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FDA-DIA Scientific Workshop on Follow-on Proteins

February 16, 2005

Closing Remarks from Gordon Johnston, GPhA VP for Regulatory Affairs
February 16, 2005

I want to thank FDA and DIA for the opportunity to summarize the position of the Generic Pharmaceutical Association regarding the critical need to establish a definitive, flexible and science-based abbreviated approval process for affordable biopharmaceuticals.

This DIA and FDA Scientific Workshop has been a useful forum to confirm the science underlying biogenerics. We believe this forum has indeed pushed us closer to our goal -- that is, providing consumers with timely access to affordable biopharmaceuticals. As numerous GPhA members noted during this forum, safety and efficacy are of the utmost importance, and affordable medicine truly impacts the patient who might otherwise not have access.

We always must be mindful of allowing science to be the engine that makes these important products available to those who are in need.

Today, the question is not ‘if’ generic biopharmaceuticals will become a reality, it is ‘how.’ Recalling FDA’s previous experience with abbreviated data packages to approve biological products, as well as scientific principles outlined by Drs. Cooney, Sasisekharan, and Kozlowski, among others, provided a firm foundation for moving forward.

A lot has been written and said about this issue, including here, in the first FDA Scientific Symposium, in Congressional debate, and in the media, regulatory and scientific arenas. But GPhA believes that all parties -- including brands, academics and generics -- can and should agree on several significant points.

First, all parties should agree that safety and efficacy must be the primary objective of establishing a definitive abbreviated process for the approval of generic versions of biopharmaceuticals. It is an important, fundamental principle that will be ensured by both industry and FDA.

Second, all parties should agree that biopharmaceuticals comprise a continuum of complexity from relatively simple biopharmaceuticals, such as penicillin, as mentioned by Dr. Cooney on Monday, to those that are highly complex. As such, a “one-size fits all” technical and regulatory paradigm would be inadequate.

Third, while we should all agree, it appears that academia and the generic industry generally believe that an abbreviated regulatory process is clearly within the scope of current science. Thus, it is possible to codify a regulatory process that will permit approval and marketing of a vast array of biopharmaceuticals with relatively low to modest complexity, and to expand that system in the coming years to permit the approval of generic versions of even the more complex products.

It is safe to say, however, that the parties differ on some issues of science. In general, the discussions have split along the lines of pure science and “economic science.” Given the split of scientific and business interests, the parties will never agree on the fundamental question of this forum, which is “Can a definitive, flexible abbreviated approval process be immediately established that will enable the timely introduction of safe and effective affordable biopharmaceuticals?” Our industry response to this question is a resounding, “Yes”.

Yes -- it is time to codify a regulatory pathway for the introduction of affordable biopharmaceuticals and for FDA to issue its recommended scientific principles for an abbreviated pathway. These principles should be based on the agency’s historic experience with these products as well as the scientific approaches discussed at both of the workshops on this topic. When one filters out the brand’s rhetoric, it is abundantly clear that the science supports such a framework.

Science and technology have progressed rapidly. Just a decade ago, we would not have been discussing the possibility of affordable biopharmaceuticals. As Acting Commissioner Crawford said last year, “Two years ago, the scripted answer was ‘they’re too complex, we can’t do that.’ And ‘everybody knows you can't have generic biologics. Well, they're not any less complex, but the means of evaluating them biochemically and with instrumentation is very much improved over those two years. We're very committed to try to put in place a reasonable way of dealing with generic biologics. No longer will we answer by saying 'the complexity's too great, we'll get back to you in another decade. Those days are over. We have to put a system in place to deal with it.”

In fact, Dr Cooney, the Acting Chair of FDA’s CDER advisory committee for pharmaceutical science, remarked that “it is the incorporation of prior knowledge, innovation of new technology and new methods, and publicly available data that defines the operative space we work in.” Approval of generic versions of biopharmaceuticals can operate within those parameters by using current knowledge coupled with modern techniques and methods that are more predictable and less costly.

The immediate implementation of a definitive abbreviated approval framework -- driven and supported by science -- must be based on the principles of comparability. This approach is not new. Rather, it is an extension of scientific principles on comparability and abbreviated approval processes that was formalized in the FDA almost a decade ago. These very principles already are used to permit brand manufacturers to change the production process, cell line, manufacturing site, and formulation of many biologics, such as recombinant proteins and monoclonal antibodies, without clinical data supporting safety and efficacy. They have also permitting albumins and allergenics, among other products, to come to market with abbreviated data packages.

The primary basis for the abbreviated approval process should be a comparison of the brand and generic biopharmaceutical. A scientific framework for the approval of abbreviated data packages of biopharmaceuticals should be based on the complexity of the product on a case-by-case basis.

At the heart of this approval system are product comparative characterization studies. And, as we all recognize, state of the art characterization technology consists of physicochemical, immunochemical, and in vitro biological studies. Those physical and chemical studies include, but are not limited to, the proteins’ sequences, disulfide linkages, and three-dimensional structure. These studies also use such analytical tools as mass spec, circular dichroism, near Infra Red, and NMR, among others. Significantly, these tools have been refined to provide dramatic increases in sensitivity over time. For example, at this meeting we were informed that mass spec methods have increased in sensitivity by about one million-fold over a mere ten-year period.

Moreover, it also is time to recognize that FDA has accepted comparative characterization studies under a comparability approach as evidence to support many brand product and manufacturing changes. In fact, FDA’s Dr. Stephen Kozlowski opined that under the agency’s comparability approach, “structure equals function.” In other words, based on adequate characterization and historical use, a biopharmaceutical product can be recognized as safe and effective for its intended use based on analytical and biological characterization.

