Spotlight On Compliance

The FDA launches guidance initiative

J. Mark Waxman, JD
Foley & Lardner

Mr. Waxman reports no financial relationships with companies related to the content in this CE/CME activity.

To keep IRBs informed on current FDA thinking, the agency has created the Good Guidance Practices (GGPs) program. This is a process whereby dated and obsolete guidance is replaced by new information sheets on a variety of topics, along with the opportunity to comment.

Recently, the FDA announced a series of new or updated guidance documents. It must be noted that these documents are not binding. They do, however, represent the FDA current thinking on the topics covered. What follows are comments on several of these guidance documents.

Waiver of IRB Requirements for Drug and Biological Product Studies. This guidance represents an updating of its September 1998 predecessor. It addresses a series of issues related to when IRB requirements may be waived by the FDA. While the FDA may waive any IRB requirement in specific cases or classes of research, it will do so only when "alternative mechanisms" for patient safety protection exist. Three important circumstances are discussed:

— For the conduct of a foreign clinical trial under an IND. Here, receipt of a waiver will require an independent ethics committee which operates in accordance with good clinical practices. The guidance notes that such waivers are not available for medical devices (under §520(g) of the FDCA)1 because IRB review is a statutory requirement;

— Emergencies requiring use of a test article, provided the necessary report is made within five working days following use, and subsequent cases are approved by an IRB; and

— Local IRB review may be waived when a centralized IRB process is used. (21 CFR § 56.114).

IRB Inspections. In another update of a 1998 guidance, the FDA addresses issues related to IRB Inspections. This guidance again provides an accessible guide to elements that might be reviewed by an internal audit or compliance process to prevent issues arising during the course of either a surveillance or directed (i.e., focused on a specific trial or group of trials) inspection.

IRBs should keep in mind that:

— Records of IRB membership, procedures and guidelines, meeting minutes and study documents will be copied; and

— The failure to meet operational requirements may result in significant sanctions, including study terminations.

Frequently Asked Questions (FAQs) About Medical Devices. This update of a 1998 guidance takes the reader through a broad series of questions regarding the relationship between the IRB and trials involving medical devices. Beginning with the definition of what is a medical device ("…instrument, apparatus … continuance … intended for use in the diagnosis…or in the cure, mitigation … or prevention of disease, in man or other animals…and which does not achieve its primary intended purpose through chemical action … and which is not dependent upon being metabolized…") through this classification system, and into the IRB responsibilities.

One interesting element of the discussion relates to humanitarian use devices — devices intended to benefit patients with conditions manifested in less than 4000 individuals in the United States per year. A humanitarian device exemption allows a request to be made that authorizes marketing of an HUD, without a full blown pre-market approval, provided the FDA is satisfied with the risk/benefit analysis. Once an HDE is granted, there are specific rules applicable to IRB processes, including that it may approve the use of the device "as it sees fit," for up to one year.

The guidance goes on to discuss the fact that given the HDE, use of the HUD does not constitute research or an investigation that would require informed consent from study subjects. The FDA does caution, however, about off-label uses, suggesting that approval from the FDA under its compassionate use policy be pursued.

Significant Risk and Non-significant Risk Medical Device Studies. The FAQ guidance discusses in general terms the Investigational Device Exemption (IDE) and the nature of those studies that may be exempt from the IDE regulation (21 CFR § 812) — a non-significant risk (NSR) device study. This guidance addresses, in some detail, the difference between the significant risk (SR) and NSR devices, and the different responsibilities the IRB has in each case.

While defining each, an important part of the guidance is its focus on the factors to consider, and the recommendation for the IRB to write its decision into its minutes. Those factors are:

— The basis for the risk determinations;

— The nature of the potential resulting harm; and

— Will the subject need to undergo an additional procedure as part of the study.

The guidance documents do not raise new or controversial issues. The guidance they provide is both accessible and of real educational value for IRB Board members, PIs, research staff and administration.

Inspections of clinical investigators. This is another update of 1998 guidance and seeks to address inspections under the FDA’s Bioresearch Monitoring Program (BIMO). An investigator will seek to verify:

— Who actually implemented the various steps in the protocol, from obtaining informed consent to collecting adverse event data;

— Where specific aspects of the investigation were performed; and

— The activities of the monitor; from communications to evaluations of progress.

A warning is also worth noting: inspectors may review medical records of participation subjects to verify the diagnosis and ensure eligibility criteria were met prior to enrollment, as well as to ascertain whether post-operative or implant care and monitoring called for was actually provided.


  1. The Food, Drug and Cosmetic Act ("FDCA") citation is 21 U.S.C. § 360; (g)(3)(A).