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Carolyn H. Asbury University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION As drug development costs began to rise in the late 1960s and 1970s with new Food and Drug Administration (FDA) requirements for demonstrating relative safety and efcacy, manufacturers of drugs, biologicals, and diagnostic agents faced a dilemma. How could they consider developing drugs that were important medically but not likely to be protable? Drugs for diseases and conditions that were rare in the United States were one of severaland the most visibleof such drug types. Rarity meant few patients would be available to participate in clinical trials of safety and efcacy under the sponsors Investigational Exemption of a New Drug (IND) application. Slow patient recruitment into trials increased development time, with the 17-year patent-protection clock ticking. And once the pharmaceutical sponsor received approval for the New Drug Application (NDA) required for interstate marketing, there would be few customers. This generally translated into a low return on investment (ROI). Moreover, the time devoted to testing and gaining approval for a drug for a rare disease was an opportunity cost. Manufacturers would otherwise have devoted the time and resources to products with more favorable market returns. Six other drug categories were of limited commercial interest. They included products for (1): 1. Chronic diseases, requiring extended testing phases to assess long-term effects, using up critical patentprotection time; 2. Single administration, such as vaccines, requiring separate production facilities, used by many but on a one-time basis, and carrying high liability risks; and diagnostic agents that had relatively low sales volume; 3. Women of childbearing age, presenting unparalleled liability risks; 4. Children and the elderly, both of whom were excluded from clinical testing at the time. Children presented high liability risks and could be difcult to enroll in clinical trials. Elderly people, who often had multiple conditions, were excluded from trials by the FDA because the multiple conditions and drugs used to treat them would confound trial results. (Once a drug was

marketed, physicians could prescribe it for these two populations. However, optimal dosing had not been determined, and likely drug interactions in elderly patients had not been identied); 5. Diseases, rare or common, for which the intended drugs were not patentable including shelf chemicals, drugs known to exist, natural chemicals, and drugs for which the patent had expired; 6. Substance abuse or relapse prevention, intended for a population considered to be a high liability risk, uncooperative with treatment trials, and requiring extensive records once marketed; and 7. Developing countries, with the related problems of distributing and paying for products. Observing that certain drugs could be in common use but were not potentially protable enough to invite commercial introduction, Provost referred to them in the American Journal of Hospital Pharmacy in 1968 as homeless or orphan drugs (2). This chapter focuses on orphan drugs for rare diseases. It provides background on the issues and on attempts to deal with thema description of the Orphan Drug Law, enacted in 1983, to address these issuesand an accounting of progress and problems to date emanating from the law.

BACKGROUND The 1938 Food, Drug and Cosmetics Act and the 1962 Kefauver-Harris Amendments to it substantially altered drug development in this country. They strengthened the safety and efcacy determinations of drugs, but at cost, one of which was industry disinterest in drugs for rare diseases. The 1938 law required proof of safety after diethylene glycol, used as a sulfanilamide vehicle was found to form lethal quantities of oxalic acid in the body. This resulted in 100 fatalities, mostly children (3). The law required manufacturers to provide evidence that the drugs were relatively safe. For the FDA to keep a drug off the market, however, the onus was on the agency to prove that the drug was not safe. The thalidomide disaster changed that situation. Tragic birth defects were reported
Encyclopedia of Pharmaceutical Technology Copyright q 2002 by Marcel Dekker, Inc. All rights reserved.

