Bioterrorism and Research Policy

Efforts to develop anti-terrorism treatments and to fully include women in studies will both affect clinical research.

The September 11 attack on New Yorks World Trade Center and the Pentagon in Washington dramatically revised the political agenda in the nations capital. The new focus on national defense and international affairs at the White House and Congress greatly reduced interest in domestic health policy issues, including stem cell research, the cost of new medicines, and clinical trial oversight.

One result of the terrorist attack was the cancellation of a September 12 briefing to mark the official release of the final report of the National Bioethics Advisory Commission (bioethics.gov/ human/overvol1.html). In August, the Commission issued recommendations that call for a new federal agency to ensure the rights and safety of human research participants. Now Congress is even less likely to address the issue, unless new scandals involving human research protections erupt.

The nations campaign to thwart terrorism is generating new efforts to protect the public against biological warfare, which could increase investment in research on new therapies to treat and prevent infectious diseases. There has been considerable talk in recent years of the need to develop new therapies and diagnostic tests in this area, but a sense of immediacy has been missing from the debate, comments BIO (Biotechnology Industry Organization) president Carl Feldbaum. Now he expects a much greater commitment of both public and private resources to develop vaccines and therapies against a biological attack, as well as to treat infectious diseases and injuries related to combat.

President Bush touched on this issue in announcing that his new Office of Homeland Security will oversee counter-bioterrorism initiatives of government agencies. The Department of Health and Human Services (HHS) previously announced a five-year plan on this subject. The program involves increased surveillance by the Centers for Disease Control and Prevention (CDC), more support for research by the National Institutes of Health (NIH), and efficient FDA oversight.

At FDA, Andrea Meyerhoff in the Office of Science Coordination & Communications is coordinating agency efforts with CDC to expand the National Pharmaceutical Stockpile and to facilitate approval of critical antibiotics, vaccines and other treatments. Center for Drug Evaluation and Research (CDER) director Janet Woodcock has assigned anti-bioterrorism initiatives involving drugs to the new Office of Pediatric Drug Development & Special Initiatives. This is directed by Diane Murphy, who has been in charge of the review of anti-infective products as head of CDERs Office of Drug Evaluation IV. One assignment for FDA and CDC is to ensure the physical security of pathogenic agents and toxins in research facilities. HHS has asked pharmaceutical and biotech companies to examine what reagents and products they use that could interest terrorists, as well as what technologies could be used to defend against biological or chemical attacks.

These initiatives would gain more support from a proposal developed by Senators Edward Kennedy (Democrat, Massachusetts) and Bill Frist (Republican, Tennessee). They want the White House to provide some $1.5 billion to increase R&D on new therapeutics and diagnostics, fund government purchase of vaccines and antibiotics, improve regulatory review of bioterrorism products, and expand the capacity of local health agencies and hospitals to deal with health emergencies.

Research ethics
One task for FDA is to clarify its policy for conducting clinical trials of therapies for treating exposure to toxic substances. The agency issued a proposed rule in October 1999 on Evidence Needed to Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted. The policy calls for FDA to have authority to approve treatments for exposure to deadly chemical, biological, and nuclear substances based on animal studies to establish efficacy, in addition to safety studies in humans. FDA recognizes that requiring human efficacy studies could block the development of such therapies, but that waiting until a toxic accident occurs to test such products is not very practical.

Debate over how to test protective therapies arose during the Persian Gulf War when the Department of Defense (DOD) sought to administer an experimental anti-botulinum vaccine to soldiers, but failed to seek informed consent. This led FDA to address the broader issue of whether it is ever ethical to expose volunteers to toxic substances to test the efficacy of a protective therapyand, if not, to determine what criteria FDA can use to approve a therapy for an indication that has not been fully tested in humans.

FDAs policy staff is working on a final proposal that aims to clarify how sponsors may develop and test new products to treat infectious diseases as well as protect against biological weapons. CDER expanded labeling for Bayers Cipro (ciprofloxacin) as a treatment for exposure to anthrax based on primate studies showing reduced mortality following exposure to anthrax spores for the treatment group. FDA is determining what study data is needed to label other drugs for protection against biological threats. It also is developing a process to permit the use of investigational drugs in case of such an attack.

