207 Regulatory affairs Regulatory frameworks and decisions matter to the development of biotechnology and the approvals for biotechnology products Editorial overview Gilbert S Omenn Addresses University of Michigan Medical MI 48109-0624, USA; e-mail: Current Opinion School, Medical email@example.com in Biotechnology 1999, Sciences I, Ann Arbor, 10:287-288 http://biomednet.com/elecref/0958166901000287 C Elsevier Science Abbreviation FDA US Food Ltd ISSN and Drug 0956-l stipulations by these agencies and by the manufacturing practices inspectors of the FDA. The release of organisms, whether genetically modified or not, into the general environment or into controlled agricultural settings posed quite different sets of questions and raised quite different historical analogies. 669 Administration ‘I‘he most crucial general policy decision by regulatory agencies in the Ilnited States. Hurope, Japan. and other countries dealing with diverse products from biotechnology is whether to regulate the product or the process. In the late lY7Os, the ITS Food and Drug Administration (I:I).4), stimulated by the Industrial Applications Subcommittee of the Interagency Recombinant I)NA Advisory Committee, determined that various kinds of therapeutic agents synthesized with techniques of’ genetic engineering or biotechnology would be reviewed for purity, safety, and efficacy, just like their counterpart therapeutic agents. No presumptions of special hazards and no additional protocols for biotechnology methods would be laid on [l]. -I-his decision was not shared universally by regulatory agencies. In the cases of bioenginerred pesticides, regulated by the IJS Environmental Protection Agency (EPA), and genetically modified crops or animals, regulated by the Ijepartment of Agriculture. the methods themselves were the centerpiece of new or modified regulatory frameworks. Focus on the methods led to protocols for special research studies and special risk assessments at the EPA, and debates within and across the agricultural and environmental communities about the biological, social, economic, and political risks of introducing modified species [Z.;i]. The different strategies of the different agencies are quite understandable. New therapeutic agents are governed by the Food, Drug, and Cosmetics Act and its amendments, which require the FDA to balance any potential risks to patients, workers, and the general population against expected benefits to patients for which there are clinical indications demonstrated hy research trials. ‘I‘he use of genetically modified oqqanisnls to produce the agents occurs in closed systems in the laboratory and the pharmaceutical manufacturing plant. In this context, the interests of the Occupational Safety and Health Administration and the National Institute of Occupational Safety and Health were satisfied with rigorous walk-through inspections and In this 1YYY Kegulatory Affairs issue of CZUTOZ~Opinion in we present five cogent papers addressing a broad array of applications and regulatory regimes in the global economy. These papers show that websites are becoming standard references for up-to-date information on the statutes. regulations, policy guidance. and actions of regulatory agencies. Hiotehology, Gordon Binder (pp .W-3(K), Chairman/CEO of Amgen Inc., the premier biotechnology firm, and president of the Pharmaceutical Research and Manufacturers Association, reviews the first year of the implementation of the farreaching provisions of the FDA Modernization Act of 1997 (Public Law 105115, Nov 21. lYY7). ‘I‘his article and other public policy reviews [d,S] document the enormous task for a regulatory agency to implement the complex ptovisions of statutes and their amendments. A program of user fees paid by the pharmaceutical and biotechnology firms that produce the candidate agents, initiated in lYY2, was renewed. ‘I’his program continues to impress both the companies and the patient advocacy groups eager to have evidence on safety and efficacy reviewed promptly, so that patients can gain earlier access to worthy new agents. ‘I-here are critics, however, who complain that the burden of proof has shifted from companies claiming safety and efficacy to FDA staff trying to protect against possible toxicity. The Act also codifies multiple paperwork reduction elements that should be win-win steps, part of the Clinton Administration’s ‘Reinventing Government’ initiative. Fast ‘liack designations have led to competition among companies for the advantage of more expeditious approvals in marketing their products. As Binder notes, however, several features have lagged. including the sensitive matter of prioritizing both existing and new agents for trials in children and the highly competitive matter of marketing to physicians unapproved uses of drugs. biologics, and medical devices based on peer-reviewed articles and possibly even manuscripts not yet published. A federal court has now ruled that FDA restrictions on company statements may violate First Amendment rights ! My impression, overall, is that the FDA has done remarkably well to build and balance a sense of partnership with its several stakeholders - patient groups, pharmaceutical and 288 Regulatory affairs biotech manufacturers, the research and clinical ties, and agency watchdog organizations. communi- ‘I‘he companion paper by ‘l’akao Hayakawa (pp 307-311) of the Division of Biological ( ihemistry and Biologicals at the