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Manufacturers, FDA, and research organizations are collaborating on efforts to spur innovation and streamline drug production.
The US Food and Drug Administration celebrates its 100th year in 2006, and Acting Commissioner Andrew von Eschenbach is considering this an appropriate time to build for the future as well as look back on important achievements. At several recent advisory committee and industry meetings, von Eschenbach described how molecular discoveries are creating enormous opportunities and difficult challenges for biomedical research and new drug development. His response is to implement FDA's Critical Path initiative, which he termed "one of my highest priorities" at a conference sponsored by Windhover Information (Norwalk, CT, www.windhover.com) last month. To fulfill FDA's prime mission of ensuring that new interventions adhere to the highest standards of safety and efficacy, von Eschenbach said that the agency must collaborate more with other government organizations, with academia, and with its industrial partners to find better ways to spur innovation.
Such efforts are familiar to FDA's acting commissioner. As head of the National Cancer Institute (NCI, Bethesda, MD, www.cancer.gov), von Eschenbach supported joint projects with FDA to spur the development of new cancer drugs. The NCI–FDA interagency oncology task force has established a joint fellowship program and common information technology support for clinical trial automation. More recent NCI initiatives aim to qualify biomarkers for detecting cancer in certain patient populations and to examine using imaging technologies to monitor therapeutic effects on cancer tumors.
Crisis and opportunity
FDA's Critical Path report issued in March 2004 describes the high cost and disappointing results of the current drug development process. New drug approvals have flattened out in recent years, particularly for new molecular entities. This trend is even more troubling at a time when the public and private sectors combined are spending some $100 billion on biomedical research, estimates FDA Deputy Commision Scott Gottlieb.
Now, several occurrences may be creating a perfect storm for public–private collaboration on new drug research and development. First, scientific discoveries are creating clear opportunities to use biomarkers, computer models, genomics, and new technologies to develop more informative research methods. Advances in informatics also permit scientists to analyze vast amounts of data that can streamline drug development and clinical testing processes.
At the same time, the pharmaceutical industry faces a crisis. With pipelines drying up, revenues falling, and drug safety problems generating public hostility, manufacturers are under pressure to find more efficient ways to develop and produce safe and effective medical products. Although pharmaceutical companies are concerned about protecting commercial secrets and intellectual property, they realize that it is too costly to develop biomarkers and genomic tests on their own and that more cooperative efforts make sense.
Heightened focus on drug safety has pushed pharmaceutical innovation out of the limelight for the past two years, but experts regard these concerns now as bolstering efforts to identify new tools to reduce toxic side effects and limit patient exposure to inappropriate therapies. To counter demands for clinical trials that test more patients longer, FDA seeks to find better ways to assess safety issues than sponsoring huge randomized trials based on an empirical approach. Tests that can identify patients who respond more positively to a drug can lead to safer medicines, and more targeted clinical studies can avoid needlessly exposing nonresponders to a test product.
Manufacturers also are recognizing the importance of improving the industrial model for drug manufacturing, notes FDA Deputy Commissioner Janet Woodcock, who heads FDA's Critical Path effort. Although other industries have standardized requirements for parts and components, differing physical characteristics of excipients play a huge role in manufacturing variability and "often cause GMP problems," she said. "There's no need for the production of solid oral dosage forms to be as complex and costly as it is," she observes. Nonetheless, talk of more industry collaboration "would have fallen on deaf ears" 10 years ago, she acknowledges, because manufacturers did not realize until recently how much money outdated manufacturing processes are costing them.
Because FDA lacks the resources to support research on these issues, the agency seeks to examine Critical Path opportunities through joint projects with pharmaceutical companies and research organizations, either individually or through group collaborations (see sidebar, "Listing opportunities"). In addition to financial resources, Woodcock notes a need to share the industry's knowledge base, including actual assays and databases.
