International Journal of Technology Assessment In Health Care, 8:4 (1992), 573-582. Copyright © 1992 Cambridge University Press. Printed in the U.S.A.
EVOLUTION AND CURRENT STATUS OF THE ORPHAN DRUG ACT Carolyn H. Asbury The Pew Charitable Trusts
Abstract The 1983 Orphan Drug Act was designed in response to market and regulatory disincentives that limited industrial interest in developing drugs needed by people in the United States with rare diseases and conditions. These disincentives evolved from changes in the pharmaceutical industry and in regulatory testing requirements. In the eight years since the Act and subsequent amendments have been in effect, the law has been associated with the new development and approval of 40 marketed drugs and 12 biologicals to treat rare (orphan) diseases. An additional 281 drugs and 141 biologicals have been entered into development and designated as orphans. Finally, the law has mandated exploration of whether the incentives of the Act are necessary and appropriate for stimulating industrial development of orphan medical drugs and devices. Despite this progress, controversies have arisen over three profitable orphan products that have benefited from the law's provisions. This has created the need for continued assessment of the Act's benefits and costs.
The Orphan Drug Act (ODA; H.R. 5238) was signed into law in January 1983 to stimulate industrial development of drugs and biologicals needed by people in the United States with rare diseases and conditions (15). To offset the disadvantages of a small market, the ODA invoked several measures to enhance revenues, including a sevenyear period of exclusivity for a product intended for an orphaned condition and a tax credit for a portion of the expenses related to human clinical trials. The ODA also sought to minimize expenses by requiring the U.S. Food and Drug Administration (FDA) to clarify the regulatory guidelines for the approval of orphan products. The ODA's provisions are focused solely on drugs, biologicals, and antibiotics intended for rare disorders. The law's incentives currently do not apply to similarly intended medical foods and devices, although these products are eligible for federal clinical trials authorized by the law. Moreover, the law is confined to addressing only two factors that confer orphan status: low prevalence of the condition for which the product is intended and the lack of a patent (which confers 17 years of market protection) specifically for products for rare diseases. The law does not address the lack of patent protection for products that are intended for larger markets or product liability. Finally, the law does not directly affect drugs needed in developing countries, although it may indirectly do so if those diseases occur infrequently in the United States. In the first eight years that Public Law 97-414 has been in existence, market availability of newly developed industrial-sponsored drugs, biologicals, and antibiotics for The views expressed in this article are solely those of the author; official endorsement by The Pew Charitable Trusts is not intended and should not be inferred.
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rare diseases has increased nearly fourfold, credited primarily to the provision of market exclusivity (21). Data are not available to determine whether the regulatory provisions have decreased development time or expenses. Also during this time, several modifications have been made to fine-tune the law, including controversial amendments intended to close perceived loopholes in the market exclusivity provision. These amendments were passed by Congress in 1990 but were vetoed by the president that year. The issue remained controversial during discussion of the 1991 congressional legislative initiatives concerning orphan products, in which recommendations were made to remove market exclusivity after total sales reached $150 million. This article is intended to provide an historical perspective on the approach to orphan drugs taken in the United States and to identify briefly a few international efforts stimulated by the United States' experience.
THE EVOLVING NEED FOR SPECIAL MEASURES The ODA emerged from a confluence of technological advances, public and congressional concern, and heightened responsiveness of regulatory and industrial entities in the United States. In part, the orphan status of products for rare diseases was a casualty of the evolution of the pharmaceutical industry and the laws pertaining to protection of its products. Early Industrial and Patent Changes
While in the early part of this century pharmaceutical firms competed through prices for similar products and advertised directly to the consumer, in the 1930s and 40s, two profound changes occurred in the pharmaceutical industry. The first was the discovery and development of antibiotics to treat infectious diseases, transforming medical therapy. The second was a ruling by the U.S. Patent and Trademark Office that although antibiotics were formed from natural substances not eligible for product patent protection, they were patentable as medically useful entities. Pharmaceutical firms capitalized on this situation by becoming vertically integrated organizations that relied on patentable products, intended for large markets, to fuel further research and development (R&D); this fostered competitive advantages through the introduction of new products (37). Regulatory Changes
Ironically, the antibiotic sulfanilamide, which helped to usher in this new era of therapeutic opportunities, also precipitated new FDA safety testing requirements in 1938 after an elixir used to deliver the product in liquid form was found to have caused more than 100 deaths (35). Manufacturers then were required to provide evidence that drugs were relatively safe. With the new scientific base, drug development proliferated. In 1955 alone, for instance, 357 new products were approved by the FDA (18). Yet, as of 1965, only four products had been marketed by industry for rare diseases, while an additional 34 experimental products were available to specialists (27). Recognizing the paucity of industrial interest in cancer drugs, despite technological feasibility, the National Cancer Institute (NCI), one of the National Institutes of Health, sought to facilitate product development. The NCI invited industry to submit chemicals to an NCI screening program. Those that were identified as bioactive and potentially promising were funded by the NCI for further testing (7). Development of drugs for diseases or conditions with relatively low prevalence had become particularly problematic in the 1960s after the 1962 Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act tightened safety testing require574
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ments and also required that evidence of a drug's efficacy be provided to the FDA for approval before its interstate sale. By the late 1960s, when this amendment became operational under administrative rules established by the FDA, a three-stage process was implemented for investigating products in human clinical trials after initial animal testing. Referred to as an Investigational New Drug (IND) application, the product is provided first to a small number of healthy volunteers to assess relative safety; then to a small number of patients to assess safety and efficacy in treating the condition(s) for which it is intended; and, finally, to a large number of patients to assess safety, efficacy, and optimal dose. This information is then provided to the FDA in a New Drug Application (NDA) for approval review. During the late 1960s and 1970s, this process required an increase in development time of at least two years, to an average of about five years, and R&D costs grew from approximately $4.7 million to an estimated $54 million (14;31). Because drugs for rare diseases generally meant a small return from sales on this R&D investment, they too became a rare occurrence. THREE DISINCENTIVES: SMALL MARKETS, UNPATENTABILITY, AND PRODUCT LIABILITY
By the late 1970s, increasing numbers of articles were appearing in the scientific literature describing the difficulties that clinical researchers were having in translating encouraging scientific results into commercially available products for patients with rare diseases and conditions. Researchers reported problems in interesting pharmaceutical firms in "adopting" chemicals or biologicals that showed therapeutic promise and in undertaking further development or securing FDA approval (7;38). Firms cited such obstacles as finding sufficient numbers of eligible patients to participate in clinical trials and determining the likely requirements for clinical trials to demonstrate efficacy with these small numbers of participants. Sponsors that did develop and seek approval for drugs for rare diseases considered them public service products because sales were low relative to the R&D costs incurred. Evidence of an industrial void in the development of drugs for rare diseases was reflected not only by the efforts of the NCI but by other National Institutes of Health programs, such as one to develop drugs for treating epilepsy (7;19). By the 1970s, unpatentable products (shelf chemicals, natural substances, products whose patents had already expired, and those "known" through publication), whether for small or large markets, were now relegated to orphan status. The National Heart, Lung, and Blood Institute, for instance, was funding clinical trial research on unpatentable cardiovascular drugs, such as propranolol, intended for relatively large markets (22). The issue of liability also intensified during this time, limiting the industry's interest in contraceptives, vaccines, and, to some extent, substance abuse therapies. Additional disincentives for products for substance abuse were difficulties in recruiting participants into clinical trials, risking image problems by manufacturing products for treating "junkies," and the likelihood that substance abusers would be uninsured and therefore unable to purchase substance abuse treatment, including pharmaceutical therapeutics (4). Finally, for products needed by developing nations, patent protection, product distribution costs, and price issues diminished industry's interest. PRECURSORS TO LEGISLATION
