Speeches & Testimony

THERAPEUTICALLY EQUIVALENT BIOLOGICS

Abbey S. Meyers
President
National Organization for Rare Disorders (NORD)


Capitol Hilton Washington, DC March 19, 2003

Welcome. I am Abbey Meyers, President of the National Organization for Rare Disorders (NORD). NORD is a voluntary health agency dedicated to the identification, treatment, and cure of rare "orphan diseases" through programs of education, research, advocacy, and services to patients and families. There are an estimated 6,000 rare disorders that combined together affect approximately 25 million Americans.

We are here today to identify and discuss an issue that affects not only people with rare diseases, but all consumers with serious medical conditions. The goal of this conference is to identify the major issues surrounding access of patients to therapeutically equivalent biologic treatments. We will raise questions about the scientific, economic, regulatory feasibility and desirability of multiple-source biologics. This meeting is designed to be a catalyst for raising public interest and encouraging public debate about these issues.

We will use the term "therapeutically equivalent" and "generic" interchangeably because the public already understands the term "generic drugs". We understand that the term "generic" for biologics differs from "generic" as used for drugs, because we realize that biologics are human proteins, enzymes, blood or plasma products, while drugs are replicable chemical entities. In using the term "generic biologic", we will assume that it is a therapeutically equivalent biologic, and that it must be equally safe and equally therapeutic to the innovator product for it to gain FDA marketing approval.

NORD's interest in therapeutic equivalents, or what we are calling "generic biologics", is multidimensional. Molecular biology and molecular genetics hold the promise of developing whole new classes and types of therapies to prevent, treat, or cure diseases. This is the case not only for rare diseases, called "orphan" diseases because they affect fewer than 200,000 patients in this country, but also for common diseases. Moreover, these new scientific fields are likely to create small subsets of patients with common diseases who respond to highly targeted therapies. So, subgroups of patients with common diseases will ultimately fall into "rare" disease classifications of those common diseases. Today, according to a Tuft's University study, approximately 65 percent of FDA-designated orphan products (those for patient populations of fewer than 200,000 people in the U.S.) were developed by the biotechnology industry.

What are the concerns? The first is access. Most orphan biologics are made by only one manufacturer. This is the case even after the manufacturer's seven-year orphan product exclusivity or their patent expires, because currently there is no apparent pathway for FDA approval of generic biologics. We have experienced critical shortages of several lifesaving biologic treatments, sometimes repeatedly over the years, because the sole manufacturer has not been able to make enough product, or has had problems with production. For instance, we have experienced repeated shortages of recombinant Factor VIII for hemophilia, and Prolastin for Alpha-1-Antitrypsin deficiency, which triggers rationing of these treatments. These shortages are omens for lack of needed biologics for other diseases in the future. This is unacceptable, particularly because the biotech industry appears so vulnerable to manufacturing limitations.

The second concern is financial access to needed biologics. Access to affordable treatments is a question repeatedly raised by our health insurers, Medicaid, Medicare, and healthcare providers. Generic drugs are significantly less costly to patients and their insurers than are brand name drugs. Would this be the case for generic biologics? We need to learn what the economic consequences are likely to be. The orphan disease community recognizes the critical importance of the biotechnology industry in the development of new treatments because approximately 5,000 of the 6,000 orphan diseases are genetic disorders, and many will need enzyme, hormone, and protein therapies that are biologics, not traditional drugs. Yet today, most biotech companies are start-up firms. Financially, they say, they must charge very high prices for their products to recover a return on their costly investments. But as biotechnology treatments proliferate, the health care system could implode as a result of these extraordinary costs. In the heated debate about health care costs, however, especially the rising cost of prescription drugs, but also the rising costs of some generic drugs, there has been little discussion about the likely effects of developing and marketing generic biologics. If they will be less expensive, how much would the cost be reduced?

