<FDA Policy Results In Exporting Pain Studies Overseas>

The International Research Foundation for RSD / CRPS has received complaints from investigators about the way the FDA and Institutional Review Boards handle the

The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from an Investigational New Drug (IND) Application with the FDA if all the following criteria apply, as set forth in 21 CFR §312.2(b):

Requirements 1, 2, 4, and 5, relate to administrative requirements that must be met in order to conduct the study but, requirement 3 is specifically related to safety and has important meaning with regard to minimizing risk to research subjects, particularly with respect to doses above the labeled dose, use with other treatments, and use in different populations. Therefore, requirement 3 is an important criterion for clinical investigators to consider in designing a research study.

This Special Report focuses on criterion 3 and how the FDA can make a decision without applying any published standards which results in a decision that can be considered arbitrary. The FDA itself has recognized that arbitrary decision-making can lead to the appearance of unfairness or retaliation. In a memo to all FDA employees, the Commissioner of Food and Drugs wrote: "... all FDA employees must make every effort to avoid even the appearance of unfairness or retaliatory action. . . . questions can be, and have been, raised about the fairness of agency proceedings and retaliatory actions against companies who challenge or criticize the agency."

If the FDA fails to properly grant a qualified application for IND exemption and requires the investigator to file an IND, the consequences can be onerous for the investigator both before and after the study begins. Filing an IND involves an enormous amount of paper work, time and expense. Some investigators hire experts who specialize in IND submissions to complete the task while others may be forced to abandon an important study.

The issue is further complicated when some IRBs (Institutional Review Boards) act contrary to FDA regulations (see 21 CFR §56.111, “Criteria for IRB Approval of Research”) by requiring investigators, without exception, to file an application for IND exemption with the FDA. Some IRBs claim that this policy will protect the research facility from a law suit by shifting liability from the research facility to the FDA in the decision-making process. When this happens, it is an example of the IRB failing to recognize that the FDA considers the investigator to be the one best qualified to determine the exemption. “The FDA recognizes that a considerable amount of professional judgment must be exercised in determining whether the conditions of an investigation ‘significantly increase’ the risk associated with use of the drug. Because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of medicine, the individual investigator should usually be able to determine the applicability of the exemption.” 52 FR 8802, March 19, 1987.

A broader view of risk management suggests that this tactic of shifting liability to the FDA might actually increase liability. Assume that an investigator submits a research proposal to an IRB that provides the research subject with the only hope for a potentially life-saving treatment. Assume the IRB then violates an FDA policy, such as requiring all investigators to submit an application for an IND exemption, thus forcing the investigator with a legitimate IND exemption into the time consuming process of filing for an IND exemption, or perhaps even abandoning the study. Assume, as a result of that violation, the research subject, having no other alternative, is forced to go outside the United States to receive the same investigational treatment, and suffers an adverse event. If the research subject files a lawsuit against the IRB, we might never know if such a case would succeed, but it certainly would not make for good public relations.

The human consequence of improper FDA action can be devastating. For example, if the patient elected not to go outside the US, but instead chose to wait for the IND exemption and it was improperly rejected by the FDA, the consequences could be catastrophic. It would not be surprising under this circumstance if the patient gave up all hope and committed suicide. Suicide is not an uncommon consequence of RSD / CRPS.

The International Research Foundation for RSD / CRPS has received complaints from investigators about the way the FDA and IRBs handle the IND exemption issue. On September 6, 2006, the Foundation wrote a letter to the FDA Office of Drug Evaluation, stating:

The Foundation requested that the FDA clarify its criteria for IND exemptions for the benefit of both investigators and IRBs. On October 10, 2006, the Foundation received the following response from FDA :

“At this time, we do not have any written guidance on standards or criteria for exempting an investigational study from the requirements for an IND other than what is found in our implementing regulations at 21 CFR 312.2(b). Questions from investigators about a particular study are referred to the review division with the clinical expertise pertinent to the indication to be studied. The reviewing medical officer reviews the study and applies the criteria in the regulation.”