Orphan Drugs


in infants born to women in Europe and Canada who had taken the drug while pregnant. At the time the news broke, Congress was working on amendments to the 1938 law that required sponsors to provide proof of drug efcacy before receiving market approval. The thalidomide catastrophe propelled Congress to require sponsors also to show proof of safety. To implement these two requirements, the FDA created the IND process requiring sponsors to test for and establish relative safety before embarking on clinical trials to determine drug efcacy. The FDA set up the NDA approval process for ruling on safety and efcacy before the drug could be marketed interstate (4). An essential interplay developed between patent protection and regulatory requirements. Patent protection became essential for emerging products developed by research-intensive, vertically integrated rms that looked to a few major market winners to survive in this era of increased development costs (5). Patent time used in the IND and NDA premarket stages reduced the time remaining for manufacturers to protect their products, once marketed, against less costly generic drug competition. Drug development also became more expensive. Development costs in the late 1960s and early 1970s, before the FDA amendments became operationally implemented, were estimated to range from a low of $2.7 million to a high of $16.9 million per new chemical entity (NCE) (6, 7). By the late 1970s, the estimate had risen to $54 million (8). Since then, estimates have continued to leap upward: $124 million in the late 1980s, $231 million in 1991, and $500 million today (9, 10). By the late 1960s and early 1970s, market winners generated most of a companys prots and also helped encourage brand loyalties by prescribing physicians. Other drugs needed to at least break even. Although not blockbusters, these drugs generally were for large markets. Drugs for rare diseases usually did not break even and became therapeutic orphans. They became wards of government and university-sponsored development efforts. Cancer treatment drugs were among the rst wards of government. Even before the 1962 amendments to the Food, Drug and Cosmetics Act, the federal government had developed and maintained a role in stimulating the development of cancer drug treatment that was not being addressed by industry. The National Cancer Institute (NCI) created the Cancer Chemotherapy Program in 1955 with a $5 million Congressional authorization. Congress decided that the NCI should take on the challenge. Impressed with industrys spectacular antibiotics development, Congress recognized that a low ROI was precluding industrys interest in exploiting the early successes in antitumor drugs (antifol aminopterin for acute childhood leukemia and

methotrexate for uterine choriocarcinoma). Beginning as a small grant-oriented program to develop antileukemia agents, the program was based on the use of transplantable tumors in syngeneic rodents as a system for testing new drugs. After the NCI drafted an agreement allowing for the trade secret status of data, industry submitted compounds for screening of bioactivity. Within three years, the Cancer Chemotherapy Program had grown into a $35 million industrial contract effort. After a few missteps, when the FDA would not accept the cancer-funded research results as provided, the FDA and NCI developed a clear understanding of how data needed to be provided. From that point until at least the early 1980s, the NCI was involved in the development and/or clinical testing of every antineoplastic drug available in the United States (11 13). In 1966, the National Institute of Neurological and Communicative Disorders and Stroke, as it was then named, established the Antiepileptic Drug Development Program to develop clinical trial methodologies and then to conduct clinical trials of antiepileptic agents already available in other countries. The program later developed a screening program similar to that of the NCI. The Institute led INDs for drugs that entered clinical testing, and by 1981, four drugs had commercial sponsorship by the NDA stage (14, 15). Although most of the federal funding for drug programs by the National Institutes of Health (NIH) was for the development of drugs for rare diseasescancers and epilepsythe NIH also devoted funding to development of other categories of orphan drugs. These included drugs to prevent and treat substance addiction and relapse, contraceptives for women of childbearing age, and some vaccines being developed by NIH and by the Centers for Disease Control (now the Centers for Disease Control and Prevention). Before 1983, when the Orphan Drug Act was signed into law, NIH drug development programs and grant-supported research had resulted in 13 drugs for the treatment of rare diseases being approved and on the market. In the 17 years before the Orphan Drug Law, the pharmaceutical industry had developed and marketed 34 drugs or biologicals for use in rare diseases or conditions (16). Ten of these marketed orphan drugs and biologicals had been developed solely by industry without government or university support (17).

