Treating Rare Diseases: The Orphan Drug Act

Naureen Mirza




            A rare disease is a disease that effects only a small patient population yet they effect between ten to twenty million people in the United States alone. [1] Drugs are often “orphaned”, or never are produced and sold on the market, even when a compound is thought to be useful for the treatment of a rare disease.  Due to the small number of patients suffering, and the resultant lack of revenue they provide, pharmaceutical companies do not have any incentives to develop drugs and treatments for rare diseases. Therefore the pharmaceutical company may have the ability to supply orphan drugs, even when there is a demand, but this demand is not significant enough to manufacture the needed product. This is also partially due to the lack of sponsorship, or no one to “adopt” the orphan drug, to conduct the necessary testing to obtain the necessary approval from the Food and Drug Administration (“FDA”). [2] 

Pharmaceutical companies are also faced by restrictions in where time and money can actually be invested into.  They often have limited resources available to them for research and development (“R&D”), so research must be prioritized.[3]  The drugs or treatments that will bring in the largest amount of revenue will be ranked highly and be of most importance, while developing treatments for rare diseases will fall very low.  Generally, bringing any drug into the market can be very costly and time consuming.  The estimated cost of bringing a single drug through screening processes and FDA procedures to obtain approval is between $350-500 million. [4]  Companies report that nearly $21 billion was spent just on research and development for treatments.[5]  It can take up to ten years just to bring a single drug into the market in addition.[6]  As a result of these economic factors, treatments for rare disease are often “orphaned” and given very little recognition from the pharmaceutical industry.

Beyond the costs to the organization itself, companies have an additional responsibility to their shareholders.  In order to fulfill a shareholder’s investment, a company must continue to grow and bring in revenue. An estimated 10% growth per year is necessary to meet the expectations of the company’s stockholders.  To accomplish this goal, a company must introduce at least five new products into the market every year. Of the products that actually made it into the market between 1990 and 1994, only a small percentage achieved the minimum sales of $350 million required to be considered successful.[7] 

An additional disincentive faced by the pharmaceutical industry is that many of the compounds found to treat rare diseases are not eligible for any form of patent protection.  A patent is the exclusive right to make, use or sell a product.[8] Therefore, competitors are not able to sell a product that is the same as a product already protected by a patent.  Without this type of protection a company would be left open to immediate competition with generics, which are usually offered at a lower price.[9]  Generic drugs are less expensive than brand-name drugs, even though they are chemically identical and also meet the U.S. Food and Drug Administration standards for safety, purity and effectiveness.[10] The introduction of a generic into the market drives market prices down due to competition and therefore reduces the amount of revenue a “non-generic” could have potentially brought in.  The high costs of bringing a drug into the market, added to the concerns about the amount of revenue a drug can actually bring in, the financial responsibility to shareholders and the lack of patent protection all outweigh a pharmaceutical company’s incentive and/or ethical obligation to provide drugs to those suffering from rare diseases.

The United States government soon realized the need to create incentives for pharmaceutical companies to develop drugs for rare diseases.  It is the government’s responsibility to ensure “base-line well being of its citizens” and the government is already active in health issues and shaping health related policies.[11]  In the early 1900s the government used to be involved with developing new drugs and treatments. New therapeutic treatments were often developed in federally operated labs, nonprofit medical research centers as well as within the pharmaceutical industry.  By the 1960s, most new drugs were manufactured for profit and the focus of federal labs and research universities soon turned to only basic research and clinical studies.[12]

Although the government no longer develops treatments itself, it potentially has the power to pass laws that will control drug pricing and to compel companies to produce particular products.  This type of enforcement through law could be a “highly dangerous proposition as interference with the ability to profit from one’s labor or inventions would stifle innovations and productivity.” [13]  Congressional response to this concern led to the promulgation of the Orphan Drug Act.  This Act was created to overcome the barriers confronting pharmaceutical companies by primarily establishing economic incentives to overcome them. The Pharmaceutical Manufacturers Association (“PMA”) quickly opposed any legislation and insisted that the industry could meet the needs of all patients if the FDA would relax the approval procedure for all drugs.  This would decrease pre-market approval costs incurred by pharmaceutical companies and promote innovations for all drugs, not just those for rare diseases.[14] Surprisingly, the FDA also opposed any new legislation and stated the problem could be fixed by relaxing the approval process specifically for orphan drugs due to their unique and special need. [15]  Regardless of these objections, the Orphan Drug Act was passed by Congress.