I%ational Institute of Health Sciences in ‘Ii)kyo, providcs an unusually detailed picture of the approval process for new drugs in Japan. All pharmaceutical companies are now eager to market their products globally, often through corporate alliances. ILnder the International Conference on Harmonization, important eff(,rts have been underway for severdl years to achieve nearly consistent criteria for toxicological studies and for clinical efficacy studies of therapeutic agents and to redlIce the often onerous documentation, requirements for dllplicative research, delays in access for patients, and trade barriers long associated with disparate national policies and practices. ‘I-he Central Pharmaceutical Affairs (:ouncil (CPL4C) described by Hayakawa appears to be a close: parallel to the expert advisor) committees empaneled b;, the IIS FDA. The regulatory- status of diagnostic products and tests is entirely different from that for therapeutics. In many biotech companies, diagnostic tests are part of the business strategy along with therapies. ‘I’homas Frank (pp 289-2833, of hlyriad (Genetic 1,aboratorics in I:tah. explains the regulatory context for diagnostics, using that firm’s cutting-edge experience with gene-sequencing technologies for detecting variants of the genes discovered to predispose women to breast cancer and ovarian cancer (HKL;l/ and RRC42). ‘I’hc critical issue here is whether the conlpany markets a laborar-ory service, covered by the (:linical 1,aboratories Impro\,ement Act ((:I,IA) and administered the (:are Financing by tlealth Administration. or a test kit, which is regulated by the FI)A. \lany of us in the field of clinical genetics recall the extreme caution exercised by the I;DA in approving the test kit for a11 alpha-fete-protein test of maternal strum. now used widely to detect the prescncc of neural tube closure defects in fetuses. ‘I’he I- I>A sought testimony from many professional societies and required genetic counseling as part of the testing. Frank also describes the striking differences in approach and regulation for research laboratories and clinical iaboratorie\. Clinical labs must meet stringent criteria under (X,1/\ for quality control, with stringency related to the complexity of the test. .4n emerging research area with dramatic implications is the production of vectors, cell isolation, and genetic manipulations to permit gene therapy trials for specific clinical indications. Steel and Roessler (pp 295-297), of the IJniversity of Rlichigan Human Applications Laboratory, describe the requirements for <ompliance with each of the scvc’n components of Good Manufacturing Practices (GMP). This regulatory regime is administered in the form of guidelines by the Center for Biologics Evaluation and Research [CBER]) at the FDA. Just as the FDA has effectively encouraged manufacturers of new therapeutic agents to consult openly with FDA staff about the design and endpoints of clinical trials, the FDA strongly encourages academic and commercial production facilities to consult with the CBER about GMP production for the rapidly expanding variety of biologics. Steel and Roessler clarify differences in academic and commercial approaches and in the relevant regulations and guidelines. They illustrate the production facilities required for developments in this field with a brief section about the Human Applications Laboratory in the Ilniversity of Michigan’s Clinical Research Center. ‘I’he international team of Mitten, MacDonald, and Klonus (pp 298-302) presents an update on the regulation of foods derived from genetically engineered crops. Many readers may be surprised to learn how, remarkably, herbicide-tolerant soybean, insect-resistant corn, herbicide-resistant canola (oilseed rape), and insect-resistant cotton have increased their share of the hectares planted with these crops. ‘I‘hese new crops are expected to permit major reductions in use of chemical herbicides and insecticides. ‘I’he Organization for Economic Cooperation and Development and the World Health Organization have embraced the concept of substantial equivalence as the cornerstone of safety assessment for genetically modified foods and crops. ‘I’he authors present a global perspective. The most complex regulatory and political situation is in the European Community, especially with regard to lubeling for consumers. All of these articles paint a vivid picture of remarkable progress and increasingly well-organized and harmonized regulatory frameworks. References 1. Omenn GS: Government as a broker between private public institutions in the development of recombinant applications. In Proceedings of Ihe Battelle Conference Genetic Engineering: 1987 Resfon, VA, vol 1. Columbus: Press; 1981:34-36. and DNA OR Battelle 2. Omenn GS: Controlled testing and monitoring methods for microorganisms. In Biotechnology Risk Assessment. Edited by Fiksel JR, Covello VT. New York: Pergamon Press; 1986:144-l 63. 3. Omenn GS (Ed): Environmental Biotechnology: Environmental Chemicals Through Biotechnology. Plenum Press; 1988. 4. Merrill Affairs 5. Levitt GM, Woody KK: The Food and Drug Administration Modernization Act of 1997: impact and implementation. Business 1999;19-25. 6. RA: Modernizing 1999, 18:96-l Washington Legal edn 2, 51. Federal the 1 1. FDA: an incremental Reducing Risks New York: revolution. from Health J BloLaw Foundation v. Friedman, vol 13 Federal Supplement District Court, Dtstrict of Columbia, 1998.