By the late 1970s, the FDA and the Pharmaceutical Manufacturers Association (PMA) were beginning to examine orphan problems and opportunities to address them. The INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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PMA had updated its list of service drugs, which had grown from 34 to 39 products — most of them experimental by 1970. Two federal interagency task forces were convened by the FDA, one in 1974 and the other four years later (9). Concurrent with the 1978 Interagency Task Force, the PMA established its own parallel process to explore issues and develop a new list of service drugs. Journal articles and book chapters contained both the sagas of scientists unsuccessfully trying to interest pharmaceutical firms in adopting their products and industry comments suggesting that promising drugs do make their way into commercial development (1;3;17;32;38;39). This evidence set into motion a loop of events from Congress to Hollywood and back that eventually culminated in the enactment of the ODA. LEGISLATION
The plight of patients with rare diseases first surfaced in Congress through hearings on H.R. 7089 introduced in 1980 by Representative Elizabeth Holtzman. The legislation called for an Office of Drugs of Limited Commercial Value to be established at the National Institutes of Health to assist in the development of drugs for diseases or conditions of low incidence. Compelling testimony by patients with devastating rare diseases for which there was no therapeutic help available was reported in the Los Angeles Times and highlighted in an episode of the television series "Quincy." The series' star, Jack Klugman, joined patients in a 1981 hearing on legislation introduced by Representative Theodore Weiss; all participants stressed that there were no villains, just difficult barriers that needed to be overcome. Shortly thereafter, Representative Henry Waxman, Chairman of the House Subcommittee on Health and the Environment, introduced H.R. 5238, the Orphan Drug Act (4;38). A Congressional Survey
Before holding hearings on H.R. 5238, the Subcommittee surveyed the PMA companies that had sponsored rare disease products to help characterize industrial activities on rare disease drugs to date and to identify some market and regulatory issues that might be amenable to legislative remedy. This information was provided in a subcommittee report (28) and analyzed and reported in a 1985 monograph (4). Firms that were members of the PMA had sponsored 34 marketed and 24 experimental compassionate IND drugs (made available to specialists) for use in rare diseases since 1966. Of the marketed drugs, only 10 had been developed without substantial federal support. An additional 13 approved orphan products had been sponsored directly by federal agencies or academic scientists during this period. Several factors characterized these drugs. Most drugs were for very small numbers of people: 82% of the PMA-sponsored drugs were for conditions affecting fewer than 100,000 people in the United States; 10% were for up to 500,000 people; and the remaining 8% were for up to one million people. Most drugs (83%) had a relatively low return on investment compared to other products that were developed by the companies, while development costs were greater than average for 12%. Many orphan drugs were also useful for common diseases; of the 34 marketed orphan drugs, eight initially had been developed for use in common diseases or conditions. One in 4 of the remaining 26 orphan drugs subsequently had gained supplemental approval for use in a common condition. Therefore, one of the incentives for developing and marketing an orphan drug was the potential that it might later be found useful for a common indication. Conversely, however, because physicians can prescribe drugs for uses other than those contained in the labeling, the ques576
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tion arose of how many other drugs marketed for common uses also might be tested and approved for use in rare diseases if the problems associated with clinical trials and costs could be minimized. Most drugs tended to have patent protection. While nearly two-fifths of the marketed orphan products developed in the 1960s did not have product patents, by the 1970s only 29% were without such protection. This shift suggested that the availability of a patent had become a more prominent market requirement. Drug development and approval times were no shorter than those for more commonly used products. Rare disease drugs took an average of 5.75 years to be developed and slightly more than two years to receive approval. Despite a higher than average price, most drugs had a low return on investment. Retail costs for three-fifths of the drugs were greater than average, while the return on the investment was considered less than average for all but four products. Sales data from other sources suggested that 44% of the marketed orphan drugs had annual sales of less than $3 million each; more than half of these had sales of less than $1 million annually (2). FDA clinical testing guidelines often were considered unclear. Nearly one-half of the drugs' sponsors considered the approval requirements for safety and efficacy to be unclear, and 80% reported that eight FDA guidelines were not a good indication of the data actually required by the agency to secure approval for a drug. Nearly one out of five marketed orphan drugs had been the subject of a liability claim. This suggested that clinical trials might be too small to detect some adverse effects; however, no firm conclusions could be drawn because comparative information is not available on the frequency of claims for products intended for common diseases. Moreover, because liability is adjudicated through state tort rather than federal law, it was not addressed in the legislation (4). During the time that legislation was being considered, several important private sector activities also emerged. The PMA established a Commission on Drugs for Rare Diseases to identify promising therapeutic entities that lack commercial sponsors and to try to facilitate adoption by PMA-member companies. The Generic Pharmaceutical Industry Association similarly has sought sponsorship for more fully developed products. Finally, the National Organization for Rare Disorders (NORD), comprising voluntary health agencies representing up to 20 million people, was highly instrumental in bringing the issues of orphan diseases and drugs to public and congressional attention; NORD also intensified efforts to encourage industrial development and sponsorship and increased informational links between clinical researchers and patients. PROVISIONS OF THE ODA
Survey information, testimony, lobbying, and advice from NORD, pharmaceutical groups, regulators, and scientists helped inform the design of H.R. 5238 to stimulate development and market availability of rare disease drugs and biologicals. In its final form, H.R. 5238 passed Congress in mid-December 1982, was signed into law in January 1983 as Public Law 97-414, and has been amended three times since. The law has three major market provisions. As originally passed, the law accorded a seven-year period of postapproval exclusivity to unpatentable drugs. Market exclusivity is granted only for the orphan indication. Therefore, other products can be approved for that same orphan indication, and products that are identical to one approved for a rare disease can be approved for use in a common disease. Second, the law provided a tax credit to cover 50% of the costs of clinical trials; the remaining 50% of such costs are deductible, resulting in a total reduction in tax liability of 73%. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Third, the law authorized a federal grants program, to be administered by the FDA, to support clinical trials of promising orphan products (40). To implement these market incentives, the law required the FDA to establish a process for identifying and designating drugs and biologicals as orphans, depending upon whether they are intended for a rare disease or condition. This designation originally was to be based on a determination that the condition occurs so infrequently in the United States that the sponsor has no reasonable expectation of its sales generating sufficient revenues to offset development costs. Rather than bring a test of "commercial value," however, this determination was to identify whether the expected low use was the major factor in the decision to develop a drug (24). This process proved unworkable, however, as manufacturers indicated to the FDA that estimates of development costs and anticipated sales revenues were highly speculative so early in the research process, when the degree of safety and effectiveness is virtually unknown (23). Therefore, this criterion was changed in a subsequent amendment. In other regulatory provisions, the FDA also was to provide to sponsors, upon request, recommendations on investigations that likely would be needed and to encourage sponsors to design "open protocols" that would enable physicians to gain access to the product for their patients not participating in clinical trials (if it is the only therapy available). Finally, the law mandated the creation of an Orphan Products Board in the Department of Health and Human Services to stimulate and coordinate public and private orphan product activities (24).
