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FDA, NIH, and industry seek new strategies to spur drug development and promote access to therapies.
Drug-development pipelines have shrunk; fewer new products are being approved for market; and the prospect of significant declines in revenues due to the looming "patent cliff" is prompting pharmaceutical companies to scale back research and development (R&D). Pfizer rocked the industry in February by announcing a major cutback in R&D spending, including plans to shutter its long-time research facility in Sandwich, United Kingdom, and to reduce its Groton, Connecticut, research facility. As part of a move to cut its $9-billion R&D budget to some $6-7 billion by 2012, Pfizer is moving antibacterial research from Groton to Shanghai, China, and will use its Cambridge, Massachusetts, research operation to form more links with small biotechnology firms in the area.
The crisis in the pharmaceutical industry is generating a serious search for new business models. Manufacturers are looking to partner more with small biotechnology 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. America's position as the world leader in biomedical R&D is "under siege today," and facing its biggest threat in 65 years, commented former Congressman John Porter, at a forum in March 2011, sponsored by ResearchAmerica. "Is America going to put progress on hold?" he asked in calling for decision-makers to consider the importance of science and innovation in making spending decisions. These trends are shaping many aspects of biopharmaceutical development, production, and marketing.
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, prior to approval as well as after a drug comes to market, can add to development costs, and ultimately weaken 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 to avoid wasting millions of dollars on unsuccessful studies. The Biotechnology Industry Organization (BIO) reported in February that only one in ten new drugs make it from Phase I studies to FDA approval, based on an analysis of thousands of drug-development efforts from 2003 through 2010.
Most disappointing is an actual decline in new drug approvals by FDA last year, a troubling shift after two years of slight increases. The agency cleared only 21 new molecular entities (NMEs) in 2010, down from 25 in 2009. Even more discouraging are reports that fewer applications for innovative new therapies were filed with FDA last year, squelching optimism about an upturn in product approvals in the near future. Yet, FDA is caught in a hard place, as patient advocates demand earlier access to promising therapies, while policymakers and consumer groups insist on more scrutiny of test products to better detect potential safety problems.
The approval downturn kept several highly touted experimental products from the market. Cardiovascular safety issues prompted FDA to reject new diabetes therapies and kill several new weight-loss drugs, while also pulling Abbott's Meridia product from the market. More recently, a promising fast-acting inhaled insulin product (MannKind's Afrezza) was put on hold following FDA requests for more data on product usage and safety. The agency drew heat for turning down an application from Cell Therapeutics for pixantrone, a treatment for non-Hodgkin's lymphoma that showed some efficacy, but not enough for FDA approval. Cancer advocates continue to oppose a move by FDA to narrow its approved indication for Avastin, insisting that the benefits outweigh new evidence of serious side effects.
There are some bright spots amidst these disappointments. Last month, FDA approved a new treatment for melanoma, Bristol-Myers Squibb's (BMS) Yervoy (ipilimumab). The drug is the first to prolong lives of patients with this deadly skin cancer and a vast improvement over existing therapies. Even better for the manufacturer is an expectation that this new monoclonal antibody, which enlists the body's immune system to attack cancer cells, could lead to similar treatments for other cancers.
FDA also made headlines earlier this year by approving the first new treatment for lupus in more than 50 years—Benlysta (belimumab), developed by Human Genome Sciences with support from GlaxoSmithKline. The drug's discovery relied on information resulting from human genome mapping and represents the first real success in this field after multiple failures.
BMS cites its new cancer drug as evidence that an increased focus on pharma R&D can yield big dividends. "R&D pays," stated CEO Lamberto Andreotti in an interview with the Wall Street Journal, noting that the firm is investing research money very carefully in a range of disease classes and expects to have four more new therapies approved by FDA in another year. Merck similarly told Wall Street analysts in February that it's not cutting back on its $8 billion R&D spending plans, even though the decision may result in missing long-term profit forecasts.
Last year's slim drug-approval list included several notable products. Amgen won approval for osteoporosis treatment Prolia (denosumab), and Roche's Genentech brought out Actemra (tocilzumab), an intravenous drug for rheumatoid arthritis. Boehringer Ingelheim won the race to bring to market a new blood-thinner Pradaxa (dabigatron), although others may catch up soon. Probably the most exciting new product was Dendreon's therapeutic prostate cancer vaccine Provenge (sipuleucel-T). Other new vaccines for meningococcal disease and pneumococcal disease also were approved by the Center for Biologics Evaluation and Research (CBER).