The passage of the Orphan Drug Act has been attributed in part to television; starting with the medical drama “Quincy” which aired an episode depicted a young boy with Tourette syndrome, a classic orphan disease. [16] In 1980, Rep. Henry Waxman received an urgent phone call from the mother of a boy, Adam Seligman, whose drug treatment for the rare disorder Tourette syndrome had been seized at the Canadian border. Since the drug was approved in Canada but not in the United States, Adam's doctor had to make alternative arrangements to bring the drug from Canada for his patient.[17] Meanwhile, Adam’s mother was anxiously waiting as her son’s medication was running out.

Shortly thereafter, hearings were held by Waxman to determine the extent of the rare disease problem.[18] Because of an article covering these hearings, Jack Klugman, an actor of the hit TV show “Quincy” decided to create an episode devoted to Tourette syndrome and the orphan drug problem. After it aired in March 1981, viewers responded quickly by sending thousands of letters voicing their support and asking how they could help.[19]  With the issue in the public eye, Waxman introduced an orphan drug bill and held a second hearing which included Klugman as a witness. The media covered the hearing extensively because of Klugman’s celebrity involvement, and even greater public support followed. The bill was still stalled within Congress, so in response, Klugman put together another "Quincy" episode, mirroring the real-life holdup of the bill taking place on Capitol Hill. 500 "extras" were used in the shows who were actual victims of orphan disorders.[20]  Public sentiment was successfully stirred and the efforts eventually led to the passage of the Orphan Drug Act.[21]

The Orphan Drug Act (“Act”) was passed in 1982 and went into effect in 1983.[22]  The Act was designed to encourage the development of orphan drugs through economic incentives and by providing special assistance with the FDA drug approval process.  In passing the Orphan Drug Act, Congress was motivated by public opinion but also had to weigh the economic needs of the pharmaceutical industry.  Through this Act, “the public’s interest is served by encouraging drug development for an economically nonviable market.”[23] 

In the United States, an “orphan drug” is defined as a drug useful for a condition that is considered to be a rare disease.  Representative Henry Waxman, the co-sponsor of the Orphan Drug Act, stated, “[t]he naming of drugs for rare diseases as ‘orphan drugs’ was not done frivolously…They are very much liked children who have no parents, and they require special effort.”[24]  At the time of the Act’s passage, a rare disease meant any disease or condition which occurs so infrequently that there is no reasonable expectation that the cost of developing and actually placing a drug on the market for such a disease or condition will recover sales within the United States for such a drug.[25]  These terms were intentionally left vague by Congress so that the FDA would have the responsibility to define them.[26]  If a drug met these definitions then they would be designated as an “orphan drug” and would be entitled to the incentives provided under the Act. 

A great administrative burden was placed on the FDA and the organizations applying for orphan designation due to the way the definitions and requirements of the Act were initially outlined.  The FDA required companies to submit detailed financial reports and market data to show that sales were not recoverable for a drug before it was given the designation as an orphan drug.[27]  This involved elaborate research and detailed paperwork from the company that were both time consuming and costly. Additionally, the Act offered protection only to compounds which were not patent protected, and also excluded any compounds which could possibly even obtain a patent.  To qualify for marketing exclusivity, a major incentive discussed later, the drug must not have a patent and prove to be unpatentable.[28]  Proving a product cannot be patented is another time consuming and inefficient process.

Six incentives that were provided by the Orphan Drug Act:

1.      assistance from the FDA,

2.      open clinical trials,

3.      tax credits,

4.      grant funds,

5.      marketing exclusivity, and

6.      the Orphan Drug Product Board.[29] 

The Orphan Drug Board was created to coordinate the government orphan drug program.  It is situated within the Department of Health and Human Services which has authority over the FDA.[30] The administrative burden and cost of obtaining drug approval was reduced by providing assistance from the FDA.  The FDA aids companies and sponsors that gain orphan designation by helping them design the necessary clinical trials necessary to obtain marketing approval.[31] This guides companies in their research and makes the approval process more efficient and less costly.