In response to FDA urging, companies now are "stepping up to the plate," Woodcock says. For example, Novartis (www.novartis.com) announced in September that it is working on three research collaborations with FDA. One is examining how to apply process analytical technology (PAT) to identify new methods for ensuring quality manufacturing. FDA and Novartis are negotiating a Cooperative Research and Development Agreement (CRADA) that calls for the joint evaluation of research findings and will give FDA experience in implementing and validating proposals under its PAT guidance. Another project involves a CRADA to develop preclinical biomarkers that evaluate renal toxicity. The third collaboration will examine hurdles related to developing a diagnostic kit with a drug product. Novartis plans to conduct an observational study involving several compounds in its pipeline for which a genomic diagnostic may be of value.
Under a CRADA, a manufacturer or group of companies supplies the funding and resources, including data about drug characteristics, research results, or innovative manufacturing approaches. FDA offers advice on study designs and agrees to evaluate results and use them to support a regulatory test or standard. Academic or nonprofit organizations offer research facilities and act as neutral parties to manage funding and protect proprietary information.
A central Critical Path undertaking is to establish broad consortia to identify and qualify new biomarkers. These tend to be complex arrangements because they involve evaluating assays from several partners that are each anxious to retain its intellectual property. Most pharmaceutical companies have their own biomarker development programs for use in predicting animal toxicity and selecting drugs for development, points out Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research (CDER, Rockville, MD, www.fda.gov/cder). But FDA supports collaborative arrangements to validate biomarkers that can be used across the industry.
Without a new scientific framework for using more biomarkers in product development, explains Douglas Throckmorton, CDER deputy director, it will be hard to move from today's population-based therapies to drugs targeted to individuals most likely to respond. One such effort is being launched by the Critical Path Institute (C-Path, Tucson, AZ, www.cpath.org), a nonprofit organization founded by Ray Woosley with support from FDA, SRI International, and the University of Arizona. C-Path has launched a Toxicogenomic Cross Validation Consortium to bring together pharmaceutical companies to validate each other's safety test methods. Six leading firms are participating, and FDA hopes to use the results to develop guidances on applying new technology for preclinical safety screening.
In a separate effort, FDA announced in November a project to develop assays for drug liver toxicity. FDA's National Center for Toxicological Research (NCTR, Jefferson, AR, www.fda.gov/nctr) and Massachusetts-based BG Medicine (Waltham, MA, www.bgmedicine.com) have signed a CRADA for a liver toxicology biomarker study to identify standard tests for the early stages of drug development. The aim is to assess liver toxicity problems that often are a main cause for drug development failures. The project will examine data from pharmaceutical companies that, in turn, gain access to project data and the opportunity to license discovered biomarkers.
Internally, FDA is surveying its medical officers about what biomarkers have been used in applications and accepted as surrogate endpoints over the years. FDA plans to form a working group to develop guidance on biomarkers and to support Critical Path collaborations.
FDA's pharmacogenomics initiative also is providing important information about how industry is using genomic data to identify drug targets and devise development programs. In March 2005, FDA established a voluntary genomic data submissions process, which encourages pharmaceutical companies to share pharmacogenomics data with the agency under a program that allows the discussion of development issues outside the normal application review process. FDA has received some 30 submissions dealing with a broad range of research issues that are being addressed by a special pharmacogenomics review group. FDA has included the European Medicines Evaluation Agency in some meetings to encourage a common approach to assessing genomic submissions, which may become a topic for review by the International Conference on Harmonization.
FDA staffers also hope to issue a draft guidance on drug–diagnostic codevelopment in the near future. This guidance will describe how to link the development of targeted drugs with a test or diagnostic to identify individuals with a genetic makeup which responds to a product. Diagnostics are crucial to the development of personalized medicines, but appropriate timing of drug and diagnostic development is a big concern, along with fear that FDA may require codevelopment with certain new drugs.
Streamlining clinical trails
Another major Critical Path effort involves using models and new approaches to make the clinical research process more efficient and less costly. Model-based drug development involves using Bayesian statistical methods to better predict clinical trial outcomes. The aim is to get the dose correct early in the drug development process to reduce Phase III study failures, which continue to run a 50% drop-out rate. Such approaches can provide information that is useful for deciding to halt development early, and can help avoid killing a good drug.
