October 1, 2011 (Vol. 31, No. 17)

Significant Rulings Made Early On Laid the Foundation for Current Growth

Several seminal regulatory decisions made 20–30 years ago enabled biotechnology to flourish in the U.S. and in certain parts of Europe and Asia. Having served as U.S. FDA Commissioner during much of the 1980s, I thought it would be useful to review these developments in light of their effects on the evolution of biotechnology.

The major scientific advances resulting in the advent of recombinant DNA technology (rDNA) in the U.S. were based on extensive fundamental research supported in large measure by the NIH. Scientists called for a research moratorium after DNA from one organism was introduced and replicated in another species in 1973—plasmids containing frog RNA were spliced into E. coli—and when studies demonstrated that a mammalian tumor virus could be replicated in E. coli. The moratorium was followed by a meeting at Asilomar in 1975.

This new technology evoked concern in the scientific, academic, political, religious, and legal communities. The NIH-chartered recombinant DNA Advisory Committee (RAC) extensively debated the path forward and finally issued guidelines for rDNA research.

Frank E. Young, M.D., Ph.D.

However, harnessing this technology to produce medicinal and agricultural products vexed regulatory agencies. I’m sure it is difficult for those who did not live through this contentious period to appreciate the depth of the controversy regarding appropriate boundaries, if any, for industrial-scale production of safe and effective products using rDNA.

A number of key events that shaped much of today’s regulatory landscape occurred in the 1980s and 1990s.

One of the most important FDA statements that greatly stimulated the growth of biotechnology during its formative years was that no NEW regulations would be required for the regulation of recombinant products.

New Legislation

First, did rDNA technology need new legislation or would the usual regulatory framework apply to rDNA-generated biologics and diagnostics? This was a question that would determine the future of biotechnology.

USDA and EPA favored a more stringent regulatory approach, while FDA opined that existing regulations were sufficient to evaluate rDNA products. This was a battleground because a number of congressional and state legislative bills were introduced in the 1970s to regulate rDNA research.

While at the University of Rochester I was heavily involved in rDNA research. My laboratory discovered the third site-specific endonuclease, Bam H1. I was also a participant in the Asilomar meeting, the author of appendix A of the Asilomar guidelines, and served as a charter member of the Recombinant Advisory Committee before joining the government as FDA Commissioner.

This expertise strengthened the resolve of FDA that neither new legislation nor regulations were required. Furthermore, I was charged by Secretary of Health and Human Services Margaret Heckler to revitalize the drug and biologics evaluation process with particular emphasis on biotechnology (as well as on medical devices, including diagnostics developed through rDNA).

These actions were implemented through an FDA-developed action plan that had input from consumer groups, academe, and industry. The action plan helped galvanize the FDA’s decision-making in formulating the regulatory framework for rDNA and monoclonal antibodies.

Another important development was the decision to divide the Center for Drugs and Biologics into two organizations: Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Biotech products were assigned to CBER because this new field needed to have a cadre of well-trained scientists to evaluate the safety and effectiveness of rDNA and monoclonal antibody products.

Furthermore, it was posited that these reviewers needed time for their own research in molecular genetics and immunology to hone their qualifications for evaluating new scientific advances.

Regretfully, the emphasis on science and biotechnology diminished in the 1990s, but lip service remains. The “research reviewer” is now an endangered species. Physicians and scientists with expertise in biotechnology instead were recruited to the Office of the Commissioner to support domestic and international policy considerations.

Harmonization Issue

During the 1980s, the Office of Science and Technology Policy (OSTP) catalyzed a coordinated framework for the harmonization of regulations throughout the federal government. This required active cooperation by the Department of Health and Human Services (DHHS), EPA, and USDA. Policy differences had to be hammered out. Participants, primarily from FDA, EPA, NIH, and USDA, worked to develop this watershed coordinated policy for harmonizing regulations covering biotechnology.

This process proved successful and regulations, deemed appropriate, were subsequently promulgated in accordance with this framework.

Another major initiative was taken by secretarial-level officials from a number of federal departments and agencies that nominated a Biotechnology Working Group, which was to be composed of representatives from FDA, EPA, NIH, and USDA.

This working group, chaired by the FDA Commissioner, was charged with negotiating the U.S. position on biotechnology at the Paris-based Organization for Economic Cooperation and Development (OECD). More specifically, the working group served as the U.S. delegation to the Ad Hoc Group on Safety and Regulations in Biotechnology of OECD.

