FDA Faces New Leadership and Major Changes

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Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-11-01-2002,

The agency is shifting regulation of biotech therapies to its drug center, a streamlining initiative to be implemented by a new FDA commissioner.

After months of speculation, the White House finally nominated its lead health policy advisor, Mark McClellan, as Food and Drug Administration commissioner. McClellan, a physician and economist, has been a member of the White House Council of Economic Advisors, where he has served as the key Bush administration spokesperson on health issues. As an MD with no direct ties to the pharmaceutical industry, he fits the basic criteria set for confirmation by the Democrat-controlled Senate.

Talk of McClellans appointment to head FDA circulated through Washington for several months, but he was too involved in negotiations over Medicare policy and prescription drug coverage to change hats earlier. The 25 September announcement set the stage for the Senate to approve the nomination quickly enough to allow McClellan to move into the FDA post this year.

The new commissioner differs from his predecessors in that he has little direct experience with FDA regulation and policy, having been more involved with health payment and cost-effectiveness issues. But his credentials for the job are strong, and he benefits from deep ties to Texas politics and the White House. His mother is Texass state comptroller, and his brother, Scott, is the current White House press spokesman. McClellan has an MD from Harvard and a PhD in economics from the Massachusetts Institute of Technology (MIT). He previously held a post in the Clinton administration and is not considered a political ideologue. In fact, he garners praise on all sides for being open-minded and conscientious, traits important for anyone overseeing an agency that regulates a broad range of critical consumer products.

Full plate at FDA
As commissioner, McClellan will have to tackle a number of difficult administrative and policy initiatives while also managing a growing agency. In the absence of a permanent leader, these tasks have been handled by FDA deputy commissioner Lester Crawford, who has demonstrated strong leadership skills and a willingness to address thorny issues. McClellan would do well to encourage Crawford to continue as his right-hand aide, a role that may compensate for the commissioner nominees own lack of administrative experience.

In August, Crawford launched a major FDA reexamination of good manufacturing practices (GMPs). This move is part of a broader shift to risk-based regulation at the agency, an approach that aims to focus FDAs limited resources more on high-risk products and activities. At the same time, the agency has experienced its biggest growth in the last 30 years, Crawford noted at the PDA/FDA Joint Regulatory Conference in September. FDA has gained 800 employees to support antibioterrorism activities. The agency has also been granted authority to hire another 450 staffers under the Prescription Drug User Fee Act (PDUFA), which Congress reauthorized in June. That measure is expanding FDA surveillance of new drugs during their first years on the market.

Another important initiative is FDAs reexamination of its legal authority to regulate commercial speech related to drugs and other regulated products. The agency is reviewing comments on this topic as part of a broad review of its policies regarding prescription drug advertising, product labeling, drug marketing to physicians, and additional communications issues affecting public health.

Shift in biologics
Probably the most challenging initiative on FDAs plate is the proposed transfer of oversight for therapeutic biotech drugs from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER), which was announced 6 September. The plan is for CBER to retain authority over vaccines, blood and blood products, and a new office overseeing gene therapies, somatic cell products, tissues, and other cutting-edge technologies. Monoclonal antibodies and proteins are slated to go under CDERs oversight next year, along with the staff, laboratories, and resources to support regulation of these products.

The shift aims to allow CBER to focus its expertise on vaccines and blood products that are critical for our homeland defense, Crawford commented at the PDA conference. In the face of growing criticism of the change, Crawford took pains to highlight CBERs important role in encouraging development of new therapies and vaccines to counter emerging disease and protect public health. Crawford explained that shifting therapeutics to CDER made more sense than completely combining the two centers, and he emphasized the importance of retaining five centers at FDA.

Crawford acknowledges that consolidating the review of drugs and biologics under one roof is a very sensitive undertaking. The first challenge of the high-level transition team headed by FDA senior associate commissioner Murray Lumpkin is to determine which biotech products should shift to CDER. The stated objective of the change is to consolidate FDA review of medical products that are similar in clinical development, clinical data analysis, and use in medical practice. Whether or not therapeutic protein vaccines or recombinant blood products should remain in CBER or move is not clear.

Decisions on which product categories go where will affect the assignment of CBER reviewers among CDER new drug review offices and also determine which CBER compliance and advisory functions shift to CDER, including personnel responsible for providing advice on clinical trial design and for postmarketing surveillance. Crawford emphasizes that no staff reductions will be made due to this consolidation, but considerable uncertainty exists in the agency about how the change will affect CBERs research-review model. Several observers predict a major brain drain from the agency as top scientists leave for academia, research institutes, and industry.

Although manufacturers publicly support the consolidation, some privately acknowledge that they never envisioned such a major organizational change. Their complaints about slower application reviews and problems clarifying drug development requirements in CBER were intended only to improve CBERs management and systems, they say. During PDUFA negotiations earlier this year, industry had argued for policies to improve CBERs record for approving applications in the first review cycle and for reaching agreement with sponsors on product development programs. The issue gained the spotlight during the Congressional investigation into ImClones development of the colorectal cancer therapy Erbitux. At a hearing before the House Energy & Commerce Committee in June, members of Congress criticized CBER officials for permitting the company to file a license application on what appeared to be an inadequate therapy development program. The investigation by the House panel into the resulting insider trading scandal prompted further Congressional inquiries into significant differences between CBER and CDER regulatory practices.

