly increase the risks "(or decreases the acceptability of the risks)" associated with the use of the drug product.  This can only mean that the risk is determined to be minimal and reasonable in relation to anticipated benefits – the exact same risk/benefit analysis required to be performed by an IRB pursuant to 21 CFR §56.111(a)(1) and (2). Therefore, the FDA acknowledges that there may be increased risk to human subjects in studies involving marketed drugs and yet the study will be exempt from an IND application. For example, such a study might be a patient population where there is a life-threatening disorder and there is no effective therapy. Under these circumstances, the increase risk created by the study drug is reasonable in relation to anticipated benefits. Under both the IRB regulation and IND exemption regulation, it remains the investigator’s responsibility to use starting doses that appear safe based on approved labeling or detailed literature reports, use incremental changes in dose or schedule, and carefully evaluate toxicity prior to dose escalation.

 

Nonetheless, the FDA maintains that an IRB is not violating regulations when the IRB has a policy requiring all investigators to file an IND application, for the sole purpose of shifting liability to the FDA by forcing the FDA to perform the same risk/benefit analysis required of the IRB while the FDA determines if an IND exemption is applicable.

 

 

Reference:

Joe Griffin

Office of Medical Policy

FDA

June 4, 2007

 

 

It would therefore appear that the FDA is not likely to take enforcement action against an IRB that deliberately avoids its regulatory obligation to make an independent assessment of the acceptability of the risks and potential benefits of a planned clinical study by requiring every investigator to submit an IND application to the FDA, even when the IRB’s expressed intention is to shift liability to the FDA by doing so.

According to the FDA, it is not a violation of their regulations even if an IRB determines that a study meets all the criteria set forth in 21 CFR §56.111, including assessment of risk for a lawfully marketed drug in the United States, and then requires as a condition of IRB approval in every case that comes before it that the investigator must submit an IND application so the FDA can also decide if the risks are acceptable pursuant to the IND exemption criteria of 21 CFR §312.2(b)(1).  This policy of the FDA is an invitation to IRBs to deluge the FDA with unnecessary work.

 

Prior to publishing this Part III of the series, on June 28, 2007 the International Research Foundation for RSD / CRPS furnished the FDA Office of Medical Policy a copy, and requested, “If our findings in Part III do not accurately reflect the position of the FDA’s Office of Medical Policy, please let us know no later than July 5, 2007."  On July 2, 2007 the FDA responded, “We do not agree that the information provided you by the FDA supports all the conclusions in your 'findings'.”  On July 2, 2007 the International Research Foundation for RSD / CRPS  made the following request to the FDA:

 

 

"As we have advised the FDA, our goal is to provide accurate information for the use of investigators and IRBs.  We have no interest in publishing erroneous information.  Please identify the conclusions which the FDA does not agree are supported by the information provided by the FDA, so that we may revise or delete them as appropriate in order to assure accuracy."

 

On July 2, 2007, the FDA informed the Foundation it would not identify conclusions in this report that it believes are not accurate. The FDA stated, "We have put a lot of thought into our responses to you and feel that our explanations were pretty clear.  We think that if you publish our responses in their entirety, the information will be kept in context."

 

The FDA has lost sight of the stated purpose of the Foundation’s initial inquiry, to provide guidance to IRBs and investigators.  When the Foundation pointed out in its original correspondence to the FDA what appeared to be contradictory information published by the FDA and asked for clarification, the agency responded.  Now that the Foundation has summarized in this Part III the information it received from the FDA, the FDA claims our conclusions are not supported by the information the FDA provided, and at the same time refuses to identify what it believes has been misstated.  FDA’s non-response to a simple request that it identify conclusions in the final report which do not accurately reflect information provided to the Foundation by the FDA will only serve to perpetuate an image of the FDA as a bureaucracy that will not stand accountable before the public.    

A key consideration for investigators and IRBs, which the Foundation has attempted to clarify in this report, will apparently remain unanswered by the FDA.  The FDA has stated that IRBs independently assess acceptability of risks and potential benefits when evaluating a given study in accordance with FDA regulations.  The FDA has also stated that there is no FDA regulation that expressly instructs an IRB to require an investigator to file an IND with the FDA.  The Foundation has therefore concluded, and stated in our report:

 

 

"It would therefore appear that the FDA is not likely to take enforcement action against an IRB that deliberately avoids its regulatory obligation to make an independent assessment of the acceptability of the risks and potential benefits of a planned clinical study by requiring every investigator to submit an IND application to the FDA, even when the IRB’s expressed intention is to shift liability to the FDA by doing so."

 

This is key to understanding the FDA's position that IRBs must "independently" assess risk / benefit in approving a study pursuant to FDA regulation 21 CFR §56.111(a)(1) and (2). The FDA’s refusal to identify the conclusions in this report with which it disagrees leaves unanswered a question which we have attempted to answer based on all the information provided by the FDA:  Whether IRBs may delegate to the FDA the required independent assessment of risk / benefit for all studies involving legally marketed drugs in the United States as a condition for final IRB approval of a clinical study.

The Foundation will continue to explore all available means to obtain an answer from the Office of Medical Policy. We are providing copies of all correspondence between the FDA and the Foundation used to develop this report at the following site:

 

 

FDA Correspondence

 

 

 

Timothy Lubenow, MD

Vice President

Anthony Kirkpatrick, MD, PhD.

Chairman, Scientific Advisory Committee

Jerry H. Trachtman, ESQ

General Counsel