Regulatory Beat: Politics vs. Science in Biomedical R&D

Although biomedical researchers in both public and private organizations like to believe that government regulations and policies are based on scientific evidence, many aspects of the development and production of drugs and biologics are shaped by political concerns. The debate over drug importation is a prime example of politics trumping science as members of Congress reject the consensus of scientists and policy experts that opening US borders to therapies from abroad raises serious public health concerns. Similarly, FDA's rejection of non-prescription drug status for the morning-after pill, called Plan B, reflects political demands more than clinical evidence (see "Missed Opportunity").

Members of Congress often weigh in on FDA decisions to approve or reject new treatments for cancer and other life-threatening diseases, even when the science is weak. Pressure from policy makers to reduce spending on prescription drugs, moreover, is building support for more generic products, a trend that may shape the looming debate on "follow-on" biologics. This could have a direct effect on pharmaceutical and biotech manufacturers.

IGNORING STEM CELL SCIENCE

Although the first embryonic stem cell was isolated in a US laboratory, future advances may occur elsewhere due to current administration policies. In August 2001, President Bush limited federal funding of embryonic stem cell research to already-established cell lines. Unfortunately, less than 20 of the 78 originally identified lines now appear to be available for research. To fill this widening gap, British officials have opened a national stem cell bank to store and distribute embryonic and adult stem cells to scientists around the world. And US states and research institutions are launching locally funded stem cell research initiatives.

However, pressure to liberalize federal policy may be having some impact. In April, 206 members of the US House of Representatives sent a letter to President Bush urging reconsideration of the current policy, and about 50 senators signed a similar plea for flexibility. Former First Lady Nancy Reagan made headlines recently by strongly supporting stem cell research as a way to find cures for Alzheimer's and other diseases.

NIH Director Elias Zerhouni responded to the House's letter with a carefully crafted statement that offered research advocates some hope for future change. Although Zerhouni reiterated the Bush administration's policy that public funds should not encourage destruction of human embryos that have potential for life, he also acknowledged that access to additional stem cell lines could speed scientific research. Zerhouni subsequently explained that the current policy is based on the president's moral and ethical concerns and admittedly not on scientific evidence. The hope is that the White House might open the door for researchers to access embryos abandoned in fertility clinics and slated for destruction anyway.

ENCOURAGING AIDS COMBOS

On another front, the worldwide clamor for low-cost, fixed-dose combinations (FDCs) of antiviral drugs for third-world countries produced a positive response from Washington. At the opening of the recent World Health Organization annual meeting in Geneva, Health and Human Services Secretary Tommy Thompson announced a program promising speedy approval of already-marketed AIDS drugs that manufacturers will co-package in easy-to-use blister packs or reformulate as single pills.

To encourage manufacturers to submit applications for these products, FDA issued a draft guidance for industry on May 14 that spells out what sponsors must do to gain speedy approval (see www.fda.gov/cder/guidance/ ). The guidance lists drug regimens and components that FDA believes have sufficient clinical safety and efficacy data to support concomitant use and that fit agency criteria for two- and three-drug regimens. It notes that FDA has systems in place to handle priority review and fast-track designation of critical therapies. Plus, according to the guidance, FDA has the authority to refer to existing clinical safety and efficacy data, including published reports, to approve new combination drugs with little additional testing. FDA also expects to waive user fee payments and pediatric study requirements to speed these medicines to market. Manufacturers will need to propose systems for collecting and reporting adverse drug reactions in developing countries, an activity that local health agencies distributing the products are more likely to handle.

Although skeptics complained that the FDA fast-track FDC approval initiative merely repeats the World Health Organization program to "prequalify" FDCs and will delay access to needed therapies, the policy is generating a positive response from manufacturers. Right after Thompson's announcement, California-based Gilead Sciences announced FDA granted priority review to its previously filed application for a fixed dose co-formulation of two approved antiviral medications: Viread (tenofovir) and Emtriva (emtricitabine). Both products have been on the market for more than a year and should receive an approval decision in the fall or sooner.

Similarly, GlaxoSmithKline is hoping for speedy FDA approval for a combination of its Epivir (lamivudine) and Ziagen (abacavir). GSK also may develop a broader FDC with Boehringer Ingelheim's Viramune (nevirapine), while Gilead is working on a combination pill with Merck and Bristol-Myers Squibb. These manufacturers may first develop co-packaged versions of these therapies while testing and seeking FDA approval of new combo treatments.

The fast-track approval strategy addresses the fact that the President's Emergency Plan for AIDS Relief (PEPFAR) is required to purchase only those drugs that demonstrate safety and effectiveness to a "stringent regulatory authority" such as FDA. Using taxpayer dollars to purchase drugs not approved for use at home threatened to open the door to charges that the US was foisting lower-quality treatments on poor nations, which can lead to drug resistance.

By establishing an FDA review system for these products, the State Department will be able to purchase them for use in foreign markets. FDCs produced by generic drug makers that include patented products may be distributed by US health programs in areas where the manufacturer does not enforce its patents, but not in the US. Thus, the program carefully addresses political demands while accommodating scientific requirements.

MISSED OPPORTUNITY ON PLAN B

If there was a scientific rationale for rejecting the over-the-counter drug application for the morning-after pill, called Plan B, FDA officials failed to articulate it to the medical community or the public. Last December, two FDA advisory committees voted convincingly (23 to 4) to approve an OTC switch application from Barr Pharmaceuticals, a recommendation that FDA staffers usually follow. But in this case, agency officials responded to high-level demands to find a legitimate rationale for rejecting the submission.

Steven Galson, acting director of the Center for CDER, sent a non-approval letter to Barr in May. Because it is unusual for the CDER chief to sign such a letter, it suggested that Galson was overruling the pro-approval sentiment of his staff. FDA based its decision on a lack of data on appropriate use of the therapyby young women (under 16). In response, Barr is seeking dual status for Plan B: OTC access for adults (entails ID checks) and prescription status for patients under 16. Such a dual labeling system raises a host of novel legal issues that could take some time for FDA to resolve.

FDA's action rekindled charges that its regulatory policy often stymies access to new treatments. More than 40 members of Congress sent a letter to acting FDA Commissioner Lester Crawford urging reversal of the Plan B decision. Manufacturers and political observers wonder if FDA is becoming more risk-averse in bringing new products to market, and the agency missed an opportunity with Plan B to lay such fears to rest.