Terrorists Steal Limelight from Human Subjects

A major thrust of the Bush administrations budget plan for 2003 is to shore up the nations defenses against terrorism. The result is more funding for biomedical research by the National Institutes of Health and for efforts to spur development and approval of new drugs and vaccines by the Food and Drug Administration. The focus on combating bioterrorists, though, has removed efforts to protect participants in clinical research from the limelight. The buildup in human subject research protection efforts that began last year will continue, but there are few added resources in this area.

The budget plan for the Department of Health and Human Services (HHS) gives a slight boost to the Office of Human Research Protections (OHRP). It will gain $1 million, for a total of $8 million, to implement HHS rules, negotiate formal assurances with research organizations, investigate compliance issues, and support professional and public educational efforts. One new initiative is to strengthen ties with international organizations involved with human research issues.

Even though HHS proposes a $1.7 billion FDA budget for 2003, up $123 million, it includes no additional funding for clinical trial oversight. Last year, FDAs budget proposal listed protecting volunteers and the integrity of data in clinical trials as a top priority. It boosted FDAs resources by $10 million to increase clinical trial inspections and to better coordinate bioresearch monitoring (BIMO) activities for drugs, biologics, and medical devices. For 2003, the administration aims only to maintain the higher BIMO inspection levels gained last year. Expect this to involve about 750 site visits concerning drug research, 190 inspections concerning biologics, and 270 inspections concerning medical devices. There will be 100 foreign BIMO inspections for drugs and a handful for biologics and medical devices.

Efforts to bolster protections for participants in high-risk clinical trials such as gene therapy studies remain a priority for FDAs Center for Biologics Evaluation and Research (CBER). The center will provide more guidance in this area and is developing a gene therapy subject tracking system to assess and promote the safety of individuals participating in these high-risk studies. FDAs Gene Therapy Monitoring Analysis Working Group will review clinical monitoring programs, identify common variables of inadequate programs, evaluate the quality of gene studies, and identify sponsors or investigators with financial or other significant conflicts of interest. CBER plans to convene a conference of investigators to discuss monitoring practices further.

More for oversight & safety
FDAs budget plan provides about $450 million for the Center for Drug Evaluation and Research (CDER) and $200 million for CBER to support timely approval of new drug applications. Other key budget features include:

Specific funds to increase staff pay ($29 million). Prior to this year (2002), the agency had to cover the mandated cost-of-living adjustments and raises out of its general appropriation, which translated into an actual reduction in resources available for program operations.

Expansion in FDAs field force to permit more timely inspections of regulated products. A major thrust is to increase inspections of domestic food processors and food imports, but the agency will gain about $10 million to conduct more inspections of U.S. and foreign manufacturers of drugs and medical products, and to maintain current levels of BIMO inspections, as noted above.

Added resources for patient safety initiatives and programs to reduce adverse events related to drugs and medical products. FDA will gain $5 million to improve its adverse event monitoring system and to support FDA involvement in government-wide patient safety initiatives. These funds will support electronic data entry initiatives to enhance FDAs adverse event reporting system (AERS) and to encourage more reporting by drug manufacturers.

Countering terrorism
Much of FDAs added resources come from $160 million provided to counter possible biologic-based terrorist attacks. This amount includes $54 million to encourage the development and production of new vaccines, drugs, and diagnostic tests that could be used to protect the public health in emergencies. Many activities fall under this heading, including research on novel methods for evaluating new drugs and diagnostics to ensure safety and effectiveness.

One important initiative is to finalize a proposed rule for testing therapeutics to treat lethal diseases. The policy would apply to situations where controlled efficacy studies in humans cannot be conducted due to ethical and safety concerns. A final rule is in the works to identify what information is sufficient to provide substantial evidence of efficacy in new drugs and biological products likely to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances.

Another goal is to develop procedures and protocols to permit the use of investigational therapies in emergency situations.

Andrea Meyerhoff oversees these efforts as director of antiterrorism programs in the office of the FDA commissioner. She serves as FDAs point of contact on bioterrorism for other government agencies, as well as for FDA centers. One of her tasks is to identify medical products in the development pipeline that might address bioterrorism concerns and be needed in a health emergency. Meyerhoff offers assistance to companies unfamiliar with FDA policies that are developing new therapies or diagnostic technologies with public health benefits.

User fees skyrocket
All these funding increases for FDA assume that Congress will approve a huge increase in user fees collected from manufacturers under the Prescription Drug User Fee Act (PDUFA). The budget calls for a whopping 60% jump in fees for biologics and drugs to almost $300 million, up $103 million over this years total. One result of such an increase is that user fee revenues would underwrite more than 50% of FDAs new drug review program, exceeding the original limit set by Congress. In fact, without such a big increase in fee revenues, the total FDA budget would rise by only 1.3%.

