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An MD&DI April 1998 Column

CLINICAL TRIALS

In some cases, an FDA exception regulation offers patients access to investigational devices without giving prior consent.

In the past it has been difficult or nearly impossible for medical device manufacturers to conduct clinical research in critical care and emergency medicine in the United States. Regulations permitted clinical research when the research subject, or the subject's legal guardian, was able to understand the nature of the clinical research and give informed consent prior to exposure to the investigational product. While this system worked well in situations where participation in the clinical research study was planned in advance, challenges arose when patients experienced unanticipated, life-threatening situations where rapid medical intervention was required, such as in the treatment of trauma, stroke, and heart disease. FDA, physicians, patient advocacy groups, and manufacturers recognized that the informed consent regulations in effect at the time prevented many types of emergency medicine clinical research.

To circumvent some of the obstacles presented by these regulations, some institutional review boards (IRBs) approved studies where "deferred consent" was obtained from patients after the test article was administered. By 1993, FDA had become aware of this practice and expressed concern. Discussions over the next two years resulted in the September 21, 1995, Federal Register notice (60 FR:49085—49103) that proposed granting an exception to obtaining prior consent in certain circumstances. The "Protection of Human Subjects; Informed Consent" regulation (61 FR:51497—51531) became effective in October 1996. It permits, under strict controls, the use of investigational products in emergency situations without prior informed consent.

The regulation applies only to research involving patients needing emergency medical intervention who cannot give informed consent due to a life-threatening medical condition and who do not have a legally authorized person to represent them during the time in which treatment must be initiated. This regulation cannot be used as a convenience for research sponsors or study personnel in a study of a non-life-threatening condition.

To take advantage of this exception to prior informed consent, research sponsors must submit the study protocol and related materials to FDA as components of a separate investigational device exemption (IDE), even if an IDE has already been submitted for previous, more-conventional studies. This requirement allows FDA to prevent a trial from beginning, pending resolution of any issues that may become apparent during the review process. State and local regulations are not preempted by this regulation; in some cases, local regulations will continue to prohibit clinical research without prior informed consent. Sponsors must check with research sites to determine if any local regulations apply.

SPONSOR AND IRB RESPONSIBILITIES

Unfortunately, finding a research site with detailed standard operating procedures (SOPs) in place for IRB oversight of such studies may be a challenge. Most patients affected by the 1996 regulation participate in research conducted in conjunction with universities and teaching hospitals. While experimental treatments may be initiated outside the hospital setting, nearly all of these patients are eventually transported to hospital emergency rooms. As a result, the major U.S. commercial or central IRBs have little experience with the new regulation.

Research sponsors also need to consider the clinical capabilities of the professionals who serve on the particular IRB. In addition to reviewing the study as it progresses, the board also must determine whether the study protocol meets FDA requirements for a without-prior-consent trial. At the least, the IRB must include a licensed physician unaffiliated with the research under review, as well as other professionals who can determine and ensure that all of the following are true:

Finally, IRBs must communicate with the community at large and consult, when appropriate, with individual members of the community where the research is performed. IRBs have wide latitude in determining the extent of consultations, but the community as a whole must be informed of the study, including its risks and benefits, before it is begun and informed of the study results once it has been completed. Expenses for community consultants and meetings are commonly paid by the research sponsor.

In addition to reviewing the IRB's efforts in the above areas, the research sponsor must establish an independent data monitoring committee to oversee the clinical investigation. Members of this committee must not be affiliated with the study in any other way. FDA expects members to be physicians, biostatisticians, and bioethicists. The committee should receive data throughout the course of the study, as specified in the study protocol, to ensure that the study protocol "remains appropriate on both safety and scientific grounds." If the study fails to do so, the committee must recommend to the sponsor that it be modified or stopped.

PRACTICALITIES

Many of the requirements included in this regulation are new and present challenges to all of the professionals involved in conducting the study. For example, documenting the search for the next of kin prior to administering the test article may not always be compatible with the workflow of a busy emergency medicine department. Interactions with the community at large, while an important part of the process, require disclosure of information that would be considered proprietary for most other studies. Other interactions with the community, such as open meetings and media relations, require personnel from both the research sponsor and the clinical researcher's office to develop skills that will enable them to function effectively in these new settings.

This time line represents a hypothetical study. Specifics such as the indication for use of the investigational device, the study design, composition of the target study population, and local variations in institutional review board (IRB) procedures will significantly influence the timing of most of these items. N = the duration of the study.

Research sponsors should be aware that IRBs have different approaches to this regulation, and these differences will significantly affect review times and costs. IRB review and approval times may extend from six months to one year, with community outreach and evaluation consuming most of that time. No consensus exists between IRBs and FDA regarding what constitutes adequate community outreach. Some IRBs convene a panel of community representatives and discuss the study with them; some conduct newspaper and local television interviews. Other IRBs perform extensive community interaction, with representatives speaking with two or three local groups every month.

Some FDA staffers have suggested that some institutions need to expand their outreach efforts. With a relatively small base of experience, and the variable nature of communities and of the research, it is difficult for IRBs, clinical researchers, and research sponsors to determine the appropriate level of consultation. FDA is currently preparing an information sheet—expected to be available this summer—that will provide additional guidance for all parties involved in this process.

CONCLUSION

A larger number of medical device manufacturers are becoming involved with clinical research since clinical research data are becoming a more common component of 510(k)s. FDA continues to add new regulations and modify existing ones. Medical device manufacturers who sponsor clinical research should continue to track shifts in the regulatory landscape to take advantage of any changes that can help make conducting clinical research less of a trial.

Barry Sall is a senior regulatory consultant in worldwide regulatory affairs services at Parexel International (Waltham, MA).

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