These trends may generate some tension between maintaining safeguards for clinical study subjects and accelerating the overall research process. Some ethicists are concerned that antibioterrorism efforts may encourage researchers and regulators to ignore safety and privacy issues. The Food and Drug Administration will play a central role in monitoring activities involved with testing and producing new vaccines for smallpox and anthrax, and it does not want to appear as a roadblock to development of needed treatments. At the same time, “The last thing we want to do is approve a vaccine from a new source that is not safe or effective,” said FDA’s top deputy commissioner Bernard Schwetz at a meeting of the agency’s Science Board in November. FDA is working to define those circumstances where the agency may permit the use of unapproved drugs in emergency situations. A related task is to clarify agency policy for when data from animal tests or surrogate markers can supplant or replace the clinical evidence usually required to approve a new therapy.

Increased oversight
FDA and the Office of Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) have been expanding and solidifying programs to strengthen human subject protections. These efforts will continue in the year ahead. Traditionally, the main objective of FDA’s bioresearch monitoring (BIMO) program has been to maintain the integrity of clinical data submitted in market applications. In recent years, the agency has increased oversight to focus more on ensuring the safety and protection of study participants. According to David Lepay (FDA senior advisor for clinical science), one reason for this development is an increase in problems and rule violations among clinical investigators. He attributes this development to the overall expansion of clinical studies and investigations; increased study enrollment of vulnerable populations, such as children and the elderly; testing of more innovative technologies; and expansion of clinical research in nations that lack strong rules governing biomedical research.

Lepay heads FDA’s relatively new Office for Good Clinical Practice (OGCP) in the commissioner’s office. OGCP was established to coordinate GCP policy and bioresearch monitoring programs across agency centers. It also serves as a liaison with OHRP and other government agencies involved with human research subject protection. OGCP will benefit from added resources provided in FDA’s budget for 2002, which gives the agency $10 million to monitor clinical trials. This is expected to permit FDA to increase by one-third the 1,000 or so inspections it does each year related to clinical research. While investigators will continue to follow up on complaints, the agency also plans to conduct more “state of the field” inspections for gene therapy trials and pediatric studies.

Added funding will help FDA and OHRP pursue a number of initiatives in the coming year:

Strengthen the IRB system. FDA is working with OHRP to establish an IRB registration program that will provide a more accurate picture of the scope of these oversight boards and their capabilities. Research institutions that receive government funding now have to register their IRBs as part of the federal assurance process, and FDA is looking to create a similar system for the IRBs it oversees. Also in the works is a voluntary accreditation program for IRBs that aims to better define and clarify IRB functions and responsibilities in order to reduce redundancies.

Enhance safety. FDA is revising rules to provide additional safeguards for children participating in clinical trials and is looking at new policies involving pregnant women, human fetuses, neonates, and other vulnerable populations.

Expand use of data monitoring committees. FDA issued a draft guidance on DMCs in November, followed by a meeting to stimulate the research community to read and comment on the proposal by February. FDA officials regard DMCs as useful for improving oversight of any high-risk or innovative trial and for helping sponsors decide when to revise protocols or to end a study early. FDA hopes to issue a final guidance by year-end.

Increase review of academic research institutions. OHRP has launched an ambitious program to conduct “quality improvement evaluations” at every major medical school and research organization in the United States. These are based on a self-evaluation process that may or may not lead to site visits.

Manage conflicts of interest. FDA continues to implement its policy for reporting investigator financial conflicts of interest (COI) while also examining other potential conflicts arising from compensation to subjects, controls on the publication of study results, and efforts to exert pressure on IRBs. In addition, OHRP is developing guidance to minimize and manage COI at academic research institutions, which have been fairly critical of the proposal. OHRP director Greg Koski is making changes and hopes to issue a final version this year.

Set standards for foreign studies. A report from the HHS Office of the Inspector General (OIG) released in September indicates that overseas researchers registered with FDA have increased from 271 in 1990 to more than 4,400 in 1999. Moreover, about 25% of new drug applications contain non-U.S. studies with data important to approval decisions. Because FDA lacks the resources to monitor most foreign studies, the agency is encouraging worldwide adoption of harmonized good clinical practices (GCPs) through the International Conference on Harmonisation (ICH). The OIG also calls for FDA to help train foreign ethics boards and to seek voluntary compliance with U.S. research standards by foreign investigators.

Updating fees and policies
A major challenge for FDA and sponsors this year will be to agree on policies for reauthorization of the Prescription Drug User Fee Act (PDUFA), which expires in September. There is broad interest in continuing the user fee program, but FDA and manufacturers have different proposals for revising this program that supports the development, testing, and approval of new drugs and biologics.

The agency wants to boost current fee revenues, which it claims are too low to cover the many tracking and performance requirements of the current program. FDA also wants fee revenues to be available to support the review of investigational therapies, of fast track programs, and of postapproval monitoring. Pharmaceutical companies, however, want to retain performance standards so that FDA will be accountable for meeting certain timeframes related to product development and application review. The agency formally kicked off the negotiating process at a PDUFA public meeting in December. The debate promises to be heated, but the general success of the program over the past 10 years makes compromise likely before the renewal deadline.

The need to reauthorize PDUFA this year may provide an opportunity to review a number of FDA policies, as occurred five years ago when Congress enacted the FDA Modernization Act (FDAMA). Any FDAMA revision is expected to be more modest than the 1997 bill, although some “modernization” initiatives are likely to surface. These may address international standards, postapproval safety monitoring, clinical research safeguards, and measures to enhance FDA management of counter-bioterrorism programs.

Science vs. safeguards
Publication of the human genome more than a year ago has generated promises of a new age of biomedical discovery, as scientists expand their understanding of the causes of human disease and of issues related to pharmaceutical innovation. At the same time, policy makers are concerned about how individual genomic information may violate personal privacy standards. There also is heated debate over the ethical implications of research using embryonic stem cells and research likely to lead to cloning of a human being.

Last summer, the Bush administration sought to resolve the stem-cell research controversy by adopting a compromise policy. It permits the federal government to support R&D using existing embryo banks but with limits to appease those who consider it unethical to pursue any activity that results in the destruction of human embryos. Congress halted efforts to regulate this area to see how the Bush policy may affect cutting-edge research. However, the legislators revived calls for a total ban on cloning when a private company announced in November that it had succeeded in creating human embryos through cloning.

These issues will be examined further by the new White House Council on Bioethics, which will advise Bush on policies related to biomedical science and technology. The panel also may review ways to protect human research subjects and the consequences of limiting scientific investigation. Scientists and sponsors will be interested in how these deliberations shape ethical guidelines for new biomedical investigation and discovery.

SIDEBAR: Clinical Costs Key Issue
The debate over user fees this year will touch on how much FDA regulation contributes to the increasingly high cost of testing and bringing new drugs to market. Adding fuel to the fire is a new industry-backed study that puts the cost of developing a new prescription medicine now at $802 million. Over the past 15 years, R&D costs have risen much faster than inflation. According to the Tufts Center for the Study of Drug Development, the increase is largely due to soaring clinical trial expenditures. That trend reflects increased difficulty in recruiting subjects, expanded focus on drugs to treat chronic and degenerative diseases. Tufts acknowledges that its new estimate includes the cost of research failures and of capital, but industry critics charge that the study is biased and that it demon