The Gathering Storm Nonetheless, several articles published in medical journals by academic researchers chronicled their plight in formulating new dosages for available drugs or


Orphan Drugs

encapsulating chemical ingredients for clinical tests in patients with rare diseases, because no pharmaceutical sponsor had come to their rescue (18 20). One of these researchers, Cambridge Universitys John Walshe, proclaimed that this do-it-yourself problem had gone far enough and should be placed on a sound commercial basis (21). The FDA published a list of potentially promising therapeutic agents that were under development primarily by academic or government-based scientists who had failed to nd commercial sponsors to undertake the costly phase III clinical trials for efcacy, le the NDA, and market the product (22). In 1979, the FDA convened a Task Force on Drugs of Little Commercial Value to determine how to nd commercial sponsors. That same year, Louis Lasagna, who was then at the University of Rochester, invoked Provosts notion in an article in the journal Regulation by asking who will adopt the orphan drugs (23)? NIH-funded academic researchers were reporting failed attempts to interest industry in taking on and securing NDA approval for drugs it had not developed. Industry had cited three major problems. First, NIH-funded scientists may not have gathered and analyzed data according to FDA requirements. Second, the trade secret status of data could not be preserved if the researcher had previously published information in the scientic literature. And third, many of the NIH-funded studies were of drugs that were not (or no longer) patentable. The FDA task force recommended that incentives be provided to industry to develop drugs of limited commercial value, but that any prots made from those incentives be returned, in whole or in part, to the government. (24). This arbitration-type approach was based on the assumption that industry would be willing to make trade-offs with the FDA on behalf of these drugs. But this assumption was made in the absence of any indication from industry that this was the case (25). Although the task force was the rst ofcial policy response to the orphan drug situation (apart from the NIH-sponsored research responses), there were several private-sector efforts underway to promote the development and availability of orphan products. The Pharmaceutical Manufacturers Association (PMA, now called the Pharmaceutical Research and Manufacturers of America, or PhRMA) had been seeking sponsors among its member companies for promising orphan therapeutics. And a consumer group, the National Organization for Rare Disorders (NORD), was growing in number (now representing more than 20 million patients and their families) and undertaking efforts to raise public awareness and to help link patients to researchers conducting clinical studies of their diseases or conditions.

Lightning Strikes A researcher at the Mount Sinai School of Medicine New York, who was seeking a pharmaceutical company sponsor for the drug L-5HTP for myoclonus, appealed to his Congressperson, Elizabeth Holtzman (D-New York) for a legislative remedy to the plight of orphan drug research. She introduced a bill in 1980 to establish the Ofce of Drugs of Limited Commercial Value to assist the NIH in developing drugs for the treatment of rare diseases (26). Although no action was taken on the bill, the committee heard testimony from a young California man suffering from Tourettes syndrome, a genetically determined neurological condition causing its victims to twitch, tic, and have uncontrollable verbal (and often abusive) outbursts. When haloperidol proved unsuccessful in controlling his symptoms, the patient had tried desperately to obtain and try pimozide, a drug available for the condition in Canada and Europe, but not in the United States. A Los Angeles newspaper carried an account of the testimony, which caught the eye of the producer of the television series Quincy. Before long, a Quincy episode was devoted to dramatizing the conundrum of patients trying to cope with Tourettes syndrome and of industry trying to contend with the commercial disincentives to develop drugs to treat these patients. The episode demonstrated that there were no villains and no remedies. In a compelling scene before a Congressional committee, Quincy delivered an impassioned appeal to Congress to nd a remedy. Shortly thereafter, Quincy star Jack Klugman was asked by Congressman Henry Waxman (D-California) to appear at a hearing on an orphan drug bill that was similar to Holtzmans, introduced by her colleague Representative Ted Weiss (D-New York). Klugman testied at the hearing, using the identical appeal he had delivered on the show (27). A Wall Street Journal editorial, entitled Leave of Reality, likened Klugmans appearance before the Waxman subcommittee as an orphan drug expert to having Leonard Nimoy (Mr. Spock on Star Trek) testify as an expert on the nations space program (28). By the end of 1981, Congressman Waxman had introduced H.R. 5238, the Orphan Drug Act. The orphan drug survey To nd out the current status of development of drugs for the treatment of rare diseases, the subcommittee surveyed the industry, the NIH, and the FDA on three groups of drugs: 1. Products listed by PMA (now PhRMA) member companies as drugs for the treatment of rare diseases