The Foundation’s letter requesting clarification of IND exemption criteria was also sent to the Office of Medical Policy at the FDA. The Foundation was told by the FDA Office of Drug Evaluation that the Office of Medical Policy is the FDA's "expert" on the IND exemption policy.Their response was different from that of the Office of Drug Evaluation. The Office of Medical Policy informed the Foundation that while it does not have “generalized guidelines” for determining when an IND is needed, including when an IND is or is not needed for a clinical investigation of a marketed drug, it is “currently developing that guidance.” The FDA Office of Medical Policy further stated that, “Yes we do have guidance to assist manufacturers and investigators in determining whether an IND is needed for a study of a marketed cancer therapy. The analyses and examples in that guidance concerning whether risk is significantly increased provide some insight into how FDA thinks about this issue generally and thus may be relevant to studies of marketed drugs in other therapeutic areas. At present, this guidance is likely the most useful information available from FDA on this issue.” (emphasis added)

On October 13, 2006, the Foundation informed the FDA Office of Drug Evaluation that in creating research protocols, investigators may use as guidance the FDA criteria promulgated by the Office of Medical Policy to meet the requirements for an IND exemption. The FDA Office of Drug Evaluation was also informed that drugs for CRPS patients are sometimes used under clinical circumstances similar to that found with cancer patients; like some cancer patients, CRPS patients sometimes fail all reasonable treatment options; and that this medical condition can have potentially life-threatening consequences (i.e., suicide).

Contrary to the assertion by the FDA Office of Medical Policy that its guidelines published for cancer studies are “the most useful information available from FDA” on the issue of IND exemption for all drugs, the FDA Office of Drug Evaluation advised the Foundation that the FDA guidelines published for cancer studies should be applied only to cancer drugs. In addition, the Office of Drug Evaluation advised the Foundation if the subjects in a study involving CRPS patients failed all reasonable treatment options that failure would NOT be a relevant factor in determining an IND exemption. This is contrary to the guidelines promulgated by the Office of Medical Policy.

The Foundation’s September 6, 2006, inquiry to the FDA was referred by the Office of Drug Evaluation to Bob Rappaport, MD, Director, Division of Anesthesia, Analgesia and Rheumatology Products, FDA Center for Drug Evaluation and Research. He also stated that the IND exemption criteria promulgated by the Office of Medical Policy should be applied only to cancer drugs. When asked what criteria he applies in reaching a decision about an IND exemption in the area of pain studies, Dr. Rappaport refused to consider the criteria published by the FDA Office of Medical Policy for cancer patients, even though the FDA considers this guidance to be the most useful information available from the FDA when deciding an IND exemption for all drugs.

The Chief, Project Management Staff, Division of Anesthesia, Analgesia and Rheumatology Products at FDA has been made aware of this apparent contradiction in policy within the FDA. It is the Foundation’s hope that useful guidance from the FDA on IND exemptions will result.

CONCLUSION: Investigators need to be aware that pain studies submitted for an IND exemption to the division of the FDA directed by Dr. Rappaport will not be evaluated pursuant to the exemption guidelines promulgated by the Office of Medical Policy. He has taken this position despite the fact that the Office of Medical Policy is designated by the FDA as the "expert" on the IND exemptions and despite that office stating that the guidelines are “the most useful information available from FDA” for all drugs when designing a study to minimize risk to research subjects. The actual criteria which will be applied to an application for IND exemption remains unstated by Dr. Rappaport's division at the FDA. We can probably expect more investigators to seek research centers overseas for their pain studies as long as the FDA fails to consistently apply a stated guidance for investigators and IRBs to follow when trying to determine if a study qualifies for an IND exemption.

[Editor’s note: It was suggested to Dr. Rappaport by the Foundation that perhaps the reason the Office of Medical Policy promulgates standards and criteria for IND exemptions is to avoid arbitrary and capricious decisions by the FDA on the IND exemption issue. He said it was "unprofessional" to make such a suggestion. ]

On October 29, 2006, the following persons at the FDA were invited to reply to this report and have their views published on this web site. As of November 20, 2006, we have not received a reply.