Changes in the Law
The law has been amended three times since its enactment, and a fourth bill to amend the law by closing a loophole in the market exclusivity provision was passed by Congress in 1990, but was not signed into law. First, a 1984 amendment (Public Law 98-551) changed the requirements for orphan designation and based it on a disease prevalence of 200,000 in the United States (33). Products intended for larger populations can receive an orphan designation only if evidence is provided that expected sales in the United States will not cover development costs. This population criterion of 200,000 had been advocated by the Department of the Treasury and the FDA and passed, despite Office of Management and Budget concerns that it might induce manufacturers to use high prices to recover all of their costs, or even turn a profit, within this population ceiling. Within five months of this change, the number of orphan designations granted by the FDA increased from 22 to 53 (41). A 1985 amendment (PL 99-91) extended orphan status to antibiotics, which had been omitted unintentionally in this law; provided market exclusivity to patented orphan products that had little patent time remaining; and established a National Commission on Orphan Diseases to assess public and private sector efforts to develop, approve, and distribute rare disease drugs (29). In 1987, a bill (H.R. 3459) was introduced to allow shared approval of potentially profitable orphan products being developed by more than one sponsor. The bill also sought to extend grants of eligibility to orphan medical foods and devices and to require a study to determine whether the law's incentives are needed, and appropriate, to encourage development of orphan medical foods and devices (25). Controversy that erupted over the proposed shared approval of products precluded passage of the bill. But the provisions pertaining to orphan medical foods and devices were enacted the following year in Public Law 100-190 (30).
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From 1983 through 1990, orphan product development and approval has increased largely as the law intended. Based on a list developed by the FDA in 1989 and supplemented in 1990, 40 orphan drugs and 12 biologicals were developed and approvedall but three sponsored by industry firms. Twenty-six of the 40 approved drugs are new molecular entities (NMEs); the remainder are new formulations, combinations, or indications of existing products (12;13). Most of the NMEs were ranked by the FDA as providing important or moderate therapeutic gains (10). Three products were cited as "breakthroughs in medical therapies benefiting patients with previously untreatable diseases" (erythropoietin for anemia associated with chronic renal failure; alpha-1 proteinase inhibitor replacement therapy for panacinar emphysema; and ganciclovir for cytomegalovirus retinitis) (34). Other important orphan indications include AIDS, various cancers, growth failure, and Parkinson's disease (12). In addition to these approved drugs and biologicals, 281 drugs and 141 biologicals have been entered into development and designated as orphans (13;20). Controversies over Market Exclusivity
Although the FDA provided interim guidelines for obtaining orphan designation, it was not until February 1991 that the agency issued proposed rules, for public comment, to effect the market exclusivity provision (8,11). Lacking these rules, controversies have arisen over three highly profitable orphan products produced by competing sponsors. These controversies initially led to the failed "shared approval" amendments of 1987; they were refined and again introduced in H.R. 4638 in 1990 (16;26). This time, the bill passed, but the president vetoed it. The major issues surrounding all three controversies involve the criteria by which one product is judged to be different from another for purposes of market exclusivity and the question of whether exclusivity in these three instances has created an unnecessary monopoly and high-priced products. All three products have major therapeutic and financial importance. These three cases suggest that, especially in the biotechnology industry (where patent determination decisions are especially difficult), the market exclusivity provision is possibly being used as a substitute, albeit more narrow and shorter, for patent protection (5). In the case of recombinant human growth hormone (r-hGH), Genentech received FDA orphan designation and approval for its product, which is used to treat about 12,000 children in the United States who lack sufficient amounts of the endogenous pituitary hormone. Eli Lilly also sought and received orphan designation and market approval for its product, which is chemically identical to the naturally produced pituitary substance and differs from Genentech's product by one less amino acid group. Genentech unsuccessfully brought legal action to try to bar Lilly's product from the market; instead, the two products share an annual market of approximately $150 million, with annual expenses per child running between $10,000-$20,000, depending upon the dosage needed (5). In the case of aerosol pentamidine, used to prevent HIV-related Pneumocystis carinii pneumonia, Lyphomed received orphan designation and exclusive market approval, barring approval of Fisons' version of the product. Fisons claims it was second in the race because it followed FDA advice about clinical trials. Lyphomed's product, which cost $23 million to develop and will require an additional $15-$20 million for postmarketing studies, costs about $2,400 per patient annually (5).