New opportunities
Feldbaum and other industry leaders have met with HHS secretary Tommy Thompson and with DOD officials to discuss what manufacturers can do and are doing in these areas. DOD is particularly interested in learning more about products developed for the commercial market that could be important for the military, such as new wound-healing treatments. DOD and BIO may sponsor a joint conference next year to discuss military needs for biomedical therapies, vaccines, antidotes, and other treatments.

The new focus on bioterrorism also may stimulate investment in the relatively moribund U.S. vaccine industry. Feldbaum observes that vaccine development needs increased public funding, an FDA fast-track review process, and liability relief, particularly for small companies. Although DOD has supported studies of vaccines for AIDS and other diseases, biomedical research has not been a high-profile activity of the huge military establishment. Now Feldbaum detects a seismic shift in DOD interest in what academic institutions and private companies are doing, which could lead to more funding for large-scale clinical trials. Although some observers argue that the danger of biological warfare has been exaggerated, others note that supporting R&D for new products to treat infectious diseases could benefit public health.

Sex equity
In addition to encouraging development of new anti-terrorism treatments, the special initiatives staff in CDERs new pediatrics office is heading efforts to clarify FDA policy on trials that involve drugs used during pregnancy. FDA and HHS recently awarded contracts to two biomedical research centers to study appropriate doses for hypertension drugs (lobetol and atenolol) in pregnant women. The aim is to improve labeling of medicines commonly used during pregnancy. The research also will give investigators experience in conducting clinical trials involving pregnant women. That could support FDAs program to ensure that new medical products are tested and labeled for women as well as men. FDA has eliminated earlier rules that limited the overall participation of women in clinical research. In 1993 the agency formally revoked a 1977 policy that restricted the enrollment of most women of childbearing potential in Phase 1 or Phase 2 trials. Recent policies require that sponsors include analysis of demographic subgroupssuch as men and womenin new drug applications (NDAs). Another rule permits FDA to put an investigational new drug on clinical hold if the sponsor excludes women from studies of critical therapies.

Members of Congress want to know if these policy changes have altered research practices. In August, Congresss General Accounting Office (GAO) issued a report indicating a good deal of progress since its last study in 1992: Women accounted for more than half (52%) of clinical study participants from 1998 to 2000. However, the report noted that womens participation still varied greatly in early trials, and was noticeably low in small safety studies. This is an important shortcoming, GAO analysts state, because early studies provide toxicity and dosing information that shape the design of later, larger trials.

GAO also questions whether sponsors and FDA reviewers analyze data sufficiently to assess possible differences in mens and womens responses to drug dosing. Of the 36 NDAs that GAO examined, about one-third of the summary documents lacked full safety and efficacy data by sex. And almost 40% of IND annual reports lacked the required demographic information. GAO advised FDA to improve its system for tracking women in clinical trials and for monitoring whether medical officers adequately assess sex differences.

FDAs own review of this issue by its Office of Special Health Issues (OSHI) similarly found that women participate in clinical trials in numbers equal to men, including early study phases, and that gender-specific pharmacokinetic information is included on most product labeling. That report, however, acknowledges some variation in the way medical reviewers in CDERs drug evaluation offices present and discuss sex-related issues. CDER officials say they hope to see more consistent analysis of study data in the coming year as reviewers begin to use a new Clinical Review Template. The template includes a section on mens and womens exposure to the investigational product. CDER also offers its staffers an online course on sex differences and policies regarding participation of women in clinical studies. Another FDA initiative is to develop an agencywide clinical trials demographic database designed to help FDA monitor inclusion of women and other demographic groups in clinical trials and to assess any impact on safety and efficacy.

Overall, the agency will be looking to ensure equitable enrollment of women in early safety studies and consistent analysis of sex demographic data in study summaries and annual reports. Even though none of the NDAs that the GAO examined found clinical differences of sufficient significance to warrant special dosing or labeling for women, GAO notes that data in many cases indicated higher drug concentrations in women. At a time of increased concern about pharmacokinetic and pharmacodynamic differences between patients and great interest in individualization of treatment, policymakers want sponsors to fully analyze what may look like unimportant treatment