Open clinical trials are an additional incentive that benefits both the pharmaceutical companies as well as the patients suffering from rare diseases.  These clinical trial protocols are left open to increase the availability of experimental drugs to patients before they are put on the market.  This incentive allows the manufacturer to sell drugs to patients that are not part of the actual clinical trials while the testing is still going on.[32]  Additionally, funds are granted through the Act for research, clinical trials, or other “qualified testing”. Another big financial incentive offered by the Act is a 50% tax credit for money spent on clinical testing.  This number represents a compromise between the Senate and the House of Representatives.  Senate called for a 90% tax credit while the House of Representatives wanted no tax credit at all.[33]

The major and most controversial incentive, created by the Orphan Drug Act is the protection offered through the seven year marketing exclusivity provision.  During this seven year period, the FDA will not grant the necessary approval to another company for a drug for the same use.  In the United States, all drugs must be approved by the FDA before being placed onto the market.[34]  Congress harnessed this unique power of the FDA and protected orphan drugs by restricting their competitors from entering the market for a period of time.  This privilege will be revoked if a sponsor can no longer produce the orphan drug to meet the market demand or if the sponsor voluntarily consents in writing approving another application to produce the orphan drug.[35]

A. The Evolution of the U.S. Orphan Drug Act

            The Orphan Drug Act was formed incentives for pharmaceutical companies to develop and research treatments for rare disease.  Prior to the Act being passed, only ten orphan drugs were approved in the United States.[36]  In the first year of its passage, there were fifteen requests for designation of which only ten were actually granted.[37] The Act was not successful in increasing research and development. A greater response to the Act was expected from the pharmaceutical company since many companies had already developed orphan drugs and only had to bring them into the market.[38]  Because of the poor response initially, Congress took a close look at the Orphan Drug Act and it went through several phases of amendments which included changes in definitions and criteria over the next few years.

            After being in effect for only one year, the Act no longer required a company to show that a drug would be unprofitable.  Since so few patients were actually effected by a particular rare disease, Congress decided unprofitability could now just be assumed.  This 1984 amendment only requires the company to show that the disease effects less than 200,000, and thus reduced the administrative hassle of submitting data to prove the lack of profit a drug would bring.[39]  The flaws with this requirement were duly noted. The Office of Management and Budget recommended that the term “rare disease” should be clearly defined. Senator Hatch also suggested the profits should be monitored even after a drug receives designation.[40]  These suggestions were never incorporated.

            In 1985 more substantive and procedural changes were made, expanding the Act.  The most significant change was that marketing exclusivity was extended to all drugs, including those that are already patentable.[41] This change hoped to create a major incentive by offering protection (and a guaranteed monopoly) to all and also reducing the administrative burden of showing patentability. Some other minor changes included expanding the Act to encompass antibiotics. Before this amendment only traditional pharmaceutical and biotics were included.[42]  Also, the financial incentive of providing research grants was extended to all qualified testing and not just qualified clinical testing.[43] 

            Procedural changes were also made defining how a company should proceed with the application process in order to obtain orphan status and to gain the benefits of the offered incentives.  First, this set of amendments requires a company to file a request for orphan designation before submitting an application for marketing approval.  Also, companies are now required to notify the FDA at least one year prior to ending the production of an approved drug.  This notification was found to be necessary in order for the FDA to find another sponsor in time to continue production so the approved drug would continue to be available on the market.[44]

B. The 1992 Response from the FDA

Since many of the terms were intentionally left ambiguous by Congress, the FDA was left with the duty of defining the regulations and shaping the Orphan Drug Act. The FDA stated, “the main purpose of the Orphan Drug Act is to stimulate innovation in developing treatments for patients with rare diseases and conditions and to foster the prompt availability of therapeutically superior drugs.”[45]   To promote this stated purpose, the FDA promulgated several specifications to the Act.