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The last controversy entails recombinant human erythropoietin (r-EPO), which is discussed more fully elsewhere in this issue. This product prevents the need for frequent blood transfusions for patients with chronic renal failure-related anemia. Amgen Inc. received orphan designation and approval, while Genetics Institute was the first to receive a patent. In a complex set of legal decisions and challenges, Amgen prevailed with seven years of exclusive marketing rights for this indication and is testing the product for use in other conditions as well. Amgen's r-EPO product sales were more than $100 million in its first six months on the market, largely reimbursed by Medicare, which covers dialysis and related therapy for patients with end-stage renal disease (5). Estimates place 1991 sales at $300 million (36). Mainly as a result of these controversies, H.R. 4638 would have a) eliminated orphan status for epidemic-related products whose projected populations would exceed 200,000 within three years of the product's approval; and b) revoked exclusivity for approved products when the population exceeded 200,000. The bill also authorized the FDA to provide shared market access for products that are simultaneously developed for the same orphan indication, with stipulations regarding the amount of time a competing sponsor has to conduct trials and submit an NDA (16). The rationale for the amendments was that shared approval might result in lowerpriced products through competition (although this has not happened traditionally or with r-hGH) and in market access for competing sponsors who otherwise may lose the opportunity to recover R&D costs. The rationale for the pocket veto emphasized that weakening the exclusivity provision might discourage developers from continuing to develop orphan products and that changing the population limit would send the message that government can alter the playing field in midcourse (5). As technology evolves, especially in molecular biology and genetics, controversies over product differentiation decisions and prices may reopen the debate. INTERNATIONAL ACTIVITIES
Two years after the ODA was enacted, the Fulbright Commission sponsored a colloquium in the United Kingdom to explore whether a similar process might be appropriate for the United Kingdom and other European countries. The British drug approval process differs from the United States' system in some respects. The consensus, at the meeting was that the United Kingdom was well-advised to wait and examine the benefits and problems of the ODA in the United States and then determine whether the same approach, or aspects of it, might be appropriately adapted to the British system (6). A few years later, a second meeting was held with representatives from the scientific communities of several European countries. By then, the United States had gained more experience with the law and was beginning to see a substantial response by industry in requesting orphan designation and in moving orphan drugs through the development and approval process. Nonetheless, the representatives at the meeting concluded that any consideration of how to stimulate development of orphan products in Europe should await implementation of the European Community in 1992. Meanwhile, the government of Japan reportedly has begun providing $2 million annually for development of orphan products in that country. CONCLUSION
The ODA and related private sector activities have been associated with an accelerated process of development and market availability of orphan products that often repre580
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sent the only therapy available for people with rare diseases and conditions. However, the law also has created some unresolved issues that need further exploration. The first issue is whether market exclusivity may be serving inappropriately to provide market protection for some products. The second issue is whether some other option needs to be explored to protect biotechnology products, in general, whether for large or small markets. The third issue is whether the law's incentives, or some other mechanism, may be necessary and appropriate for orphan medical foods and devices. These issues present important challenges to a law that has seen many changes to date and has continually evolved to strike a balance between orphan product costs and benefits. REFERENCES
1. Althius, T. Orphan Drugs: Debunking a myth. New England Journal of Medicine, 1980, 303, 1004-05. 2. Althius, T. Contributions of the pharmaceutical industry. In F. Karch (ed.), Orphan drugs. New York: Marcel Dekker, 1982, 185-87. 3. Asbury C. H., & Stolley, P. Orphan drugs: Creating a policy. Annals of Internal Medicine, 1981, 95, 221-24. 4. Asbury, C. H. Orphan drugs: Medical vs. market value. Lexington, MA: Lexington Books, 1985. 5. Asbury, C. H. The Orphan Drug Act: The first seven years. Journal of the A merican Medical Association, 1991, 265(7), 893-97. 6. Bachrach, W. H., et al. Round-table discussion. In I. H. Scheinberg & J. M. Walshe (eds.), Orphan diseases and orphan drugs. Manchester: University Press, 1986. 7. Devita, V. T, et al. The drug development and clinical trials programs of the division of cancer treatment, National Cancer Institute. Cancer Clinical Trials, 1979, 2, 195-216. 8. Federal Register. Orphan Drug Act Regulations. Proposed Rule, January 29, 1991; Part 5, 21CFR Part 316, 338-3351. 9. Finkel, M. Drugs of limited commercial value. New England Journal of Medicine, 1980, 302, 643-44. 10. Food and Drug Administration. NMEs approved 1983-90. Rockville, MD: FDA (compiled annually). 11. Food and Drug Administration. Interim guidelines for obtaining orphan designation of a drug as an orphan drug. Rockville, MD: FDA, November 1984. 12. Food and Drug Administration. Orphan designations pursuant to Section 526 of the FederalFood, Drug, and Cosmetic Act as amended by the Orphan Drug Act (PL 97-414) through December 31, 1989. Rockville MD: FDA, 1990. 13. Food and Drug Administration. Orphan drug designation listing, 1990. Rockville, MD: FDA, 1991. 14. Hansen, R. W. The pharmaceutical development process: Estimates of development costs and times and effects of proposed regulatory changes. In R. Chen (ed.), Issues in pharmaceutical economics, 1980, 151-81. 15. H.R. 5238, 97th Congress, 2nd Session, 1982. 16. H.R. 4638, 101st Congress, 2nd Session, April 26, 1990. 17. Karch, F. (ed.), Orphan drugs. New York: Marcel Dekker, 1982. 18. Kennedy, D. A calm look at drug lag. Journal of the American Medical Association, 1978, 239(5), 423-26. 19. Krall, R., et al. Anti-epileptic drug development I. History and a program for progress. Epilepsia, 1978, 19(4), 393-408. 20. Mossinghoff, G. J., & Copmann, T. L. Orphan drugs in development. Washington, DC: Pharmaceutical Manufacturers Association, 1989. 21. Mossinghoff, G. J. Comments to the Health and Environment Subcommittee, February 7, 1990, 2. 22. NHLBIfact book for fiscal year 1978. Washington, DC: Department of Health, Education and Welfare, 1979, 79-99. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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23. Orphan Drug Act oversight, Hearings before the Subcommittee on Health and the Environment, 98th Congress, 2nd Session, 1984, 719-20. 24. Orphan Drug Act report, 97th Congress, 2nd Session, Report 97-840, part 1, September 17, 1982. 25. Orphan Drug Amendments of 1987 report, 100-473,100th Congress, 1st Session, December 10, 1987. 26. Orphan Drug Amendments of 1987. Report 100-473, 100th Congress, 1st Session. 27. Pharmaceutical Manufacturers Association. Public Service Drugs (unpublished). Washington, DC, 1965. 28. Preliminary report of the survey on drugs for rare disease. Washington, DC: U.S. Government Printing Office, March 8, 1982. 29. Public Law 99-91, 99th Congress, 2nd Session, August 15, 1985. 30. Public Law 100-290, 100th Congress, 2nd Session, April 18, 1988. 31. Report of the panel on chemicals and health of the President's Science Advisory Committee. NSF 73-500. Washington, DC: U.S. Government Printing Office, 1973. 32. Russo, J. Profitable and non-profitable drugs. New England Journal of Medicine, 1978, 299, 156. 33. S.771, 98th Congress, 2nd Session, 1984. 34. Scrip World Pharmaceutical News, January 1989. 35. Silverman, M., & Lee, P. R. Pills, profits and politics. Berkeley, CA: University of California Press, 1974, 86-87. 36. Stavro, B. Investors tracking insiders' stock sales for clues on Amgen. Los Angeles Times, March 27, 1991, Dl. 37. Temin, P. Technology, regulation and market structure in the modern pharmaceutical industry. Bell Journal of Economics, 1979, 10, 427-46. 38. Van Woert, M. Profitable and non-profitable drugs. New England Journal of Medicine, 1978, 298(16), 903-06. 39. Walshe, J. M. Triethylene tetramine dihydrochloride. In F. Karch (ed.), Orphan drugs. New York: Marcel Dekker, 1982, 58-71. 40. Waxman, H. The history and development of the orphan drug act. In H. Scheinberg & J. Walshe (eds.), Orphan diseases and orphan drugs. Manchester: University Press, 1986. 41. Young, F. Testimony before the House Subcommittee on Health on the Environment, 99th Congress, 1st Session, 1985.