FDA officials say that drug approvals are returning to former on-time schedules after sagging in recent years as the agency struggled to implement a host of new requirements established by the FDA Amendments Act (FDAAA) of 2007. Last year, the Center for Drug Evaluation and Research (CDER) began to benefit from staffing increases and regulatory clarification, which helped employees achieve review timeframes more steadily. Now the agency is moving into a "period of consolidation," says CDER Director Janet Woodcock, as it completes multiple FDAAA initiatives, negotiates a new Prescription Drug User Fee (PDUFA) program, and establishes a quality-management system for more efficient 21st century review process.
Woodcock reported in December 2010, at an FDA/CMS summit, that the agency once again was meeting user fee timeframes for processing applications, particularly submissions for NMEs, and that the "big wave in missing goals is coming down." There also are more first-cycle approvals, a key benchmark for both sponsors and regulators, and the rate of first launches in the US is holding steady.
At the same time, FDA is looking to improve the regulatory process in ways that encourage new product development. Combination therapies, for example, stand to benefit from draft guidance issued last December on codevelopment of investigational drugs used in combination, which is particularly germane to formulating new cancer therapies.
The looming reauthorization of PDUFA in 2012 is prompting a re-evaluation of the agency's Risk Evaluation and Mitigation Strategies (REMS) program to meet industry concerns about too many diverse REMS formats; lead proposals are to have less burdensome controls for REMS that only require distribution of medication guides, and to devise common formats for such documents. FDA recognizes, says Woodcock, that REMS requirements should not delay product approvals.
FDA-industry user-fee negotiations also seek to make presubmission meetings more productive and to support new strategies for streamlining product testing and application review. 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 the face of a notable rise in foreign sourcing of active ingredients as well as generic-drug production.
Another area of focus is FDA's accelerated-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. FDA officials have proposed that sponsors launch confirmatory trials before the agency grants fast-track approval to ensure that additional studies are performed according to plan.
Great difficulties in developing new drugs for broad patient populations, such as diabetics and the obese, 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. The scientists proposed that regulators consider the broader health benefits of weight loss, such as reduction in sleep apnea, in 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 drugs likely to fail much earlier in the process 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.
The changing biomedical research landscape and cutbacks in industry R&D programs are encouraging more public support for pharmaceutical research around the world. The Innovative Medicines Initiative in Europe is building a schizophrenia database of industry-sponsored clinical trials to better identify signals of patient response to test drugs. The United Kingdom's Medical Research Council has established the Developmental Pathway Funding Scheme to support basic research on drugs and medical devices, and the Wellcome Trust's Seeding Drug Discovery initiative is funding efforts to take drug candidates through early clinical trials. Both US and EU scientists are wary of being left behind by soaring Chinese investment in R&D.
At home, NIH Director Francis Collins launched a high-profile campaign to promote translational medicine as a way to spur development of new medical treatments that can benefit patients. In December, an NIH advisory committee recommended establishing an NIH National Center for Advancing Translational Sciences (NCATS), a move engineered by Collins to bring together several NIH programs that provide resources for translating basic discoveries into new medicines and diagnostics. These include a program that supports development of therapies for rare and neglected diseases, along with NIH's national network of research sites at academic medical centers supported by Clinical and Translational Science Awards.
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 up 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.
The project envisioned by Collins will help re-engineer the drug-development pipeline by investing in new assays that can screen thousands of molecules to find ones that will hit defined disease targets. Another objective is to improve assessment of toxicity, which may involve shifting from the use of animal testing to identify potential problems.
As part of the process, Collins' translational science campaign aims to 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 year 2012, which would just barely maintain current funding levels. Even during the Republican budget cutting campaign of the mid-1990s, NIH retained several strong GOP advocates on Capitol Hill and largely escaped the chopping block; that kind of support seems to be lacking among current Republican leaders.
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." Pharmaceutical companies have long lists of compounds that have been abandoned along the way, maybe because a business plan changed or the money ran out or clinical trials failed to show efficacy, Collins notes. "We have been talking with leaders in the pharmaceutical industry about an opportunity to open the freezers and make such compounds available, with appropriate intellectual property protection for them," Collins explains. "This isn't a giveaway, but could be a win-win if such a compound were found to be active for a different application than originally considered." NIH will not move into drug development per se, Collins emphasizes, but will hand promising compounds off to private sector sponsors.
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org.