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that industry sponsors had marketed or had made available on a compassionate basis to specialists; 2. Drugs and biologicals listed by the FDA as under development, but needing a commercial sponsor for FDA approval and marketing; and 3. Drugs under development by NIH scientists or grantees. From this survey, the Subcommittee learned that industry had marketed 34 drugs for the treatment of rare diseases extending back to 1965 and had made an additional 24 drugs (under development) available to physicians on a compassionate basis for treating patients with rare diseases. Most (82%) of the marketed drugs were for conditions affecting fewer than 100,000 people in the United States; 10% were for 100,000 to 500,000 people, and the remaining 8% were for up to 1 million people. Industry respondents indicated that substantial federal funding had been provided for research and/or development (R&D) for all but 10 of these marketed drugs. The picture of disincentives conrmed claims by industry spokespeople sponsors indicated that the ROI for 83% of the drugs was lower than the sponsors average return for marketed drugs, whereas development costs were higher than average for 12% of these drugs. Other issues cited by industry were the lack of clarity of FDA clinical testing guidelines when small numbers of patients were available and involved. This further eroded the sponsors ability to estimate the length of clinical testing, and therefore the length of remaining patent protection time, once the drug was approved. Survey data indicated that industry-sponsored marketed orphan drugs took an average of 5.75 years for clinical testing (from ling the IND to ling the NDA). Unpatented orphan products were increasingly unlikely to be submitted for NDA approval, suggesting the importance of having at least some period of market protection. Whereas nearly two-fths (39%) of industry-sponsored drugs for the treatment of rare diseases had been marketed in the 1960s, even though they were not protected by patent, this fell to 29% by the 1970s. Liability claims had been led against the manufacturers of one-fth of the marketed orphan drugs. The promising nding was that one in four industry-sponsored marketed orphan drugs also had a common indication. This suggested that orphan drugs were a relatively good market gamble (29).

Orphan Drug Acts Passage Provides Market Incentives and Regulatory Assistance Based primarily on Congressional testimony marshaled by NORD revealing that millions of people and their families

were profoundly affected by rare diseases and conditions, and on survey data revealing market and regulatory disincentives to therapeutic progress, Congress passed the Orphan Drug Act during a lame duck session in December 1992. Called the golden egg of the lame duck Congress by the head of the Generic Pharmaceutical Industry Association (GPIA), the bill was signed into law the rst week of January 1983 (30). The act (Public Law 97 414) was supported initially by the GPIA, which had begun seeking sponsors for developed orphan products, and eventually by the PMA after certain provisions were deleted or modied. Provisions in the law, and in subsequent amendments in 1984, 1985, and 1988, addressed market and regulatory issues and provided incentives for pharmaceutical industry development of drugs for the treatment of rare diseases. The law, as amended, denes a rare disease or condition as one that affects fewer than 200,000 persons in the United States. Alternatively, the disease or condition can affect more than 200,000 persons in the United States, if there is no reasonable expectation that the cost of developing and making a drug available for such disease or condition in the United States will be recovered from U.S. sales of the drug. Therefore, a drug can be designated by the FDA as an orphan by demonstrating applicability of the laws nancial criteria, regardless of the total number of people affected in the United States. Major provisions are the availability of two market incentives and the reduction of regulatory barriers. The FDA Ofce of Orphan Products Development administers nearly all the laws provisions. One incentive is seven years of market exclusivity granted by the FDA for a specic indication of a product. Exclusivity begins on the date the FDA approves the marketing application for the designated orphan drug and applies only to the indication for which the drug has been designated and approved. An application for designation as an orphan drug for a specic indication must be made before submission of the NDA (or biologic product license application, PLA) for market approval (31). Other sponsors can receive approval for a different drug to treat the same rare disease or can receive approval to market an identical drug for some other orphan or common indication. Market exclusivity, therefore, only precludes a second sponsor from obtaining approval to provide an identical drug for the identical orphan indication for which the rst sponsor received exclusive market approval. Initially, market exclusivity pertained only to unpatented products. A 1985 amendment allowed exclusive approval for all orphan drugs, whether patented or not. This change was designed to provide incentives for sponsors of products for the treatment of rare diseases whose patents