The FDA strongly backed the major incentive of the Act, the marketing exclusivity provision. The FDA expressed that exclusivity should be retained even when the patient population increased beyond the 200,000 maximum set out by the Act.  This would be necessary to “protect a sponsor’s good faith investment.”  Also, the FDA would strive to ensure that when companies originally apply, they correctly state their qualifications for designation by fitting within the 200,000 effected patient population qualification.  In order to accomplish this, the FDA will “scrutinize” applications to make sure the true population is indicated.  To enforce this, a penalty will be instituted for intentionally false statements of material fact.  The penalty includes the loss of designation and/or marketing exclusivity.

The criterion to determine whether two drugs were actually the same was also explained by the FDA.  Initially, it was unclear how the FDA would resolve whether a drug would be considered the same as another drug that already achieved designation. The FDA regulation now requires the second drug to show that it is clinically superior to the original orphan drug.  This can be proven by showing that the drug is either more effective, safer or otherwise makes a “major contribution to patient care.”

The Orphan Drug Act also retained the provision indicating designation can be gained by a showing by the company that it will not recoup investments.  In order to utilize this provision to obtain designation, the FDA requires the company to provide:

1.      Data of all costs incurred and will incur during development and marketing;

2.      Demonstration of the reasonableness of the cost data;

3.      Explanation and justification of the apportionment of development costs if the drug is used for other indications;

4.      Sales projections with justification of price;

5.      Report from independent accountant; and

6.      Permission for the FDA to examine relevant financial records.



The Orphan Drug has been in effect for almost twenty years, has it successfully enticed the pharmaceutical companies to develop treatments for rare disease? Has the change been significant?  Statistically, there are more orphan drugs being produced since the inception of the Act as well as an increase in funding for orphan drug programs.  This growth is evident in the fact that the Office of Orphan Products Development (OPD) has grown from five staff members to a total of nineteen.[46]  The funds available in the grants program also increased from $500,000 given in 1983 to $9 million given in 1993.[47] Two bills have recently passed that would double funding to the research grant program and would also formally establish the National Institutes of Health Office of Rare Diseases.[48]  One of these bills provides $25 million per year over the next fours years to the orphan drug research program and the other will authorize another $20 million each year for a period of the same four years to the National Institutes of Health program.

The expansion and increase in funding reflects growing activity in this area of research and development as well as the need for more staff to oversee the activities regarding rare diseases.  This funding is greatly welcomed and needed.  The bills increasing funding will hopefully “encourage more doctors to devote a career to finding an answer to a cure for these rare diseases since it is desperately needed to attract more young investigators into the field."[49] But the $25 million represents only a single dollar for each of the 25 million patients in the United States that suffer from a rare disease.

Prior to the Act very few new drugs were designed to treat rare disease.  Only 10 orphan drugs had been approved before the Act was passed.[50]  Twelve years after the passage of the Act, the FDA granted 631 orphan status designations to 450 drugs which led to 121 marketing authorizations.[51]  More than 100 products have FDA approval and are available to treat patients for rare diseases in the United States such as tuberculosis, cystic fibrosis and hairy cell leukemia[52] and it is more likely that we have these drugs now because of the Orphan Drug Act.

A study conducted by Frank Lichetenberg, a Research Associate from the National Bureau of Economic Research, indicated that these new drugs reduce mortality rates for rare diseases. Before the Act, the mortality rates for selected rare diseases were growing at the same rate as other diseases.[53]  Fives years after the Act was enacted, the mortality for diseases such as Huntington’s disease, myoclonus, ALS, Tourette’s syndrome and muscular syndrome began growing at a slower rate.  Mortality rates dramatically declined with the increase in drug approvals. One orphan drug approval is estimated to prevent up to 211 deaths.  The 216 orphan drugs approved since 1983 are estimated to have prevented nearly 108,000 deaths from rare diseases.[54] Lichentenberg’s research focused on HIV drug approvals and the mortality rates associated with them. He found HIV drug approvals have reduced mortality both directly and indirectly (via increased drug consumption). HIV mortality depends on both the quality and the quantity of medications consumed, and the new drug approvals have a sizeable impact on drug consumption.  Therefore, this study suggests the financial incentives offered by the Orphan Drug Act led to more orphan drug designations. This in turn offers patients access to drugs and decreases mortality rates.