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EVOLUTION AND CURRENT STATUS OF THE ORPHAN DRUG ACT Carolyn H. Asbury The Pew Charitable Trusts
Abstract The 1983 Orphan Drug Act was designed in response to market and regulatory disincentives that limited industrial interest in developing drugs needed by people in the United States with rare diseases and conditions. These disincentives evolved from changes in the pharmaceutical industry and in regulatory testing requirements. In the eight years since the Act and subsequent amendments have been in effect, the law has been associated with the new development and approval of 40 marketed drugs and 12 biologicals to treat rare (orphan) diseases. An additional 281 drugs and 141 biologicals have been entered into development and designated as orphans. Finally, the law has mandated exploration of whether the incentives of the Act are necessary and appropriate for stimulating industrial development of orphan medical drugs and devices. Despite this progress, controversies have arisen over three profitable orphan products that have benefited from the law's provisions. This has created the need for continued assessment of the Act's benefits and costs.
The Orphan Drug Act (ODA; H.R. 5238) was signed into law in January 1983 to stimulate industrial development of drugs and biologicals needed by people in the United States with rare diseases and conditions (15). To offset the disadvantages of a small market, the ODA invoked several measures to enhance revenues, including a sevenyear period of exclusivity for a product intended for an orphaned condition and a tax credit for a portion of the expenses related to human clinical trials. The ODA also sought to minimize expenses by requiring the U.S. Food and Drug Administration (FDA) to clarify the regulatory guidelines for the approval of orphan products. The ODA's provisions are focused solely on drugs, biologicals, and antibiotics intended for rare disorders. The law's incentives currently do not apply to similarly intended medical foods and devices, although these products are eligible for federal clinical trials authorized by the law. Moreover, the law is confined to addressing only two factors that confer orphan status: low prevalence of the condition for which the product is intended and the lack of a patent (which confers 17 years of market protection) specifically for products for rare diseases. The law does not address the lack of patent protection for products that are intended for larger markets or product liability. Finally, the law does not directly affect drugs needed in developing countries, although it may indirectly do so if those diseases occur infrequently in the United States. In the first eight years that Public Law 97-414 has been in existence, market availability of newly developed industrial-sponsored drugs, biologicals, and antibiotics for The views expressed in this article are solely those of the author; official endorsement by The Pew Charitable Trusts is not intended and should not be inferred.
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rare diseases has increased nearly fourfold, credited primarily to the provision of market exclusivity (21). Data are not available to determine whether the regulatory provisions have decreased development time or expenses. Also during this time, several modifications have been made to fine-tune the law, including controversial amendments intended to close perceived loopholes in the market exclusivity provision. These amendments were passed by Congress in 1990 but were vetoed by the president that year. The issue remained controversial during discussion of the 1991 congressional legislative initiatives concerning orphan products, in which recommendations were made to remove market exclusivity after total sales reached $150 million. This article is intended to provide an historical perspective on the approach to orphan drugs taken in the United States and to identify briefly a few international efforts stimulated by the United States' experience.
THE EVOLVING NEED FOR SPECIAL MEASURES The ODA emerged from a confluence of technological advances, public and congressional concern, and heightened responsiveness of regulatory and industrial entities in the United States. In part, the orphan status of products for rare diseases was a casualty of the evolution of the pharmaceutical industry and the laws pertaining to protection of its products. Early Industrial and Patent Changes
While in the early part of this century pharmaceutical firms competed through prices for similar products and advertised directly to the consumer, in the 1930s and 40s, two profound changes occurred in the pharmaceutical industry. The first was the discovery and development of antibiotics to treat infectious diseases, transforming medical therapy. The second was a ruling by the U.S. Patent and Trademark Office that although antibiotics were formed from natural substances not eligible for product patent protection, they were patentable as medically useful entities. Pharmaceutical firms capitalized on this situation by becoming vertically integrated organizations that relied on patentable products, intended for large markets, to fuel further research and development (R&D); this fostered competitive advantages through the introduction of new products (37). Regulatory Changes
Ironically, the antibiotic sulfanilamide, which helped to usher in this new era of therapeutic opportunities, also precipitated new FDA safety testing requirements in 1938 after an elixir used to deliver the product in liquid form was found to have caused more than 100 deaths (35). Manufacturers then were required to provide evidence that drugs were relatively safe. With the new scientific base, drug development proliferated. In 1955 alone, for instance, 357 new products were approved by the FDA (18). Yet, as of 1965, only four products had been marketed by industry for rare diseases, while an additional 34 experimental products were available to specialists (27). Recognizing the paucity of industrial interest in cancer drugs, despite technological feasibility, the National Cancer Institute (NCI), one of the National Institutes of Health, sought to facilitate product development. The NCI invited industry to submit chemicals to an NCI screening program. Those that were identified as bioactive and potentially promising were funded by the NCI for further testing (7). Development of drugs for diseases or conditions with relatively low prevalence had become particularly problematic in the 1960s after the 1962 Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act tightened safety testing require574
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ments and also required that evidence of a drug's efficacy be provided to the FDA for approval before its interstate sale. By the late 1960s, when this amendment became operational under administrative rules established by the FDA, a three-stage process was implemented for investigating products in human clinical trials after initial animal testing. Referred to as an Investigational New Drug (IND) application, the product is provided first to a small number of healthy volunteers to assess relative safety; then to a small number of patients to assess safety and efficacy in treating the condition(s) for which it is intended; and, finally, to a large number of patients to assess safety, efficacy, and optimal dose. This information is then provided to the FDA in a New Drug Application (NDA) for approval review. During the late 1960s and 1970s, this process required an increase in development time of at least two years, to an average of about five years, and R&D costs grew from approximately $4.7 million to an estimated $54 million (14;31). Because drugs for rare diseases generally meant a small return from sales on this R&D investment, they too became a rare occurrence. THREE DISINCENTIVES: SMALL MARKETS, UNPATENTABILITY, AND PRODUCT LIABILITY
By the late 1970s, increasing numbers of articles were appearing in the scientific literature describing the difficulties that clinical researchers were having in translating encouraging scientific results into commercially available products for patients with rare diseases and conditions. Researchers reported problems in interesting pharmaceutical firms in "adopting" chemicals or biologicals that showed therapeutic promise and in undertaking further development or securing FDA approval (7;38). Firms cited such obstacles as finding sufficient numbers of eligible patients to participate in clinical trials and determining the likely requirements for clinical trials to demonstrate efficacy with these small numbers of participants. Sponsors that did develop and seek approval for drugs for rare diseases considered them public service products because sales were low relative to the R&D costs incurred. Evidence of an industrial void in the development of drugs for rare diseases was reflected not only by the efforts of the NCI but by other National Institutes of Health programs, such as one to develop drugs for treating epilepsy (7;19). By the 1970s, unpatentable products (shelf chemicals, natural substances, products whose patents had already expired, and those "known" through publication), whether for small or large markets, were now relegated to orphan status. The National Heart, Lung, and Blood Institute, for instance, was funding clinical trial research on unpatentable cardiovascular drugs, such as propranolol, intended for relatively large markets (22). The issue of liability also intensified during this time, limiting the industry's interest in contraceptives, vaccines, and, to some extent, substance abuse therapies. Additional disincentives for products for substance abuse were difficulties in recruiting participants into clinical trials, risking image problems by manufacturing products for treating "junkies," and the likelihood that substance abusers would be uninsured and therefore unable to purchase substance abuse treatment, including pharmaceutical therapeutics (4). Finally, for products needed by developing nations, patent protection, product distribution costs, and price issues diminished industry's interest. PRECURSORS TO LEGISLATION