Orphan Drugs

would expire before or soon after approval, or in cases in which prior publication (usually by an academic or government scientist) had precluded issuance of a patent. A second incentive provides tax credits equal to 50% of the costs of human clinical testing undertaken in any given year by a sponsor to generate data required for obtaining FDA market approval through successful completion of the NDA process. The Internal Revenue Service administers the tax credit provisions. The act provides for the FDA to award grants to support clinical studies of designated orphan products underdevelopment. FDA grant funding as of March 2000 from the FDA totaled $126.3 million. From initial funding in 1983 of $500,000 in grants, the grant program peaked in 1994 at $12.3 million and has declined slightly but steadily thereafter, totaling $11.1 million in 1999 (32). Applications are reviewed by outside experts and are funded according to a priority score. The FDA Ofce of Orphan Product Development provides information at its website ( on investigators seeking research subjects. Listed by the name of the disease or condition, information includes a description of the study, criteria for inclusion in clinical trials (such as age, stage of disease, etc.), and contact information on the clinical investigator seeking participants for clinical trials. Patients, their families, or their physicians are able to follow up with the clinical investigator. To address regulatory barriers the FDA also provides formal protocol assistance when requested by the sponsor of an orphan drug. Although formal review of a request for protocol assistance is the direct responsibility of the FDA Centers for Evaluation and Research (one for drugs, the other for biologicals), the Ofce of Orphan Products Development is responsible for ensuring that the request qualies for consideration. A sponsor need not have obtained orphan drug designation to receive protocol assistance.

Finally, the FDA is required to encourage sponsors to design open protocols for drug availability to patients not included in clinical trials.

The Current Status of Orphan Drugs The FDA approved 201 orphan products between 1983 and March 2000 (33). In the 17 years since passage of the act, therefore, the number of approved orphan drugs has increased sixfold from the number approved in the 17 years before the act (Table 1). The drugs are classied within 16 therapeutic categories, primarily for the treatment of cancer, infectious disease, AIDS and related conditions, and central nervous system conditions (Table 2). Included in the 201 approved drugs are 24 (12%) that received FDA grant support for clinical trials (34). A list of these grant-supported products is available at the FDA Ofce of Orphan Products Development website ( orphan/GRANTS). The number of sponsors of approved orphan drugs (nearly all of them produced at pharmaceutical or biotechnology companies) has increased from 17 (for the 34 drugs marketed before the act) to 110 as of March 2000. The number of approved drugs per sponsor ranges from one to eight, with a preponderance of one-drug sponsors (Table 3). A total of 813 products have received orphan designations as of March 2000. Sponsors of approximately 25% of these designated products have led INDs for the products, indicating that they are under active development (35). Many of the designated and approved orphan products are developed at biotechnology companies. Beginning in the 1970s, molecular biology had begun to spur the creation of biotechnology research companies. These companies reportedly recognized early on that market exclusivity, and lack of competition to develop products for the treatment of rare diseases, provided protection essential to raising venture capital. As a result, orphan drugs are now among biotechnologys most prevalent, and, according to some, most lucrative products. Between 1988 and 1992, biotechnology product designations increased by 31%, from 8 to 39% of total orphan designations (36). In addition to industry, however, sponsors have included a university, an individual researcher, and a state public health unit, which in aggregate sponsored six orphan drugs at the time of approval. Lists of approved and designated orphan drugs can be obtained from the FDA Ofce of Orphan Products Development. These data suggest that orphan drug development has consistently risen over the years since the law was enacted. Aggregate sales of

Table 1 Designated and approved orphan drug products Pre-1983 Cumulative total approved orphan products Total sponsors of approved orphan drugsb
a b

1989 36

1991 54

3/2000 235




At the time, these were called drugs for rare diseases, not orphan drugs. Sponsors identied only for the two endpoints.