And, as we heard from MIT Professor Dr. Ram Sasisekharan, not only has the technology to characterize proteins significantly progressed, but also the science and methods to characterize glycans. Current technology allows us to characterize simple to moderately complex glycan products. As for more complex products, he noted that the technology exists to build an “equivalence window” using a suite of commonly available analytical tools to establish product aspects that can define equivalence. It is possible to do this today, and we support this concept.

Thus, many analytical tools are readily available to compare the physical, chemical and biological parameters of affordable biopharmaceuticals and their brand counterparts. And, we believe that a scientifically sound selection of orthogonal parameters and state of the art methods, ones that match the complexity of the product, can result in a complete picture of most biopharmaceutical products.

Of course, the extent of other studies at the subsequent levels under our approach should be determined on a case-by case basis. This can be accomplished according to the level of understanding gained from the initial physico-chemical and biological analyses. The range of studies include PK studies, PD studies, animal, and targeted clinical trials using surrogate markers or phase III clinical efficacy endpoints, if necessary.

We strongly believe that human PK/PD studies, in conjunction with adequate characterization, can support approval of many affordable biopharmaceuticals. And, in some very complex cases, additional clinical study data may be needed to confirm safety and efficacy of the product.

Rest assured, generic biopharmaceuticals will also follow the same rigorous pharmacoviligance requirements as their brand counterparts.

Dr. Mark McClellan, the former FDA Commissioner, supports these concepts. Last year he said, “The science may be adequate now to proceed on several relatively simple biologics that were approved as NDAs, and hence are subject to the Hatch-Waxman laws. This includes certain older forms of hGH, insulin, and some interferons. These initial steps will also provide a useful foundation for considering the further scientific and legal developments required to support larger-scale generic biologics in the years ahead.” We wholeheartedly agree.

Finally, given that this is a question of science, Congress should ensure that those decisions are made in the arena best suited for their resolution, namely, within FDA.

American consumers rely on FDA to make the right scientific decisions regarding brand product formulation, manufacturing, and product specification changes based on comparability and risk assessment. The FDA approval process remains the world’s gold standard for drug approvals because it is based on a robust application of science and technology. As a result, America’s medicines are, and continue to be, the safest in the world.

We need to avail ourselves of FDA’s scientific expertise and judgment. FDA often makes risk-based decisions regarding groundbreaking therapies with data from limited testing and patient exposure, such as with orphan drugs, and through other accelerated approval mechanisms. FDA should apply the same risk-based decision-making to all facets of the approval process for affordable biopharmaceuticals, including immunogenicity. If the product risk profile is the same -- or less -- FDA should be able to approve the product and provide consumers with a choice.

Two years ago, Dr. McClellan remarked that “without a system to allow for approval of lower cost alternatives, spending on biomedical innovations would become unsustainable.”

We couldn’t agree more. Already, marketed biopharmaceutical products account for approximately $30 billion in U.S. sales and 12% of total pharmaceuticals. By 2010, sales are expected to exceed $60 billion. Because of their exceedingly high costs, biopharmaceuticals will consume a greater percentage of healthcare expenditures in the future and substantially burden health care purchasers, including the federal government, employers and consumers.

For example, the average cost to a major U.S. employer for a one-day supply of biopharmaceutical drugs is $45, while traditional drugs cost an average of $1.66 per day. Today, generic medicines can cost up to 80% less than their brand counterparts and save billions each year. Affordable biopharmaceuticals, even if they represented only a modest segment of the market, would create billions of dollars in savings each year.

For more affordable versions of generic biopharmaceuticals to reach the market, FDA must take affirmative action now to create a definitive, flexible and abbreviated approval pathway. Four years ago, FDA announced that it would be working on two biologic guidance documents on insulin and human growth hormone. According to news reports, those draft guidances were expected to be issued in sixty days. More than a thousand days later, we are still waiting.

Based on the existence of sound science, we strongly urge FDA to immediately issue its white paper as well as agency guidance documents in this area to provide timely advice to industry participants.

Given the significant lapse of time since FDA’s initial announcement, it is only right for FDA to provide an accelerated timeline so that the agency can demonstrate to the public that progress that is being made. We also urge FDA not to hold up the approval of products while it prepares to issue the guidance documents.

In addition, Congress should immediately provide FDA with the authority to make the scientific decisions, so that there will be no gaming of the approval process by special interests, and to allow FDA to do what it does best -- evaluate science and approve drugs.

In sum, as the nation debates how best to provide financial security for aging Americans, we cannot neglect available strategies to ensure that prescription medicines and good health care remain affordable. The good news is that the science of biopharmaceutical technology now is producing exciting new medicines that provide enormous benefit to millions of patients each year. The bad news is that without generic versions, the cost of these medicines will indefinitely place a tremendous financial burden on the health care system. Fortunately, Congress, with the assistance of FDA, can help secure the future of Americans’ health by establishing a definitive, abbreviated approval process for affordable biopharmaceuticals.

There is no reason to delay consumer access to affordable biopharmaceuticals when sound science supports their approval under a shortened and less costly abbreviated approval pathway. This workshop demonstrated that there are scientific approaches that permit abbreviated data packages that will assure safety and efficacy of low to moderately complex biopharmaceuticals.

We look forward to a continued partnership with FDA to finalize this abbreviated pathway and to resolve outstanding issues surrounding more complex biopharmaceutical products.