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PMA had updated its list of service drugs, which had grown from 34 to 39 products — most of them experimental by 1970. Two federal interagency task forces were convened by the FDA, one in 1974 and the other four years later (9). Concurrent with the 1978 Interagency Task Force, the PMA established its own parallel process to explore issues and develop a new list of service drugs. Journal articles and book chapters contained both the sagas of scientists unsuccessfully trying to interest pharmaceutical firms in adopting their products and industry comments suggesting that promising drugs do make their way into commercial development (1;3;17;32;38;39). This evidence set into motion a loop of events from Congress to Hollywood and back that eventually culminated in the enactment of the ODA. LEGISLATION
The plight of patients with rare diseases first surfaced in Congress through hearings on H.R. 7089 introduced in 1980 by Representative Elizabeth Holtzman. The legislation called for an Office of Drugs of Limited Commercial Value to be established at the National Institutes of Health to assist in the development of drugs for diseases or conditions of low incidence. Compelling testimony by patients with devastating rare diseases for which there was no therapeutic help available was reported in the Los Angeles Times and highlighted in an episode of the television series "Quincy." The series' star, Jack Klugman, joined patients in a 1981 hearing on legislation introduced by Representative Theodore Weiss; all participants stressed that there were no villains, just difficult barriers that needed to be overcome. Shortly thereafter, Representative Henry Waxman, Chairman of the House Subcommittee on Health and the Environment, introduced H.R. 5238, the Orphan Drug Act (4;38). A Congressional Survey
Before holding hearings on H.R. 5238, the Subcommittee surveyed the PMA companies that had sponsored rare disease products to help characterize industrial activities on rare disease drugs to date and to identify some market and regulatory issues that might be amenable to legislative remedy. This information was provided in a subcommittee report (28) and analyzed and reported in a 1985 monograph (4). Firms that were members of the PMA had sponsored 34 marketed and 24 experimental compassionate IND drugs (made available to specialists) for use in rare diseases since 1966. Of the marketed drugs, only 10 had been developed without substantial federal support. An additional 13 approved orphan products had been sponsored directly by federal agencies or academic scientists during this period. Several factors characterized these drugs. Most drugs were for very small numbers of people: 82% of the PMA-sponsored drugs were for conditions affecting fewer than 100,000 people in the United States; 10% were for up to 500,000 people; and the remaining 8% were for up to one million people. Most drugs (83%) had a relatively low return on investment compared to other products that were developed by the companies, while development costs were greater than average for 12%. Many orphan drugs were also useful for common diseases; of the 34 marketed orphan drugs, eight initially had been developed for use in common diseases or conditions. One in 4 of the remaining 26 orphan drugs subsequently had gained supplemental approval for use in a common condition. Therefore, one of the incentives for developing and marketing an orphan drug was the potential that it might later be found useful for a common indication. Conversely, however, because physicians can prescribe drugs for uses other than those contained in the labeling, the ques576
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tion arose of how many other drugs marketed for common uses also might be tested and approved for use in rare diseases if the problems associated with clinical trials and costs could be minimized. Most drugs tended to have patent protection. While nearly two-fifths of the marketed orphan products developed in the 1960s did not have product patents, by the 1970s only 29% were without such protection. This shift suggested that the availability of a patent had become a more prominent market requirement. Drug development and approval times were no shorter than those for more commonly used products. Rare disease drugs took an average of 5.75 years to be developed and slightly more than two years to receive approval. Despite a higher than average price, most drugs had a low return on investment. Retail costs for three-fifths of the drugs were greater than average, while the return on the investment was considered less than average for all but four products. Sales data from other sources suggested that 44% of the marketed orphan drugs had annual sales of less than $3 million each; more than half of these had sales of less than $1 million annually (2). FDA clinical testing guidelines often were considered unclear. Nearly one-half of the drugs' sponsors considered the approval requirements for safety and efficacy to be unclear, and 80% reported that eight FDA guidelines were not a good indication of the data actually required by the agency to secure approval for a drug. Nearly one out of five marketed orphan drugs had been the subject of a liability claim. This suggested that clinical trials might be too small to detect some adverse effects; however, no firm conclusions could be drawn because comparative information is not available on the frequency of claims for products intended for common diseases. Moreover, because liability is adjudicated through state tort rather than federal law, it was not addressed in the legislation (4). During the time that legislation was being considered, several important private sector activities also emerged. The PMA established a Commission on Drugs for Rare Diseases to identify promising therapeutic entities that lack commercial sponsors and to try to facilitate adoption by PMA-member companies. The Generic Pharmaceutical Industry Association similarly has sought sponsorship for more fully developed products. Finally, the National Organization for Rare Disorders (NORD), comprising voluntary health agencies representing up to 20 million people, was highly instrumental in bringing the issues of orphan diseases and drugs to public and congressional attention; NORD also intensified efforts to encourage industrial development and sponsorship and increased informational links between clinical researchers and patients. PROVISIONS OF THE ODA
Survey information, testimony, lobbying, and advice from NORD, pharmaceutical groups, regulators, and scientists helped inform the design of H.R. 5238 to stimulate development and market availability of rare disease drugs and biologicals. In its final form, H.R. 5238 passed Congress in mid-December 1982, was signed into law in January 1983 as Public Law 97-414, and has been amended three times since. The law has three major market provisions. As originally passed, the law accorded a seven-year period of postapproval exclusivity to unpatentable drugs. Market exclusivity is granted only for the orphan indication. Therefore, other products can be approved for that same orphan indication, and products that are identical to one approved for a rare disease can be approved for use in a common disease. Second, the law provided a tax credit to cover 50% of the costs of clinical trials; the remaining 50% of such costs are deductible, resulting in a total reduction in tax liability of 73%. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Third, the law authorized a federal grants program, to be administered by the FDA, to support clinical trials of promising orphan products (40). To implement these market incentives, the law required the FDA to establish a process for identifying and designating drugs and biologicals as orphans, depending upon whether they are intended for a rare disease or condition. This designation originally was to be based on a determination that the condition occurs so infrequently in the United States that the sponsor has no reasonable expectation of its sales generating sufficient revenues to offset development costs. Rather than bring a test of "commercial value," however, this determination was to identify whether the expected low use was the major factor in the decision to develop a drug (24). This process proved unworkable, however, as manufacturers indicated to the FDA that estimates of development costs and anticipated sales revenues were highly speculative so early in the research process, when the degree of safety and effectiveness is virtually unknown (23). Therefore, this criterion was changed in a subsequent amendment. In other regulatory provisions, the FDA also was to provide to sponsors, upon request, recommendations on investigations that likely would be needed and to encourage sponsors to design "open protocols" that would enable physicians to gain access to the product for their patients not participating in clinical trials (if it is the only therapy available). Finally, the law mandated the creation of an Orphan Products Board in the Department of Health and Human Services to stimulate and coordinate public and private orphan product activities (24).