Some concerns or weakness have also been found in the Orphan Drug Act.  For example, it does not deal with growing patient populations. The classic illustration of this issue is the growth of the AIDS epidemic.[55]  In 1989 the drug AZT was approved for orphan designation to treat those with full blown AIDS.  At the time only 45,000 patients were diagnosed.  AZT was then found to be able to treat and be useful in delaying the onset of AIDS in those that were HIV positive, a patient population of over 600,000.   This situation leads to many potential issues.  For example, “the lack of a competitive market in comparable treatments fostered by the market exclusivity provision of the Act led to instances of supracompetitive pricing for AIDS treatments.”[56]

Another issue is more procedural. Once a company receives orphan status it does not automatically obtain marketing exclusivity.  Several drugs can be designated as orphans for the same use, but then a race begins to who can obtain marketing exclusivity first.  This leads to a major waste of resources.  A company which invests time and money into developing an orphan drug may not be able to put it on the market for seven years because another company beat them by a matter of days.  The “race to develop orphan drugs adds uncertainty and unpredictability to business decisions” that normally only have small profits.[57]  There is risk of being completely blocked out of the market after investing a substantial amount of money.  An example of this problem is the race between Bristol-Myers Squibb and IVAX.  Both companies applied for marketing exclusivity for drugs that would treat Kaposi’s sarcoma.[58]  IVAX produced a generic version which would have been less costly, but it was beat by only six days by Bristol-Myers.  Bristol-Myers was also granted a monopoly within the United States for seven years and was allowed to provide a drug which would be more expensive to patients.

The Orphan Drug Act has succeeding in treating more than 10 million patients and increasing research in the arena of rare disease.  The Orphan Drug Act has also awakened awareness globally. Many other nations such as the European Union, Australia and Japan are following the United States model.  Other countries that are seeking to establish similar legislation include South Korea, Canada, New Zealand, and India.  A group of pharmacologists recently requested the Indian government to institute an Orphan Drug Act at a conference held by the Indian Drug Manufacturing Association in 2001.[59]


The problem of developing treatments for rare disease is not limited to just the United States, it is a worldwide problem.  The pharmaceutical industry is a global enterprise. More than 5,000 rare diseases affect millions of people worldwide, yet the patient population for each rare disease is still too small to entice the pharmaceutical industry to offer or manufacture a treatment.[60]  The regulations offered in the U.S., such as the Orphan Drug Act, have become a “reference point” for many other countries such as Japan, Europe, Korea and Australia.[61]  Australia has gone as far as automatically recognizing orphan drugs approved in the U.S. for the same indication when the prevalence of the disease in the Australian population is “not more than one person per 5000.”[62]

The European Union has recently approved a similar orphan drug act.[63]  The European Union had adopted a “Programme of Community Action on Rare Diseases”. The aim of this organization was to “contribute towards a high level of health protection by improving knowledge, facilitating access to information for health professionals, researchers and patients, and by encouraging transnational cooperation on rare diseases.”[64] A proposal for Regulation of Medicinal Products was published by the EU in 1998. A drug would be given designation as an orphan drug if:

1.      “It is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition effecting not more than five in 10,000 person in the community; or


2.      It is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic disease, and it is unlikely that the return from the community market would be sufficient to justify the necessary investment”[65]


            After a drug receives designation, another application will not be accepted for ten years for a drug with the same purpose, opposed to the seven year period offered in the U.S.  Similar to the U.S. regulations, this exclusivity will be revoked if:

1.      the original holder gives consent

2.      the sponsor is unable to supply sufficient amounts of the drug; or

3.      the second applicant can show that their product is safer, more effective or clinically superior.[66] 

Unlike the U.S. regulations, marketing exclusivity can be reduced to six years if after five years the criteria for designation are no longer met or the profits being made on the product are considered unreasonable.[67]  The American Orphan Drug Act does not provide for any penalties or guidelines to revoke any of the incentives offered.  Other economic incentives provided by the European Union’s Act include funds for examination fees and the possibility of other member states to waive their fees for applications to place the orphan drugs on their domestic markets.[68]

            Japan has had a financial support system in place since 1973 that focused on researching orphan drugs that has been amended in 1993.[69]  In Japan, the same rules are applied to orphan medical devices as well orphan drugs.  Orphan status is given to drugs that are:

1.      used to treat severe diseases effecting less that 50,000 patients in Japan,

2.      alternative treatments are not available, or greater effectiveness and/or safety are expected; and

3.      the development of the drug is highly probable. 