Orphan Drugs Table 2 Approved orphan drugs: Number per therapeutic categorya Number of approved orphan products N = 201 49 23 22 21 21 18 12 8 7 5 5 3 2 2 2 1


Category Cancer Infectious disease Central nervous system Hematopoetic AIDS, AIDS-related Endocrine Inborn errors of metabolism Renal Cardiovascular disease Respiratory Gastrointestinal Bone Immunological Dermatological Antidote Urinary tract

Does not include drugs for rare diseases marketed before the 1983 Orphan Drug Law.

orphan drugs have been reported to be more than $1 billion a year (37). A Resulting Issue: High Pricing for Some Products By the early 1990s, U.S. sales data collected for 41 of the approved orphan drugs that had been on the market for a year or more indicated that 75% of the products had generated earnings of less than $10 million per drug. Three products had earnings between $10 and $25 million, six
Approved orphan drugs per sponsor, March 2000a Sponsors 69 19 6 2 5 2 1 2

Table 3

Drugs per sponsor 1 2 3 4 5 6 7 8


Does not include sponsors of drugs for rare diseases approved before the Orphan Drug Act of 1983.

drugs between $26 and $100 million, and two products more than $100 million. Biotechnology rms produced four of the 11 drugs with relatively high sales. Those orphan drugs that command high prices have generated intense controversy over whether the market exclusivity provision is creating an unnecessary monopoly, keeping prices articially high. One example is recombinant human erythropoietin (r-EPO), intended for patients with chronic renal failure-related anemia. EPO eliminates the need for frequent blood transfusions by patients with end-stage renal disease who are undergoing kidney dialysis. These patients are covered under the federally nanced Medicare program. Both Amgen Inc. and Genetics Institute applied to the FDA for market exclusivity for their r-EPO products. Amgen was the rst to receive FDA approval and market exclusivity. Genetics Institute was the rst to receive a patent. On appeal, the court ruled that Amgen had exclusive marketing rights. Sales of r-EPO exceeded $100 million in the rst six months of marketing, paid for by Medicare. By 1991, sales totaled $400 million (38). Human growth hormone (r-hGH), another example, generated sales of $150 million in 1991. Intended to treat approximately 12,000 children in the United States with retarded growth caused by a lack of endogenous pituitary hormone, two companies provide r-hGH. Genentech received FDA market exclusivity in 1985. Eli Lilly received market approval two years later, based on the determination that the two products differed by one amino acid (39,40). But the shared market did not lead to price competition: each company was earning approximately $20,000 per child annually, depending on the dosage needed. A third example, aerosol pentamidine, generated sales of $130 million in 1991. Helping to prevent Pneumocystis carinii pneumonia associated with the human immunodeciency virus (HIV), the increasing number of users resulting from a rapidly escalating HIV prevalence rate was expected to soon exceed the 200,000 population gure specied in the law. This example, along with the other two, prompted efforts to seek a legislative remedy. A series of amendments were introduced and passed by Congress in 1990 that sought to eliminate orphan status for products intended for use in epidemics and to allow shared market access for identical products developed simultaneously for the same indication, in the hope that this would lead to price competition. The amendments were vetoed (41). As Arno, Bonuck, and Davis present in Milbank Quarterly, AIDS treatment drugs exemplify the policy dilemma of how to use the Act to meet the legislative intent of stimulating development of drugs for small patient populations without resulting in prices that make such drugs inaccessible (42).