Changes in the Law
The law has been amended three times since its enactment, and a fourth bill to amend the law by closing a loophole in the market exclusivity provision was passed by Congress in 1990, but was not signed into law. First, a 1984 amendment (Public Law 98-551) changed the requirements for orphan designation and based it on a disease prevalence of 200,000 in the United States (33). Products intended for larger populations can receive an orphan designation only if evidence is provided that expected sales in the United States will not cover development costs. This population criterion of 200,000 had been advocated by the Department of the Treasury and the FDA and passed, despite Office of Management and Budget concerns that it might induce manufacturers to use high prices to recover all of their costs, or even turn a profit, within this population ceiling. Within five months of this change, the number of orphan designations granted by the FDA increased from 22 to 53 (41). A 1985 amendment (PL 99-91) extended orphan status to antibiotics, which had been omitted unintentionally in this law; provided market exclusivity to patented orphan products that had little patent time remaining; and established a National Commission on Orphan Diseases to assess public and private sector efforts to develop, approve, and distribute rare disease drugs (29). In 1987, a bill (H.R. 3459) was introduced to allow shared approval of potentially profitable orphan products being developed by more than one sponsor. The bill also sought to extend grants of eligibility to orphan medical foods and devices and to require a study to determine whether the law's incentives are needed, and appropriate, to encourage development of orphan medical foods and devices (25). Controversy that erupted over the proposed shared approval of products precluded passage of the bill. But the provisions pertaining to orphan medical foods and devices were enacted the following year in Public Law 100-190 (30).
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From 1983 through 1990, orphan product development and approval has increased largely as the law intended. Based on a list developed by the FDA in 1989 and supplemented in 1990, 40 orphan drugs and 12 biologicals were developed and approvedall but three sponsored by industry firms. Twenty-six of the 40 approved drugs are new molecular entities (NMEs); the remainder are new formulations, combinations, or indications of existing products (12;13). Most of the NMEs were ranked by the FDA as providing important or moderate therapeutic gains (10). Three products were cited as "breakthroughs in medical therapies benefiting patients with previously untreatable diseases" (erythropoietin for anemia associated with chronic renal failure; alpha-1 proteinase inhibitor replacement therapy for panacinar emphysema; and ganciclovir for cytomegalovirus retinitis) (34). Other important orphan indications include AIDS, various cancers, growth failure, and Parkinson's disease (12). In addition to these approved drugs and biologicals, 281 drugs and 141 biologicals have been entered into development and designated as orphans (13;20). Controversies over Market Exclusivity
Although the FDA provided interim guidelines for obtaining orphan designation, it was not until February 1991 that the agency issued proposed rules, for public comment, to effect the market exclusivity provision (8,11). Lacking these rules, controversies have arisen over three highly profitable orphan products produced by competing sponsors. These controversies initially led to the failed "shared approval" amendments of 1987; they were refined and again introduced in H.R. 4638 in 1990 (16;26). This time, the bill passed, but the president vetoed it. The major issues surrounding all three controversies involve the criteria by which one product is judged to be different from another for purposes of market exclusivity and the question of whether exclusivity in these three instances has created an unnecessary monopoly and high-priced products. All three products have major therapeutic and financial importance. These three cases suggest that, especially in the biotechnology industry (where patent determination decisions are especially difficult), the market exclusivity provision is possibly being used as a substitute, albeit more narrow and shorter, for patent protection (5). In the case of recombinant human growth hormone (r-hGH), Genentech received FDA orphan designation and approval for its product, which is used to treat about 12,000 children in the United States who lack sufficient amounts of the endogenous pituitary hormone. Eli Lilly also sought and received orphan designation and market approval for its product, which is chemically identical to the naturally produced pituitary substance and differs from Genentech's product by one less amino acid group. Genentech unsuccessfully brought legal action to try to bar Lilly's product from the market; instead, the two products share an annual market of approximately $150 million, with annual expenses per child running between $10,000-$20,000, depending upon the dosage needed (5). In the case of aerosol pentamidine, used to prevent HIV-related Pneumocystis carinii pneumonia, Lyphomed received orphan designation and exclusive market approval, barring approval of Fisons' version of the product. Fisons claims it was second in the race because it followed FDA advice about clinical trials. Lyphomed's product, which cost $23 million to develop and will require an additional $15-$20 million for postmarketing studies, costs about $2,400 per patient annually (5).