Once a drug receives designation, it is eligible to receive: grants, tax reductions, guidance to facilitate development, accelerated procedures on new drug approval applications, a ten year period of exclusivity of the collected data from practical medical use and a ten year term for re-examination.[70]

The pharmaceutical industry participates in a strong worldwide market and rare diseases are a global concern.  The availability of drugs, pharmaceutical production and consumption is linked to developments that occur worldwide as well as domestically. “The introduction of new products and the expansion of foreign markets have kept domestic production growing” therefore it is important to encourage involvement in world markets and harmonize procedures.[71]  The majority (83.5%) of the world market is distributed among North America (36.5%), Europe (29%), and Japan (15.8%).[72]  As discussed earlier, many of the nations are instating similar plans to promote R&D for rare diseases modeling the American Orphan Drug Act.

The pharmaceutical industry is seeking a harmonization by offering ten years of marketing exclusivity for all countries and it is trying to extend these rights to any registration data, including indications of older drugs.[73]  The U.S. should provide additional incentives or the FDA should offer more guidance on marketing on the global market.  Also, there should be efforts to gain mutual recognition of approvals from other countries, as Australia does for orphan drug approved in the U.S.  There should also be harmonization to permit companies to import drugs that are marketed in a different country upon authorization.


The U.S. Orphan Drug Act primarily focuses on the pharmaceutical companies and inciting them to produce orphan drugs.  The Act, as it is, has proven to significantly increase the revenue a company can make on an orphan drug and harness’s these financial incentives to induce companies to invest. Corporate responsibility and public image should be promoted and there should be less emphasis on profitability. In addition to offering financial incentives through the Orphan Drug Act, Congress should also encourage academic researchers and others outside of just the for-profit pharmaceutical industry to develop more drugs and provide them with more incentives, funding and grants. 

Since pharmaceuticals companies are so profitable in general, it has been proposed that they should set aside a fraction of their revenues for development of rare diseases and assist governments in providing access and implementing health programs.[74]  The industry should also work with organizations such as WHO, World Bank and NGOs to build up collaborative policies. Major pharmaceutical companies should aid the WTO to set up exceptions to permit underdeveloped countries to produce or import generic drugs instead of prohibiting them. At the November 1999 conference entitled “Increasing Access to Essential Drugs in a Globalized Economy” called for “compulsory research obligations, such as requirements that companies reinvest a percentage of pharmaceutical sales into R&D, either directly or through public or private sector R&D programs.”[75]

Sometimes the pharmaceutical industry is more concerned about profits and business, forgetting that they play a vital role in the health and fitness of people. The “industry should consider its social responsibilities and not just its profits.”[76]  There are other things a company should be concerned about, such as their public image.  If a pharmaceutical researcher has come across a cure for a rare disease, why not share it and help those that need it? The argument provided by the pharmaceutical industry is, “Giving away our medicines away in general is an unsustainable and unrealistic answer because, at the end of the day, we must earn adequate return on our investment in order to fund future research.” It seems selfish and almost cruel to withhold a possible antidote from someone suffering from a rare disease.  Pharmaceuticals should be encouraged to make donations, either by their own morality or by incentives offered through the government.  Displaying good corporate responsibility is valuable for a company's image in the long run. If clients and patients perceive a company as moral and genuinely interested in the public good, they are more likely to maintain a relationship and invest in that corporation. Tax incentives over the past 20 years and corporate giving amounted to 6 billion.[77] This is a practice that should be continued and encouraged.

