FDA, NIH, pharma companies seek new strategies to spur drug development

Key Points

Drug development pipelines have shrunk; fewer new products are being approved for market; and pharma companies are scaling back R&D as patent expirations on blockbuster drugs reduce industry revenues.

The situation is prompting a serious search for new business models for new drug development. Manufacturers are looking to partner more with small biotech firms and academic research institutes, to shift research and production operations overseas, and to streamline operations and reduce waste wherever possible. The National Institutes of Health (NIH) proposes to ramp up support for translational medicine that will shepherd basic research through the R&D "valley of death" to yield new therapies. Patient advocacy groups are consulting with and providing funding for public and private therapy development programs. And FDA is eyeing new strategies to improve its application review process.

America's position as the world leader in biomedical R&D is "under siege today," facing its biggest threat in 65 years, commented former Congressman John Porter, at a forum in March sponsored by ResearchAmerica. "Is America going to put progress on hold?" he asked in calling for government decision-makers to consider the importance of science and innovation in making federal spending decisions.

Some of the blame for longer, more costly drug development falls on the shoulders of FDA. Stepped-up demand for more safety and efficacy data appears to add to development costs, and ultimately to less robust pharmaceutical R&D programs. Moreover, success rates remain notably low for new drugs in clinical development, despite years of efforts to better inform the clinical research process in order to avoid wasting millions of dollars on unsuccessful studies.

Most disappointing is the decline in new drug approvals by FDA last year, a troubling shift after 2 years of slight increases in new drugs moving through the agency.

FDA cleared only 21 new molecular entities (NMEs) in 2010, down from 25 in 2009. The rejections hit several promising experimental products, including new diabetes therapies and weight-loss drugs. Even more discouraging are reports that fewer applications for innovative new therapies were filed with FDA last year, squelching optimism about any upturn in product approvals in the near future.

Yet, several important new therapies made it to market. Amgen won approval for osteoporosis treatment Prolia (denosumab), and Roche's Genentech brought out Actemra (tocilizumab), an intravenous drug for rheumatoid arthritis. Boehringer Ingelheim won the race to bring to market a new blood-thinner Pradaxa (dabigatran etexilate). Probably the most exciting new product was Dendreon's therapeutic prostate cancer vaccine Provenge (sipuleucel-T). And new vaccines for meningococcal disease and pneumococcal disease also were approved by the Center for Biologics Evaluation and Research (CBER).

Some more good news has emerged this year. Last month, FDA approved a new treatment for melanoma, Bristol-Myers Squibb's Yervoy (ipilimumab), touted as the first drug to prolong lives of patients with this deadly skin cancer and a vast improvement over existing therapies. Another high-profile recent approval is the first new treatment for lupus in more than 50 years-Human Genome Sciences' Benlysta (belimumab).

SEEKING IMPROVEMENT

FDA admittedly is caught in a hard place. Patient advocates demand earlier access to promising therapies, yet policy makers and consumer groups insist on more scrutiny of test products to better detect potential safety problems. Moreover, the agency has struggled in the last few years to implement a host of new requirements established by the FDA Amendments Act (FDAAA) of 2007, which resulted in a slow-down in processing new drug applications.

Now staffers are meeting user fee review goals more steadily as the agency moves into a "period of consolidation," says Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER). The Center has implemented many FDAAA initiatives, is negotiating a new Prescription Drug User Fee (PDUFA) program, and is establishing a Quality Management System for more efficient 21st-century review process. There also are more first-cycle approvals, a key benchmark for both sponsors and regulators, and the rate of first launches in the United States is holding steady.

The looming reauthorization of PDUFA in 2012 is prompting a re-evaluation of many regulatory and review processes. One area of focus is the Risk Evaluation and Mitigation Strategies (REMS) program, which has been criticized by manufacturers and pharmacists for spawning too many diverse REMS formats. Proposals are on the table to reduce REMS controls for only those products that require distribution of medication guides, and to devise common formats for such documents. FDA recognizes, said Woodcock, that REMS requirements should not delay product approvals.

Discussions regarding generic drug user fees, moreover, are moving forward. A main objective for FDA is to gain additional support for more timely plant inspections in face of a notable rise in foreign sourcing of active ingredients as well as generic drug productions.

Another area of focus is FDA's accelerted approval process, which is designed to avoid delays in moving important new therapies to market. The system has been criticized because manufacturers often fail to complete agreed-on confirmatory trials in a timely manner, and some follow-up studies have shown limited efficacy and serious side effects, as with Roche's Avastin (bevacizumab). FDA officials have proposed that sponsors launch confirmatory trials before the agency grants fast-track approval to ensure that additional studies are done according to plan.

Greater difficulties in developing new drugs for broad patient populations, such as diabetic and obese patients, are prompting collaborative efforts to better understand approval requirements. Woodcock and her staff recently met with a group of obesity experts to discuss standards for bringing weight-loss drugs to market. Medical experts in the field proposed that regulators consider the broader health benefits of weight-loss, such as reduction in sleep apnea, when assessing potential side effects from drug therapy.

FDA Commissioner Margaret Hamburg continues to stress the importance of advancing regulatory science in order for FDA to be able to support the translation of science into real-world therapies. New biomarkers for toxicology can identify much earlier those drugs likely to fail and also better target therapies to individuals most likely to respond, Hamburg noted. And innovative clinical trial designs can yield answers using fewer patients and less money. The conventional thinking is that new discoveries from biomedical research will lead to new products. But, she explained at the ResearchAmerica forum, there is a regulatory science gap that can prevent new opportunities from coming to fruition.

PROMOTING TRANSLATION

The changing biomedical research landscape and cutbacks in industry R&D programs have prompted NIH Director Francis Collins to promote translational medicine as a way to spur development of new biomedical treatments that can benefit patients. In December, an NIH advisory committee recommended establishing a new NIH National Center for Advancing Translational Sciences (NCATS), which aims to bring together a number of NIH programs that provide resources for translating basic discoveries into new medicines and diagnostics, including therapies for rare and neglected diseases.

Collins believes that today there is greater private sector interest in NIH-funded preclinical and clinical testing, as well as in compound rescuing or "repurposing."

He sees such initiatives as a win-win for pharma companies and for medical research if such a compound was found to be active for a different application than originally considered. NIH will not move into drug development per se, Collins emphasized, but will hand promising compounds off to private sector sponsors.

Collins also hoped that this emphasis on translational science will convince Congress and the American public that the federal investment in biomedical research can pay off in terms of new, life-saving therapies. The Obama administration has proposed a very slight increase in the NIH budget for fiscal 2012, which would just barely maintain current funding levels. Even during the Republican budget-cutting campaign of the mid-1990s, NIH benefitted from strong GOP advocates on Capitol Hill and largely escaped the chopping block; that kind of support seems to be lacking among current Republican leaders.

As the former director of NIH's Human Genome Project, Collins is optimistic that new genetic discoveries can chart pathways for discovering new medical treatments, and that the emergence of more well-validated genes will be useful in "identifying drug targets in unprecedented numbers," he said in an interview.

The scientific enterprise is yielding a lot of new ideas about therapeutics, he observed, yet "traditional private sector efforts to capitalize on that are taking a hammering." NCATS aims to bolster the funding of research projects at a time when biotech and pharma companies face serious financial challenges. Along these lines, the initiative also will encourage more collaboration between academic researchers and biopharmaceutical companies and to strengthen ties with FDA to ensure that NIH-sponsored studies provide the data needed to support registration of new products.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.