Ethics, Kids, and Sex

As the debate on clinical research policy continues, FDA is setting standards for pediatric studies and encouraging more sex-specific analysis of clinical data.

After more than five years of deliberations, the National Bioethics Advisory Commission issued final recommendations in May for ethical research involving human subjectsEthical and Policy Issues in Research Involving Human Participantsto be available at www.bioethics.gov this summer. The commission aims to ensure that No person in the United States should be enrolled in research without the twin protections of informed consent by an authorized person and independent review of the risks and benefits of the researcha unanimous resolution adopted in 1997.

The panel calls for extending research protections to all studies sponsored by either public or private entities and for closing loopholes in the Common Rule that governs most federally funded human research. NBAC (National Bioethics Advisory Commission) found that some federal agencies fail to fully implement protections and that existing rules dont adequately protect all study subjects, particularly those in privately funded research not governed by Food and Drug Administration (FDA) regulation.

The most controversial proposal is to establish a central government agency to enforce federal protections across the research community. Although this and other recommendations surprise no one who has been following the debate, and it may merely gather dust in government offices, the document provides a benchmark for further deliberations on these topics.

The panels proposed National Office for Human Research Oversight (NOHRO) would be independent of the Department of Health and Human Services (HHS) and would develop regulations and guidance covering all types of human participant research. It would review monitoring systems, encourage ethics education, and enforce requirements and standards. Congress would have to enact legislation to create NOHRO if it is to have authority over the private sector and government agencies outside of HHS.

Not surprisingly, this new oversight plan has drawn opposition. Other government agencies consider it unnecessary and say that HHS Office for Human Research Protections (OHRP) is doing a fine job. At a meeting earlier this year, for example, an official with the Veterans Health Administration raised concerns about creating a czar of human research protections. The Federation of American Societies for Experimental Biology (FASEB) has suggested that the benefits of stronger central oversight of all human subjects research could be accomplished by expanding OHRP instead of creating a new entity. Others have questioned how OHRP, FDA, and the National Institutes of Health (NIH) would relate to something like NOHRO to avoid overlapping duties and divergent policies.

The NBAC report offers numerous other suggestions for strengthening research conduct and oversight:

• Issue guidance for how researchers should provide informed consent information to prospective study subjects and promote individual comprehension of the information.
• Require investigators to document that they have obtained voluntary informed consent.
• Examine mechanisms to enable investigators and institutions to ensure privacy and confidentiality.
• Define conflicts of interest and issue guidance to ensure that conflicts do not undermine the rights and welfare of research subjects. Sponsors and institutions should develop policies to identify and manage conflicts of interest, to specify prohibited relationships, and to ensure disclosure of conflicts to participants.
• Establish a uniform system for reporting and evaluating adverse events occurring in research to clarify the responsibilities of all parties. Recommend a compensation policy for research-related injuries.
• Require all institutions and sponsors involved in human research to provide ethics education for officials, investigators, institutional review board (IRB) members, and staff.
• Require certification of all investigators and IRB members and staff who conduct or review human research.
• Establish accreditation programs and standards for sponsors, institutions, and IRBs that do not duplicate the federal assurance process or federal registration requirements for research institutions and IRBs.
• Establish standards for IRB member selection and board composition to ensure that at least 25% are nonscientific and unaffiliated with the institution. This proposal has drawn criticism that including too many nonscientists on IRB panels may complicate reviews and decision-making.
• Set policy for how sponsors, institutions, and investigators should monitor ongoing research. Clarify when continuing review of a study by an IRB is required and when an IRB should review and approve protocol changes.
• Permit use of a central or lead IRB for multisite studies.
• Develop a research agenda to discuss emerging human research protection issues.

While advocating stronger rules and enforcement programs, the commission offers some leeway in policy implementation. Regulations should reflect the level of risk of a given study, with less oversight for research that poses minimal risk, but possibly supplementary review for studies that involve novel or controversial ethical issues. The report emphasizes a need to focus on the process of informed consent and calls for flexible policies for how investigators verify informed consent, particularly if requiring a participants signature might block enrollment in a study. The panel also wants to allow IRBs to be able to waive informed consent in situations where there is minimal risk, where data confidentiality will be protected, and where benefits gained from the study outweigh harm from not seeking consent.

This latest report from the bioethics commission may culminate the panels work. The NBAC charter was signed in 1995 but expires this October and may not be renewed by the Bush administration. During its tenure, the commission has tackled important ethical issues such as human cloning, human tissue collection, and the conduct of clinical studies overseas (see ACT View from Washington, July 2001). Further deliberations will be needed on these important, controversial topics as well as options for stronger oversight of all research involving human participants, but they may be carried on by other organizations.

Protecting children
The NBAC report also calls for the inclusion of all segments of society in research, while protecting groups vulnerable to harm or coercion. A main theme in much of the commissions work has been to ensure the rights of vulnerable populationspeople who are mentally impaired, elderly, uninformed, or very young. In 1998, NBAC issued a report recommending policies to ensure thorough IRB review of research studies involving people with mental disorders.