Orphan Drugs Devita, V.; Oliverio, V.T.; Muggia, F.M.; Wiernick, P.W.; Ziegler, J.; Goldin, A.; Rubin, D.; Henney, J.; Schepartz, S. The Drug Development and Clinical Trials Programs of the Division of Cancer Treatment, National Cancer Institute. Cancer Clin. Trials 1979, 2, 195 216. 12. Zubrod, C.G.; Schepartz, S.; Leiten, J.; Endicott, K.M.; Carrese, L.M.; Baker, C.E. Cancer Chemotherapy Reports October 1996, 50 (7); DHEW: Washington, DC, 1968. 13. Rate of Development of Anticancer Drugs by the National Cancer Institute and the U.S. Pharmaceutical Industry and the Impact of Regulation. Final Report for the National Cancer Institute; University of Rochester Medical Center: New York, 1981; 40. 14. Krall, R.A. Anti-Epileptic Drug Development. I. History and a Program for Progress. Epilepsia 1978, 19 (4), 398 408. 15. Program Performance Summary. National Institute of Neurological and Communicative Disorders and Stroke Antiepileptic Drug Development Program; NINCDS: Washington, DC, 1982. 16. Orphan Drugs in Development, 1992 Annual Survey. Pharmaceutical Manufacturers Association: Washington, DC, 1992. 17. Orphan Drug Act Report, 97th Congress, 2nd Session. Washington, DC, Sept 17; 1982. 18. Van Woert, M. Protable and Non-Protable Drugs. N. Engl. J. Med. 1978, 298 (16), 903 906. 19. Rawlins, M. No Utopia Yet. Br. Med. J. 1977, 2, 1076. 20. Rawlins, M. Editorial. Lancet 1976, 2(7970), 835 836. 21. Walshe, J.M. Treatment of Wilsons Disease with Trientine (Triethylene Tetramine) Dihhydrochloride. Lancet 1982, 1, 643 647. 22. Asbury, C.H. Medical Drugs of Limited Commercial Interest: The Development of Federal Policy; Johns Hopkins School of Hygiene and Public Health Thesis, Baltimore, 1981; 157 175. 23. Lasagna, L. Who Will Adopt the Orphan Drugs? Regulation 1979, 3 (6), 27 32. 24. U.S. Food and Drug Administration Report. Interagency Task Force Report to the Secretary of DHEW; FDA: Washington, DC, 1979;, 1 82. 25. Asbury, C.H.; Stolley, P. Orphan Drugs: Creating Federal Policy. Ann. Intern. Med. 1981, 95 (2), 221 224. 26. Holtzman, E. Rep. H.R. 7089, 96th Congress, 2nd Session. Washington, DC, April 17, 1980. 27. Klugman, J.; Seligman, A. Testimony, Serial No. 97 17, U.S. Government Printing Ofce: Washington, DC, 1981; 10 16. 28. Leave of Reality (Editorial). The Wall Street Journal March 12, 1981, . 29. Asbury, C.H. Orphan Drugs: Medical vs. Market Value; D.C. Heath: Lexington, MA, 1985; 136155. 30. Waxman, H.R. Rep. H.R. 5328, 97th Congress, 1st Session. Washington, DC, 1981. 31. FDA Ofce of Orphan Products Development, (accessed Feb 2000). 32. Personal Communication, FDA OOPD, March 2000. 33. FDA List of Approved Orphan Products through 02/24/2000, FDA: Washington, DC, 2000; Provided on Request from the FDA OOPD. 11.

Another, more recent, example is enzyme therapy for Gauchers disease, an inborn error of metabolism, treated with Ceredase. The therapy, which requires more than a ton of placenta annually to extract and make the drug, can cost as much as $500,000 per year per person, depending on the dosage needed. A 1996 National Institutes of Health technology assessment panel addressed issues in diagnosis and treatment of the disease and concluded that despite the success of enzyme therapy, treatment is limited by the cost. The panel reported that it was imperative to dene the appropriate clinical indications for treatment and to determine the lowest effective initial and maintenance doses (43). Although the survey undertaken prior to the Act found that retail costs of drugs for the treatment of rare diseases were reportedly higher than the manufacturers average for 60% of the products marketed before the act, the pricing for some orphan drugs after the act, as exemplied by these examples, is a critically important consequence of the law. This consequence merits continued public scrutiny. It is a sign of progress that for some orphan drugs, accessibility rather than availability is now the challenge requiring creative solutions.