Shifting regulation of biotech therapies to CDER has raised concerns among scientists as well as other observers. At a CBER Symposium held at the National Institutes of Health in September to commemorate 100 years of federal regulation of biological products, gene therapy researcher French Anderson, now director of the Gene Therapy Laboratories at the University of Southern California, termed the breakup of CBER shortsighted and irresponsible. He acknowledged that working with the agency is often difficult, but said that a good many of CBERs demands are important. Jay Siegel, director of CBERs Office of Therapeutics Research and Review (OTRR), maintained that product approval times from his office compare favorably with those for other drugs and that no therapies approved by OTRR have been recalled for safety reasons.

Although it may be logical to merge the medical and clinical review of biotech therapies with oversight of drugs that treat similar conditions, a much trickier task will be to transfer to CDER responsibility for reviewing and evaluating CMC (chemistry, manufacturing, and controls) data on biotech products. Clinical testing of drugs and of biotech therapies have become fairly similar, but production methods for biologics remain very different from those for conventional drugs.


Probably the biggest fear of biotech companies is that the shift to CDER will open the door to generic biologics. Manufacturers welcomed assurances from Crawford that no changes would be made in statutes governing biologics, which currently set a high barrier to generic versions. However, these products now will be regulated by CDER officials who are very familiar with generic drug policies and have indicated more interest in exploring options for the development of therapeutically equivalent biotech therapies.

FDA officials expect to have a plan for implementing the new regulatory structure for drugs and biologics before the end of the year. Deciding what programs and personnel will go where is not an easy task. Different standards for electronic submissions between CBER and CDER are a problem, as are different field inspection programs. CBER funding will be a critical topic, because that center stands to lose about three-quarters of its user fee revenues. Biotech companies planning to file new license applications in the next few months fear a slowdown in the approval process. The long-term expectation is that a more streamlined regulatory and review process should spur biotech R&D, but change is always disruptive and will present new challenges to regulators and to industry.

SIDEBAR: Koski to leave OHRP
Greg Koski, MD, PhD, is returning to Harvard University after two years as the director of the Office of Human Research Protections, DHHS.

Koski insists the move is not politically motivated. But the research community will be watching to see who the administration chooses as his successor.

The move follows the recent publication of the Institute of Medicine (IOM) report, entitled Responsible Research: A Systems Approach to Protection of Human Research Participants, which confirms and supports OHRPs efforts to broaden federalprotections for human research participants.

Koski said, Serving as the first director of the Office for Human Research Protections has been an extraordinary challenge, privilege, and honor, and wishes to thank his friends and colleagues for their support.

He is scheduled to leave at the end of November.

Uncertain time for research ethics oversight
The Bush administration raised eyebrows in the medical research community when it allowed the National Human Research Protections Advisory Committee (NHRPAC) to go out of business. The panel was established formally in June 2000 with a charter that expired in two years, unless renewed. Committee members were told privately by Health and Human Services officials last summer that the panel would continue, perhaps with some changes, and were shocked to learn otherwise with little warning. An HHS spokesperson says that secretary Tommy Thompson is not killing the committee but, in fact, will reconstitute it with a broader mandate and some changes in membership.

However, many concerns have surfaced about how and when a new NHRPAC will emerge. If indications that the new panel may have fewer than its previous 17 members prove correct, then forming committee working groups might become more difficult. Senators Edward Kennedy (Democrat, Massachusetts) and Hillary Rodham Clinton (Democrat, New York) sent a letter to Thompson in September expressing their deep concern about reports of a wholesale replacement of experts on NHRPAC and other HHS scientific advisory committees. The comments also referred to HHS eliminating its Advisory Committee on Genetic Testing and replacing most members of a panel that advises the Centers for Disease Control and Preventions National Center for Environmental Health. These developments bolster critics who believe that the changes at NHRPAC may reflect Bush administration opposition to panel recommendations for added limits on clinical research, for tighter conflict-of-interest rules, and for opposing new policies to protect the unborn.

At its last meeting in July, the old NHRPAC issued final reports regarding research on children and obtaining informed consent from the decisionally impaired. Developing a guide for IRBs to evaluate human genetics research proposals is one of several unfinished projects. Although any administration enjoys the prerogative to select advisory committee members who reflect its interests and inclinations, such advisors should be qualified experts, and panel changes should aim to minimize disruption in ongoing work.

SIDEBAR: McClellans confirmation held up by unrelated issue
Although a Senate committee on 9 October unanimously approved Mark McClellans nomination as FDA commissioner, the expected quick confirmation did not materialize. Instead, a group of senators led by Senator Jeff Bingamin (Democrat, New Mexico) is blocking the nomination until Health and Human Services Secretary Tommy Thompson explains why he withdrew backing for a bill that would make pregnant women eligible for the State Childrens Health Insurance Program.

Abortion-rights activists say they see Thompsons withdrawal of support as an effort to undermine reproductive rights for women, according to a report in National Journals Congress Daily.
ACT staff report