An exemplary model of such corporate giving is Merck.  Merck discovered a treatment for river blindness during development and research.  While investigating a heartworm treatment for animals, researchers found a drug that would prevent tropical river blindness. The drug was already produced but no one was buying the product despite the great need.  The government also provided no aid because of the lack of a market so Merck just donated the medicine. Since then 51 million treatments have been distributed.  Now the Merck project is managed in cooperation with United Nation agencies, WHO and the Task Force for Child Survival and Development.[78]  Other organizations should look to Merck as a role model and take responsibility upon themselves to offer or donate medications which they have available. As George W. Merck, the Chairman and CEO of Merck wisely stated, “We try never to forget that medicine for the people.  It’s not for the profits.  The profits follow, and if we have remembered that, they never failed to appear.”[79]

Additionally, there are alternatives for putting a drug on the market to treat rare diseases. In the United States, the regulations of FDA permit physicians to prescribe approved medications for other uses aside from than their intended indications. This practice is known as “off-label use”.[80] This method allows a physician to use an FDA approved drug to treat a patient for a symptom that the drug was not initially approved for.  A manufacturer is allowed to continue producing the drug for its approved use as well as for the additional uses that were not initially foreseen.  This way the product is still available to patients and the manufacturer does not have to wait and go through the FDA approval process for the new use. The FDA does have certain restrictions on how information can be distributed by companies to inform physicians about these alternative uses.[81]  The information can be disseminated through means such as studies published in scientific journals about the safety, effectiveness or benefits of "off label" uses for marketed drugs, biologics and medical devices. This information can only be distributed for "off-label" uses which have been, or will be, studied and submitted for FDA approval. It must also be both reliable and balanced. The FDA should be flexible with these restrictions if an approved drug is found to also treat orphan disease but has not been intended for that use yet.[82]


For additional references, see:






Examples of rare diseases:

Ø      Anorexia Nervosa

Ø      Anthrax

Ø      Carpal Tunnel Syndrome

Ø      Dysthymia

Ø      Endomyocardial Fibrosis

Ø      Growth Hormone Deficiency

Ø      Huntington's Disease

Ø      Meningioma

Ø      Rubella

Ø      Werner Syndrome


Some Orphan Drugs Approved this Year:

Ø      Zevalin for the treatment of B-Cell non-Hodgkin's lymphoma

Ø      Gleevec for the treatment of gastrointestinal stromal tumors

Ø      Remodulin for the treatment of pulmonary arterial hypertension

[1] Gary A. Pulsinelli, The Orphan Drug Act: What’s Right With It, 15 Santa Clara Computer & High Tech.L.J. 299, 304 (1999).

[2] David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 126 (2000).

[3] This also raises the issue of whether resources that are allocated to R&D of diseases which affect a greater number of the population should be reduced in order to include R&D for rare diseases.

[4] M. Lisa Swoboda The Ethics of Pharma-Economics: An Examination of the Limit of Corporate Responsibility in the Pharmaceutical Industry, 1, 4 (April 2, 1999).

[5] Id.

[6] Pulsinelli at 299, 304.

[7] Swoboda at 4.

[8] Black’s Law Dictionary 919 (7th ed. 2000).

[9] Rohde at 127.

[10] Generics are drugs which are marketing under their chemical name without advertising. For example the drug Diazedpam is a generic name for the commonly advertised brand name sedative Valium.  See

[11] Swoboda at 5.

[12] Rohde at 125, 126.

[13] Swoboda at 1,5.

[14] Rohde at 125, 126.

[15] David B. Clissold,  Prescription for the Orphan Drug Act: The Impact of the FDA’s 1992 Regulations and the Latest Proposals for Reform, 50 Food & Drug L.J. 125, 130 (1995) See also  David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 127 (2000).

[16] John Henkel, How TV Launched the Orphan Drug Law, FDA Consumer Magazine (June 1999), available at

[17] Id.

[18] Id.

[19] Id.

[20] Id.

[21] Gary A. Pulsinelli, The Orphan Drug Act: What’s Right With It, 15 Santa Clara Computer & High Tech.L.J. 299, 305 (1999).

[22] Gary A. Pulsinelli, The Orphan Drug Act: What’s Right With It, 15 Santa Clara Computer & High Tech.L.J. 299 (1999).