Third, we are concerned that lack of competition in biologics may impede new treatment advances. If biotechnology companies are able to continue to charge very high prices for their products, without competition from generic manufacturers, there may be little incentive to continue to innovate and make better and safer biologics. We look at the incentives that the "Waxman-Hatch" Drug Price Competition Act has provided to brand name drug manufacturers for improvement of their older drugs. When a patent is about to expire, many brand name companies do what they do best - they innovate. They devise long-acting versions of their old drugs, or they make oral versions of old injectable drugs, or they develop skin patches instead of pills, etc. These are improvements that consumers want and need. But without a pathway for competitive biologics, there is no incentive for manufacturers to develop improved versions of their old injectable or intravenous biologic treatments.

We understand that the first and foremost issue in determining the feasibility of generic biologics is scientific. Can therapeutically equivalent biologics be developed? Is it scientifically feasible? Does the scientific feasibility vary according to type of biological entity? Scientists have been silent on this critical issue, and we desperately need them to devote their expertise to addressing these questions.

Some scientists we've talked with say that it is not scientifically possible to develop generic biologics. Minor differences between products can make a major difference not just in efficacy, but in safety. Other scientists we've talked with say that of course it's possible to make "therapeutically equivalent" biologics. They point to multiple brands of human growth hormone, insulin, estrogen, interferon, etc., and they tell us that FDA is planning to accept abbreviated applications for generic versions of some of these products because of a legal loophole; they were initially approved as "drugs," not biologics. Moreover, generic biologics are available in eastern European countries and Asia. Apparently these products are safe, effective, and less expensive in those countries. The scientific issues of bioequivalence are the most important of the current dialogue, and we applaud the U.S. Pharmacopoeia (USP), which will be holding a conference this spring to focus on these critical scientific issues.

The scientific questions have a direct relevance to the possibility of FDA marketing approval for therapeutic equivalents. Experts tell us the FDA has no apparent regulatory pathway to approve copies of biologics. The agency says that all biologics are "different," and that their efficacy and safety depend upon how they interact with the body. In the past, the FDA Center for Biologics Evaluation and Research (CBER), which had jurisdiction over therapeutic biologics, said that each manufacturer must perform all clinical research necessary for any new biologic. This differs from regulatory approval of generic drugs, which do not have to undergo extensive clinical testing. Obviously it is less expensive to develop a generic copy of a pharmaceutical compound than it would be to copy a biologic because there is a less expensive "abbreviated" pathway for generic pharmaceuticals. Would it be possible to design a briefer and less expensive standard for clinical proof of biologic equivalency?

There have been a few instances where there are multiple manufacturers of a particular biologic treatment, such as human growth hormone, the interferons, insulin, or growth factors. But the FDA has determined that because each biologic is "different", each brand has to be fully tested as if it was a brand new product. The 1984 "Waxman-Hatch" generic drug law does not apply to biologics, so FDA says it is legally prevented from accepting "abbreviated" applications for generic biologics, as it does for generic drugs. Therefore, right now copies of biologics tend to cost the same as the brand name products, and there is no advantage to consumers.

Frankly, we have been confused by FDA's response concerning therapeutically equivalent orphan biologics: Under the Food, Drug, and Cosmetic Act, FDA tells us that all biologics are "different" and every sponsor must file a BLA for each biologic. But, for the purpose of the Orphan Drug Act, FDA says that all "similar" biologics are the "same" as the brand name product, unless they can prove that they are "different". These seem like disparate points of view that depend upon which office you're standing in when you ask the question. We need regulatory experts to tell us whether there is a current regulatory pathway for generic biologics, and if not, what mechanisms would be needed to create such a pathway?

Based on the scientific and regulatory discussions, we also need to hear from economists about the financial implications. In the case of the multiple manufacturers of human growth hormone, or interferons, or growth factors, each manufacturer's price has been similar to the innovator's price. So, even though there are multiple versions of one biologic on the market, there are no cost savings to patients or their insurers. Would the cost for generic biologics be significantly lower than the cost for the innovator biologic if abbreviated applications are never acceptable to the FDA? What factors would lower costs to consumers?

The National Organization for Rare Disorders (NORD) does not have the answers. We simply want to raise the questions, and to compel the experts to help us think through the answers, so that others, and we, can be informed participants in the debate that needs to happen. We must face these issues now for the sake of the future: access, safety, availability, efficacy, costs, and free market competition. Let the debate begin.