FDA insists that it needs more money to balance the current mismatch of workload and revenues, according to acting senior associate commissioner for management and systems Jeff Weber. The agency also wants to boost user fee revenues to support risk management initiatives and other postmarketing safety efforts mentioned above. Unfortunately, FDA has seen a big drop in fee revenues in recent years because sponsors have filed fewer applications with the agency and are seeking more waivers than anticipated.

Negotiations for PDUFA 3 are going on, and there is grumbling about the proposed fee hike from manufacturers, particularly smaller biotech firms. FDA envisions funding postapproval initiatives with a hike in product fees, as well as higher application fees. Some relief may come from recently approved legislation to renew the pediatric drug labeling program, which authorizes application fees for pediatric supplements. Moreover, FDA is talking to generics makers and medical device companies about paying fees for application reviews. PDUFA 2 expires Sept. 30, which means that FDA and industry need to reach some agreement this spring. Unlike previous years, the agency has used all of its user fee reserves and will have to lay off staffers if the fee program is not reauthorized well before its expiration date.

Budget winners & losers
With the Bush administration heavily promoting biomedical research to combat bioterrorists, theres little surprise that the National Institutes of Health are slated for another big funding boost. The budget plan seeks to increase total NIH funding by almost $4 billion to $27.3 billion, fulfilling promises to double the agencys budget in five years. Cancer research gets a big boost, as does R&D related to AIDS.

The NIH total includes $1.75 billion to counter bioterrorism, which NIH will use to spur new product development. The agency will invest about $440 million in basic research, according to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). Another $500 million will support construction and improvement of research facilities. More unusual is the agencys plan to invest considerable resources in R&D likely to lead to development of specific diagnostics, vaccines, and therapies. NIH will be looking to arrange more partnerships with manufacturers and researchers through links with research institutions and through innovative licensing agreements.

At the same time, the HHS Agency for Healthcare Research and Quality (AHRQ) faces a sharp budget cut of $50 million, to $251 million. While funding continues for several subject safety initiatives, AHRQ will have much less money to fund outside researchers studying health outcomes, quality, and costs. The proposal threatens AHRQs Centers for Education and Research on Therapeutics (CERTs), which conduct research on efforts to improve the safe and effective use of medications.

Now Congress will take its usual swipe at the administrations spending plan. AIDS activists are protesting cuts in HIV prevention programs, while AHRQ supporters are lobbying for a 30% increase in that agencys budget. Some policymakers are complaining that the continued boost in NIH funding deprives other agencies of a fair share of federal research dollars; double-digit increases in the NIH budget may be a thing of the past.

SIDEBAR: Medicare May Cut Support for Cancer Trials Subjects
Cancer patient advocacy groups are up in arms over signs that the Bush administration seeks to change the current Medicare policy of paying the routine costs of care for subjects participating in certain qualifying cancer studies. The Clinton administration approved such coverage two years ago (July 2000) to encourage more elderly patients to participate in cancer studies, as well as to provide equal access to experimental treatments for Medicare beneficiaries. The American Cancer Society and a long list of patient advocacy and cancer organizations are protesting any rollback. A prime concern is that the Medicare coverage policy would affect decisions by health plans and private insurers about supporting subjects participating in clinical trials.

SIDEBAR: FDA Gets New Deputy Commissioner
After months of stalemate between the White House and Senate Democrats over the appointment of a new commissioner for the Food and Drug Administration, Health and Human Services secretary Tommy Thompson took a short cut and named a new deputy commissioner to head the agency temporarily. The new deputy, Lester Crawford, was able to start work immediately after his 26 February appointment without going through a lengthy Senate confirmation process.

Crawford was considered a top candidate for the commissioners job last fall. As a food safety expert and veterinarian (DVM), he appealed to Thompson as someone able to promote FDAs role in ensuring the quality and security of the nations food supply. Crawford most recently headed Virginia Techs Center for Food and Nutrition Policy and served in the Department of Agriculture and as director of FDAs Center for Veterinary Medicine in the 1980s. However, consumer advocates objected to his appointment due to strong ties to industry; Crawford also has held positions at the National Food Processors Association and at an agricultural chemical firm. Moreover, Crawford is not an MD, a usual credential for the FDA commissioner.

With Crawford coming on board at FDA, Bern Schwetz is able to return to his job as the agencys senior advisor for science after being FDAs acting principal deputy commissioner for more than a year. Thompson and the White House insist that they are actively looking for a new permanent FDA commissioner, but this appointment gives Crawford an opportunity to audition for the job. The Bush administration recently rejected Alastair Wood of Vanderbilt University as a possible commissioner, apparently due to strong objections from pharmaceutical companies. Senate Democrats have nixed anyone who appears too pro-industry. If the impasse continues, Crawford could remain the de facto head of FDA for some time.