[23] Rohde at 133.

[24] Robert A. Bohrer, A Tale of Two Proteins: The FDA’s Uncertain Interpretation of the Orphan Drug Act, 12 Harv.J.L.&Tech. 365, 367 (1999).

[25] Orphan Drug Act, Pub. L. No. 94-414, §526(a)(2), 96 Stat. 2049 (1982).

[26] Pulsinelli at 306.

[27] Rohde at 129.

[28] Pulsinelli at 306.

[29] Id. at 307.

[30] Id. at 312.

[31] Id. at 310.

[32] Id. at 307.

[33] Id. at 312.

[34] Id. at 310.

[35] Id. at 310.

[36] David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 133 (2000).

[37] Id. at 129.

[38] Id. at 129.

[39] David B. Clissold,  Prescription for the Orphan Drug Act: The Impact of the FDA’s 1992 Regulations and the Latest Proposals for Reform, 50 Food & Drug L.J. 125, 130 (1995)

[40] Id. at 130.

[41] Id. at 130.

[42] Gary A. Pulsinelli, The Orphan Drug Act: What’s Right With It, 15 Santa Clara Computer & High Tech.L.J. 299 (1999).

[43] Id.

[44] Id. at 130.

[45] David B. Clissold,  Prescription for the Orphan Drug Act: The Impact of the FDA’s 1992 Regulations and the Latest Proposals for Reform, 50 Food & Drug L.J. 125, 130 (1995).

[46] Joseph A. Levitt & John V. Kelsey, The Orphan Drug Act Regulations and Related Issues, 48 Food & Drug L.J. 525, 526 (1993).

[47] Id. at 525.

[48] Micheal J. Bernstein, Bills would boost research funding for rare disorders through NIH and FDA (October 21, 2002), available at

[49] Id.

[50] David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 133 (2000).

[51] Paola Minghetti, et al., A Proposal to Improve the Supply of Orphan Drugs, 42 (1) Pharmacological Research 33, 35 (2000).

[52] Rohde at 131.

[53] Raises the issue of whether mortality rates for orphan disease should be lower compared to other diseases.

[54] David R. Francis, Orphan Drugs Cure Rare Diseases at (For an updated listing of products obtaining designation and a listing of marketing approvals see

[55] David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 135 (2000).

[56] Id.

[57] David D. Rohde, The Orphan Drug Act: An Engine of Innovation? At What Cost?, 55 Food & Drug L.J. 125, 136 (2000).

[58] James Love, Paying for Health Care R&D: Carrot and Sticks, MSF/DND Working Group, 182 (2001).

[59] Rinat Ariely, The Rise of Biopharmaceutical Orphan Drug Adoption, Frost & Sullivan (December 2001) available at

[60] Paola Minghetti, et al., A Proposal to Improve the Supply of Orphan Drugs, 42 (1) Pharmacological Research 33, 35 (2000).

[61] Id.

[62] Id.

[63] Arrigo Schieppeti et al., Modulating the profit motive to meet needs of the less-developed world, 358 The Lancet 1638 – 1640 (Nov. 10, 2001).

[64] Minghetti at 35.

[65] Minghetti.

[66] Id.

[67] Id.

[68] Id.

[69] Id.

[70] Minghetti.

[71] Kanavos at 57.

[72] Kanavos at 57.

[73] Love at 183.

[74] Schieppati at 1640.

[75] Love at 185.

[76] Schieppati at 1640.

[77] M. Lisa Swoboda The Ethics of Pharma-Economics: An Examination of the Limit of Corporate Responsibility in the Pharmaceutical Industry, 1, 3 (April 2, 1999).

[78] Id.

[79] Id.

[80] Definition provided at 

[81]  FDA Proposes Rules For Dissemination Information On Off-Label Uses, HHS News, June 5, 1998, available at

[82] For further discussion on “off label” uses, See Steven R. Salbu, Off Label Use , Prescription and Marketing of FDA Approved Drugs: An Assessement of Legislative and Regulatory Policy, 51 Fla. L. Rev. 181 (1999).