The recent surge in clinical studies involving children has generated policies to provide additional safeguards for young participants in biomedical research. Much of this interest has been spurred by the pediatric exclusivity program in the FDA Modernization Act (FDAMA) of 1997, which provides six-month patent extensions for pharmaceutical companies that conduct research to provide pediatric labeling information on prescription drugs. As a result, manufacturers have conducted nearly 60 pediatric studies in the past three years and are looking to launch more than 100 studies that could involve more than 20,000 children. The exclusivity program has to be renewed by Congress by the end of this year, and its expected continuation is likely to spur more interest in pediatric research.

In response, Congress enacted legislation last year (Childrens Health Act of 2000) that required FDA to develop rules to protect children participating in clinical trials. In April, FDA issued an interim rule designed to bring FDA-regulated pediatric trials into compliance with the Common Rule. HHS also is conducting a broad review of how the Common Rule (commonly referred to as Subpart D) provides adequate and appropriate protection for children participating in research, which may lead to changes in Subpart D and in FDAs interim rule.

For now, FDA policy sets basic criteria for pediatric research, while offering some leeway to IRBs and FDA in approving studies.¹ Normally, a pediatric trial must

• involve no more than minimal risk.
• offer direct benefit to individuals if it does involve more than minimal risk.
• lead to greater knowledge about the subjects disorder or condition, if the protocol does not meet the first two requirements. FDA indicates that it will take a broad view of who may benefit from a study, even seeing benefit for pediatric subjects receiving placebos in some cases.

A sponsor may be able to conduct a study that does not meet the traditional standards if the trial could prevent or alleviate an important health problem in children and if investigators follow sound ethical principles and solicit assent from children and informed consent from parents or guardians. In order for FDA and an IRB to assess the need for such a questionable study, FDA notes that sponsors would have to be willing to disclose trade secret or confidential information so that the agency may discuss relevant ethical issues with advisory committees and other experts. FDA officials expect that very few studies would be involved with such disclosure, but the agency may seek congressional authority to disclose proprietary information under specific circumstances as part of legislation to renew the pediatric exclusivity program.

Covering both sexes
Although women may not be considered vulnerable populations, policy makers want to ensure that clinical studies address the needs of women and other population subgroups. FDA issued a rule in February 1998 that requires sponsors to submit safety and efficacy analyses for race, age, and sex subgroups included in clinical trials. The rule does not require trials to enroll enough subjects to support subgroup analysis to demonstrate safety and efficacy for each group, however, and many New Drug Applications (NDAs) fail to do so.

In April 2001, the FDA Office of Womens Health issued a study on inclusion of women in clinical trials for biological products.² The report examined 63 Biologics License Applications (BLAs) approved by the Center for Biologics Evaluation and Research (CBER) from 1995 to 1999. It found that inclusion rates were similar for female and male subjects and that enrollment reflected the population that will receive the biological product. Analysis by sex, however, was not consistent in the applications, possibly because most clinical trials were not designed to evaluate potential differences. Data on product safety and effectiveness was not presented according to sex and the only female-specific information on the product label was that discussing pregnancy.

Consequently, FDA officials are looking to close loopholes in the 1998 policy. One proposal is for sponsors to include women routinely in pharmacokinetic (PK) and pharmacodynamic (PD) studies performed in Phase 1 and Phase 2 clinical trials in order to refine dosages for larger trials. An FDA analysis indicates that early PK and PD studies are conducted primarily in men, particularly for biotech therapies. FDAs Center for Drug Evaluation and Research (CDER) also is testing a new standardized format for NDA reviews. It requires all review divisions to examine analysis by sex as one way to ensure that sponsors submit this information in applications.

FDA is examining the need to issue more guidance or regulation to ensure adequate representation and analysis of women in clinical studies, while Congress General Accounting Office is reviewing these issues. A recent report from the Institute of MedicineExploring the Biological Contributions to Human Health; Does Sex Matter?highlighted the importance of full representation of both men and women in biomedical research.³ The panel concluded that sex does matter a great deal in how diseases and conditions affect men and women throughout the life cycle. These differences influence behavior, perception, and health and warrant an increase in sex-based biomedical research. The report recommends that sex-specific data should be more readily available, that data from longitudinal studies should be analyzed by sex, and that policy makers should clarify the terms sex and gender. The sexes may be equal, but they may sometimes require different pharmaceutical and medical treatment.

References
1. Food and Drug Administration, Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products, Federal Register, Vol. 66, No. 79, 24 April 2001, p. 20589, available at www.fda.gov/OHRMS/DOCKETS/98fr/042401a.htm.

2. FDA Office of Womens Health, Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Applications, April 2001, available at www.fda.gov/cber/clinical/femclin.htm.

3. Institute of Medicine, Exploring the Biological Contributions to Human Health; Does Sex Matter? April 2001, available at www.iom.edu.