Clinical trial enrichment approaches also can improve the research process by selecting clinical trial participants that are more likely to respond to a drug or less likely to experience safety problems. Such methods may indicate safety and efficacy more quickly and efficiently, although they may result in narrower labeling.
One issue being examined is to what extent sponsors must collect and evaluate electrocardiograph data to assess drug-induced cardiac toxicity. FDA has established a CRADA with Mortara Instrument (Milwaukee, WI, www.mortara.com) to operate an electrocardiograph warehouse system that can receive electrocardiograph data from pharmaceutical companies, instead of the summary information that sponsors traditionally submit. The Duke Clinical Research Institute (Durham, NC, www.dcri.duke.edu) seeks to build on the warehouse project by establishing a collaboration with the industry to examine whether QT prolongation data really reflect the risk of cardiac adverse effects, such as Torsade de pointes. Manufacturers have expressed concerns about sharing electrocardiograph information with anyone outside FDA, even data from placebo studies. Pharmaceutical companies acknowledge that they are dropping the development of test compounds at an early stage because of QT prolongation effects and that this is an area in which more valid markers are needed. FDA views this cardiac safety collaboration as a potential model for other efforts and is working with the parties to overcome multiple hurdles.
Although FDA's campaign to update good manufacturing practices has launched several projects in this area over the past two years, the Critical Path initiative aims to generate collaborations to further encourage innovation in manufacturing practices. To assess factors that block scale-up from test drug to commercial production scale, CDER's Office of Pharmaceutical Science is establishing a CRADA with Conformia Software Inc. (Sunnyvale, CA, www.conformia.com) to survey the industry about what issues affect the selection of drug candidates for commercial manufacturing. Conformia plans to survey industry research and development and regulatory personnel at 25 manufacturers about development information bottlenecks, pilot-plant information management, quality systems, development challenges, and manufacturing science. Participating companies will gain confidential reports about their processes, and FDA will receive a summary designed to help it develop policies related to quality drug manufacturing.
In addition, a group of 11 leading universities headed by Purdue University (West Lafayette, IN, www.purdue.edu) has formed the nonprofit National Institute for Pharmaceutical Technology and Education (NIPTE) to address manufacturing and scientific issues that affect variability in drug development. NIPTE signed an agreement with FDA in June 2005 outlining its plan to work jointly with manufacturers and FDA on research and educational projects to improve pharmaceutical manufacturing science and technologies. FDA will provide scientific expertise to NIPTE and consider its recommendations in developing new policies and guidances. The group seeks $25 million per year for five years from Congress and other government agencies to establish Centers of Excellence that will launch specific projects to reduce the high cost of drug development.
Although industry and academia must take the lead in addressing these issues, FDA recognizes the need for a better toolkit to reduce the amount of uncertainty in the drug approval process. "We're beat up for not approving things that ultimately prove to be beneficial because we're uncertain about the benefits," Woodcock complains. "And we're beat up if we approve something and then a subgroup turns out to be harmed by it. It's a no-win situation for the regulators because there are going to be people who benefit, and there are going to be people who are harmed. What we need to do is fundamentally change the dynamic and to focus therapy on the people who benefit."
FDA does not fund research, Woodcock acknowledges, but the agency has a responsibility to improve its rules and evaluation processes to facilitate drug development. She envisions new analytical and evaluation processes that can sort out people at high risk for an adverse event and who should get a much lower dose of a drug. "FDA sits at the intersection between basic science and product development, and we know where the critical lesions are," comments CDER's Throckmorton. Thus, the agency can work with people to identify the tasks and tests so that it can use that information to make regulatory decisions. FDA is cosponsoring meetings and urging collaboration and data pooling to address some of the key scientific issues in pharmaceutical research and development. In the end, FDA hopes to use the findings from emerging collaborations in formulating innovative policies and standards.
Jill Wechsler is Pharmaceutical Technology's Washingtoneditor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org.