An OECD meeting on December 2, 1985, was spirited and contentious. The U.S. team faced strong opposition. After the delegates from other nations stated their opposing views, the multinational group debated policies for the safe use of biotechnology. The U.S. took the following position:

“There is no scientific basis for specific legislation for the implementation of rDNA techniques and applications. Member countries should examine their existing oversight and review mechanisms to ensure that adequate review and control may be applied while avoiding any undue burdens that may hamper technological developments in this field.”

Japan, Switzerland, the U.K., and the U.S. argued that the industrial scale-up of biotech fermentation can be accomplished using low-risk organisms in fermentors following risk-adjusted fermentation procedures. This policy was adopted by consensus. Subsequently, the U.S. working group continued to represent U.S. policy in biotechnology at OECD.

Good Manufacturing Practices

The FDA also led a successful U.S. effort to harmonize the approach to international regulations for manufacture of all drugs and biologics. These Good Manufacturing Practices and Good Laboratory Practices were harmonized through special working groups, OECD, and other organizations to ensure safety in manufacturing with appropriate but not undue regulatory burdens.

Agreements were smoother than the initial negotiations of the Ad Hoc Group on Safety and Regulations in Biotechnology because of consensus at the OECD. In addition, the pressing need for harmonization led to cooperation among the various national regulatory agencies.

Another significant regulatory-related event took place when I, as FDA Commissioner, was nominated by President Reagan and subsequently appointed to serve on the executive board of the World Health Organization (WHO). This enabled U.S. policies developed by the U.S. interagency working group and the OECD to be represented on a larger scale at the WHO.

Since the policies were negotiated earlier at OECD, harmonization at WHO was more readily accomplished. The emergence of AIDS also emphasized the need for new diagnostics, drugs, biologics, and vaccines developed through biotechnology and classical drug development.

Tackling Agbiotech Regulation

The regulation of food products, agricultural crops, livestock, and the environmental use of biotechnology lagged behind the development of medicinal products and diagnostics via biotech methods. Debate regarding the nature of organisms modified by rDNA technology as compared to classical plant breeding approaches continued unabated.

For example, a report that was published in 1993 and prepared by the OECD Environmental Directorate in collaboration with the Directorate for Science, Technology, and Industry stated that foods or food components developed by biotechnology do not lead to foods that are inherently less safe than those developed by conventional techniques.

However, there were others who began to use the term “genetically modified organisms” to refer to those organisms that were modified by recombinant DNA technology. These organisms were implied to be more risky than those developed by the more imprecise traditional plant-breeding techniques. As a result, a new regulatory scheme emerged.

As Max Schmidt, former Commissioner of FDA, once stated: “dogs bark, cows moo, regulators regulate.” Thus began a debate on how much regulation was appropriate.

Additionally, the question of what degree of change in a product should initiate consumer labeling as a potential safety measure became contentious. For example, if a cloned gene was introduced into a turkey, should soup containing 4% turkey meat be labeled as containing a genetically modified organism? Should gelatin from such turkey bones be labeled as genetically modified? The regulatory complexity introduced by the new genetics was illustrated in a report entitled “Strategies for Assessing the Safety of Foods Produced by Biotechnology.”

The report, a joint study by WHO and the United Nations’ Food and Agriculture Organization, noted the following:

“A new paradigm for safety evaluation, with emphasis on molecular, biological, and chemical data and the use of these data to determine the need for appropriate toxicity tests, is recommended. This new paradigm for safety assessment should be applied to all forms of genetic modification of plants, including traditional plant breeding.

“The components of the safety assessment process are essentially suggestions as to the information that may be requested, rather than requirements specifying what should be provided. The detail required will depend on the nature of the genetic modification.”

I strongly recommend that regulatory frameworks covering biotechnology be based on sound science and established by regulators intimately familiar with the field. Furthermore, scientific risk/benefit analysis of regulatory frameworks should be carried out periodically to ensure safety while minimizing regulatory burdens that impede innovation.

Finally, it is important to recognize that the regulatory framework created by the FDA in the 1980s for biologics and diagnostics derived from biotechnology stimulated both the development of biotechnology and the resultant novel products for enhancing human health.

Frank E. Young, M.D., Ph.D. ([email protected]), was FDA Commissioner from July 1984 until December 1989.

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