1. Asbury, C.H. Medical Drugs of Limited Commercial Interest: Prot Alone is a Bitter Pill. Intern. J. Health Serv. 1981, 11 (3), 451462. 2. Provost, G.P. Homeless or Orphan Drugs. Am. J. Hosp. Pharm. 1968, 25, 609. 3. Silverman, M.; Lee, P.R. Pills, Prots and Politics; University of California Press: Berkeley, 1974; 2. 4. Harris, R. The Real Voice; Macmillan: New York, 1964; 21 25. 5. Temin, P. Technology, Regulation and Market Structure in the Modern Pharmaceutical Industry. Bell J. Econ. 1979, 10 (2), 427 446. 6. Report of the Panel on Chemicals and Health of the Presidents Science Advisory Committee, 73 500, NSF, U.S. Government Printing Ofce: Washington, DC, 1973. 7. Schwartzman, D. Innovation in the Pharmaceutical Industry; Johns Hopkins University Press: Baltimore, 1976; 106 107. 8. Hansen, R.W. The Pharmaceutical Development Process: Estimates of Development Costs and Times and Effects of Proposed Regulatory Changes. Issues in Pharmaceutical Economics; Chien, R., Ed.; Lexington Books: Lexington, MA, 1980; 151 181. 9. DiMasi, J.; Hanson, R.; Grabowski, H.; Lasagna, L. The Cost of Innovation in the Pharmaceutical Industry and Health Economics. J. Health Econ. 1991, 10, 107 142. 10. Rosenbaum, D.E. The Gathering Storm Over Prescription Drugs. The New York Times Nov. 14, 1999, 1, Section 4 (Week in Review).

Orphan Drugs 34. 35. 36. 37. 38. 39. 40. 41. Grant-Supported Products with Marketing Approval, FDA OOPD, Washington, DC, magrants (accessed Feb 2000). Personal Communication, FDA OOPD, March 2000. Schuman, S.R. Implementation of the Orphan Drug Act. Food Drug Law J. 1992, 47 (4), 363 403. Grady, D. In Quest to Cure Rare Diseases, Some Get Left Out. The New York Times; Nov. 16, 1999. Coster, J.M. Recombinant Erythropoietin: Orphan Product with a Silver Spoon. Intern. J. Technol. Assess. Health Care 1992, 8 (4), 635 646. Hilts, P.J. Seeking Limits to a Drug Monopoly. The New York Times; May 14, 1992, D1; 7. Asbury, C.H. Evolution and Current Status of the Orphan Drug Act. Intern. J. Technol. Assess. Health Care 1992, 8 (4), 573 582. Asbury, C.H. The Orphan Drug Act: The rst 7 years. J. Am. Med. Assoc. 1991, 265, 893 897. 42. 43. 44. 45. 46. 47. 48.

1945 Arno, P.S.; Bonuck, K.; Davis, M. Rare Disease Drug Development and AIDS: The Impact of the Orphan Drug Act. Milbank Q. 1995, 73 (2), 231 252. NIH Technology Panel on Gaucher Disease. Gaucher Disease. Current Issues in Diagnosis and Treatment. J. Am. Med. Assoc. 1996, 275 (7), 548553. Asbury, C. Orphan Drugs: Medical vs Market Value; D.C Heath and Company: Lexington, MA, 1985. Scheinberg, I.H., Walshe, J.M. Eds. Orphan Diseases and Orphan Drugs; Manchester University Press: Manchester, UK, 1986. Wagner, J. Orphan Technologies. Int. J. Technol. Assessment 1992, 8 (4), Arno, P.S.; Bonuck, K.; Davis, M. Rare Diseases, Drug Development, and AIDS: The Impact of the Orphan Drug Act. Milbank Q. 1995, 73 (2), 241 252. Henkel, J. Orphan Drug Law Matures into Medical Mainstay. FDA Consumer 1999, 33 (3), 29 32.