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The last controversy entails recombinant human erythropoietin (r-EPO), which is discussed more fully elsewhere in this issue. This product prevents the need for frequent blood transfusions for patients with chronic renal failure-related anemia. Amgen Inc. received orphan designation and approval, while Genetics Institute was the first to receive a patent. In a complex set of legal decisions and challenges, Amgen prevailed with seven years of exclusive marketing rights for this indication and is testing the product for use in other conditions as well. Amgen's r-EPO product sales were more than $100 million in its first six months on the market, largely reimbursed by Medicare, which covers dialysis and related therapy for patients with end-stage renal disease (5). Estimates place 1991 sales at $300 million (36). Mainly as a result of these controversies, H.R. 4638 would have a) eliminated orphan status for epidemic-related products whose projected populations would exceed 200,000 within three years of the product's approval; and b) revoked exclusivity for approved products when the population exceeded 200,000. The bill also authorized the FDA to provide shared market access for products that are simultaneously developed for the same orphan indication, with stipulations regarding the amount of time a competing sponsor has to conduct trials and submit an NDA (16). The rationale for the amendments was that shared approval might result in lowerpriced products through competition (although this has not happened traditionally or with r-hGH) and in market access for competing sponsors who otherwise may lose the opportunity to recover R&D costs. The rationale for the pocket veto emphasized that weakening the exclusivity provision might discourage developers from continuing to develop orphan products and that changing the population limit would send the message that government can alter the playing field in midcourse (5). As technology evolves, especially in molecular biology and genetics, controversies over product differentiation decisions and prices may reopen the debate. INTERNATIONAL ACTIVITIES
Two years after the ODA was enacted, the Fulbright Commission sponsored a colloquium in the United Kingdom to explore whether a similar process might be appropriate for the United Kingdom and other European countries. The British drug approval process differs from the United States' system in some respects. The consensus, at the meeting was that the United Kingdom was well-advised to wait and examine the benefits and problems of the ODA in the United States and then determine whether the same approach, or aspects of it, might be appropriately adapted to the British system (6). A few years later, a second meeting was held with representatives from the scientific communities of several European countries. By then, the United States had gained more experience with the law and was beginning to see a substantial response by industry in requesting orphan designation and in moving orphan drugs through the development and approval process. Nonetheless, the representatives at the meeting concluded that any consideration of how to stimulate development of orphan products in Europe should await implementation of the European Community in 1992. Meanwhile, the government of Japan reportedly has begun providing $2 million annually for development of orphan products in that country. CONCLUSION
The ODA and related private sector activities have been associated with an accelerated process of development and market availability of orphan products that often repre580
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sent the only therapy available for people with rare diseases and conditions. However, the law also has created some unresolved issues that need further exploration. The first issue is whether market exclusivity may be serving inappropriately to provide market protection for some products. The second issue is whether some other option needs to be explored to protect biotechnology products, in general, whether for large or small markets. The third issue is whether the law's incentives, or some other mechanism, may be necessary and appropriate for orphan medical foods and devices. These issues present important challenges to a law that has seen many changes to date and has continually evolved to strike a balance between orphan product costs and benefits. REFERENCES
1. Althius, T. Orphan Drugs: Debunking a myth. New England Journal of Medicine, 1980, 303, 1004-05. 2. Althius, T. Contributions of the pharmaceutical industry. In F. Karch (ed.), Orphan drugs. New York: Marcel Dekker, 1982, 185-87. 3. Asbury C. H., & Stolley, P. Orphan drugs: Creating a policy. Annals of Internal Medicine, 1981, 95, 221-24. 4. Asbury, C. H. Orphan drugs: Medical vs. market value. Lexington, MA: Lexington Books, 1985. 5. Asbury, C. H. The Orphan Drug Act: The first seven years. Journal of the A merican Medical Association, 1991, 265(7), 893-97. 6. Bachrach, W. H., et al. Round-table discussion. In I. H. Scheinberg & J. M. Walshe (eds.), Orphan diseases and orphan drugs. Manchester: University Press, 1986. 7. Devita, V. T, et al. The drug development and clinical trials programs of the division of cancer treatment, National Cancer Institute. Cancer Clinical Trials, 1979, 2, 195-216. 8. Federal Register. Orphan Drug Act Regulations. Proposed Rule, January 29, 1991; Part 5, 21CFR Part 316, 338-3351. 9. Finkel, M. Drugs of limited commercial value. New England Journal of Medicine, 1980, 302, 643-44. 10. Food and Drug Administration. NMEs approved 1983-90. Rockville, MD: FDA (compiled annually). 11. Food and Drug Administration. Interim guidelines for obtaining orphan designation of a drug as an orphan drug. Rockville, MD: FDA, November 1984. 12. Food and Drug Administration. Orphan designations pursuant to Section 526 of the FederalFood, Drug, and Cosmetic Act as amended by the Orphan Drug Act (PL 97-414) through December 31, 1989. Rockville MD: FDA, 1990. 13. Food and Drug Administration. Orphan drug designation listing, 1990. Rockville, MD: FDA, 1991. 14. Hansen, R. W. The pharmaceutical development process: Estimates of development costs and times and effects of proposed regulatory changes. In R. Chen (ed.), Issues in pharmaceutical economics, 1980, 151-81. 15. H.R. 5238, 97th Congress, 2nd Session, 1982. 16. H.R. 4638, 101st Congress, 2nd Session, April 26, 1990. 17. Karch, F. (ed.), Orphan drugs. New York: Marcel Dekker, 1982. 18. Kennedy, D. A calm look at drug lag. Journal of the American Medical Association, 1978, 239(5), 423-26. 19. Krall, R., et al. Anti-epileptic drug development I. History and a program for progress. Epilepsia, 1978, 19(4), 393-408. 20. Mossinghoff, G. J., & Copmann, T. L. Orphan drugs in development. Washington, DC: Pharmaceutical Manufacturers Association, 1989. 21. Mossinghoff, G. J. Comments to the Health and Environment Subcommittee, February 7, 1990, 2. 22. NHLBIfact book for fiscal year 1978. Washington, DC: Department of Health, Education and Welfare, 1979, 79-99. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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23. Orphan Drug Act oversight, Hearings before the Subcommittee on Health and the Environment, 98th Congress, 2nd Session, 1984, 719-20. 24. Orphan Drug Act report, 97th Congress, 2nd Session, Report 97-840, part 1, September 17, 1982. 25. Orphan Drug Amendments of 1987 report, 100-473,100th Congress, 1st Session, December 10, 1987. 26. Orphan Drug Amendments of 1987. Report 100-473, 100th Congress, 1st Session. 27. Pharmaceutical Manufacturers Association. Public Service Drugs (unpublished). Washington, DC, 1965. 28. Preliminary report of the survey on drugs for rare disease. Washington, DC: U.S. Government Printing Office, March 8, 1982. 29. Public Law 99-91, 99th Congress, 2nd Session, August 15, 1985. 30. Public Law 100-290, 100th Congress, 2nd Session, April 18, 1988. 31. Report of the panel on chemicals and health of the President's Science Advisory Committee. NSF 73-500. Washington, DC: U.S. Government Printing Office, 1973. 32. Russo, J. Profitable and non-profitable drugs. New England Journal of Medicine, 1978, 299, 156. 33. S.771, 98th Congress, 2nd Session, 1984. 34. Scrip World Pharmaceutical News, January 1989. 35. Silverman, M., & Lee, P. R. Pills, profits and politics. Berkeley, CA: University of California Press, 1974, 86-87. 36. Stavro, B. Investors tracking insiders' stock sales for clues on Amgen. Los Angeles Times, March 27, 1991, Dl. 37. Temin, P. Technology, regulation and market structure in the modern pharmaceutical industry. Bell Journal of Economics, 1979, 10, 427-46. 38. Van Woert, M. Profitable and non-profitable drugs. New England Journal of Medicine, 1978, 298(16), 903-06. 39. Walshe, J. M. Triethylene tetramine dihydrochloride. In F. Karch (ed.), Orphan drugs. New York: Marcel Dekker, 1982, 58-71. 40. Waxman, H. The history and development of the orphan drug act. In H. Scheinberg & J. Walshe (eds.), Orphan diseases and orphan drugs. Manchester: University Press, 1986. 41. Young, F. Testimony before the House Subcommittee on Health on the Environment, 99th Congress, 1st Session, 1985.
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