Developing and Marketing Orphan Drugs for Rare Diseases
Happiness comes from facing challenges and going out on a limb and taking risks.
–Diane Frolov and Andrew Schneider. From Northern Lights (1993).
NORD is the only non-profit, non-governmental agency dedicated to helping patients and families coping with all rare diseases.
–Abbey S. Meyers, National Organization of Rare Disorders (NORD) President.
A‘rare disease’ is defined in the United States as one with a prevalence of less than 200,000 patients (currently less than 0.08% of the population). Other countries generally use prevalence criteria of 0.1% to 0.5%, although they may also accord ‘orphan’ status to any untreatable disease (e.g., in Europe) or when there is proof of non-profitability regardless of disease prevalence (e.g., the United States). A rare disease may also be termed an ‘orphan disease,’ and drugs solely for its therapy termed ‘orphan drugs.’ In the United States, closely related subsets of patients must also be considered because orphan drug designation cannot be obtained if the drug can be used by such subsets in addition to those with the orphan disease; the Food and Drug Association (FDA) aggregates such subsets and will not designate a drug when the total of the subsets exceeds the 200,000 patients limit. Worldwide, the legislation is intended to incentivize pharmaceutical company sponsors to research small patient populations.
Depending upon the prevalence criterion used and the definitions of diseases, there are an estimated 4,000 to 8,000 rare (or orphan) diseases. Many involve genetic problems and often are related to birth defects that are poorly characterized or involve permanent defects of nerve, muscle, or bone that cannot be corrected with drugs. Almost all marketed drugs are used to treat some rare diseases. A few examples include propranolol, which is used to treat idiopathic hypertrophic subaortic stenosis (in addition to hypertension and angina); cimetidine, which is used to treat Zollinger-Ellison syndrome (in addition to duodenal ulcers); and antibiotics, all of which are used to treat rare as well as common bacterial infections. Pharmaceutical companies have always developed orphan drugs. The Orphan Drug Act, passed in 1983 in the United States, did not initiate, but rather stimulated, the development of such drugs.
PRINCIPLES
One of the most important principles about orphan drugs is that they form a very heterogeneous group, for the reasons given in Table 55.1.
Table 55.1 Reasons why orphan drugs are a heterogeneous group | ||||||||||||||||||||||
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Orphan drug status can supplement patent protection, because a successful New Drug Application (NDA) for an orphan product obtains seven years of marketing exclusivity, regardless of any other intellectual property rights. Thus, patents threatened by limited coverage, few years before expiry, nonpatentability (e.g., a natural product), interference from wealthier competitors, etc., may not offer as much protection as orphan drug designation by the national drug regulatory authority.
The regulatory processes for investigation and approval of orphan drugs are substantially similar to nonorphan drugs. After designation, orphan drugs are investigated under Investigational New Drug Applications, and the drug approval process is by filing an NDA, Product License Application, or Biologic License Application. The numbers of patients in licensing applications will however, be fewer than is typical, usually because of the scarcity of patients available for study.
Development costs, time to market, and commercial potential vary enormously among orphan drugs, as with all drugs. It is usually pointless to develop an orphan drug if a generic version of the same compound is already marketed or shortly will be (i.e., before the company can launch its product). Such a generic may not be indicated for the rare disease, but it is likely that it will be dispensed for the treatment of the rare disease.
CLASSIFICATION OF ORPHAN DRUGS
While several classifications of orphan drugs have been proposed, no single one has been universally accepted (Spilker 1991). This section briefly mentions the criteria on which a classification scheme could be based, followed by a proposal for a simple classification based on combined economic and medical value. The major criteria that may be used to create a classification for orphan drugs include the following:
Therapeutic or disease area of the drug
Whether the drug is marketed or investigational
Patent status of the drug (e.g., patent issued and in force, patent expired, nonpatentable, patent pending)
Generic drug status (whether or not marketed, whether the generic has the same dosage form, strength, excipients, etc.)
Size of patient population worldwide
Whether drug development costs can be recovered through sales
Availability of alternative treatments (e.g., none exist; all alternatives are highly toxic, very expensive, limited in availability, only work in a few patients)
Medical value of the drug (in the author’s opinion, this is the most important criterion for regulatory approval and marketing)
Potential use in a more common disease, as well as in another rare disease. This is often difficult to know at the outset of development, but almost every drug that reaches the market is tested by the medical community in many other diseases to evaluate its efficacy.
Whether biologically or chemically synthesized
Existence of a patient support group. If a patient support group exists it may facilitate the development of the drug by notifying its members about participation in clinical trials. The group could also have its members write letters on behalf of the product to increase awareness in the medical community.
THE ECONOMIC-MEDICAL INTERFACE
There are four situations (excluding number 3 below) where legislators are keen to give incentive to product sponsors, but where the latter may assess development potential differently.
Drugs with little commercial potential, but with high medical value. The commercial value may be subdivided as to whether the product will lose money and never pay back its development costs, or whether the sales are expected to be below an arbitrary hurdle rate (e.g., internal rate of return) and achieve less profit than desired for new projects added to the company’s portfolio. In the former case, only wealthy companies that wish to perform a community service or have a reason other than profits for developing the drug could undertake the development of a money-losing drug. If the drug has high medical value and will not lose money, there are companies that would at least consider developing it if it met their other criteria (e.g., therapeutic area).
Drugs with moderate or high commercial value and high medical value. If a few caveats were met, this category of orphan drugs would never have a problem finding a sponsor to develop the drug. For example, it is important that there not be a generic drug on the market, or else pharmacies would fill prescriptions with the generic. If a generic were available, the commercial potential of a brand-name drug would only be theoretical. This category is meant to imply that the commercial potential would be real if the product were to reach the market.
Drugs with variable commercial potential and low medical value. This category is a very realistic description for many, if not most, drugs at an early stage of development, before the drug’s clinical efficacy and safety profile are well understood. The wisest and most educated person or group of experts can only guess the value of a drug before it is tested and its profile is known. One exception to this principle is drugs that are developed in a new dosage form, but whose activity and safety are well known. Nonetheless, a drug of low medical value will rarely be developed unless a company knows that the commercial value is significant. A “me-too” drug is an example of a drug usually placed in this category.
The medical value of a drug may be independent of the efficacy and rarity of the disease. For example, in Wilson disease there are several effective products on the market, yet additional ones are still being developed. Penicillamine is often effective, but often causes serious adverse events. Zinc acetate and trientine are other products and molybdenum is being evaluated for the same indication.
Variable commercial potential for both a rare and common disease. Virtually every pharmaceutical company that develops an orphan drug hopes that the drug will be found useful in treating a more common disease but this seldom occurs.
Unprofitable drugs for common diseases. This category of drug is described in the orphan drug legislation and would include reference to tropical diseases that are not prevalent in the United States or to a drug that may be medially important for a subset of patients with a common disease but would not be expected to recoup the company’s investment. Few drugs in this category have been developed.
INTERESTED PARTIES
There are eight principal stakeholders in orphan drug development. Note that many can be either public or private institutions, as well as either individuals or larger groups. These stakeholders often have different motives in how they view orphan drugs.
Legislatures
National, provincial, and other levels of legislature are involved in orphan drug development, primarily through creating new legislation. They define the incentives. Incentives typically include product exclusivity, tax relief, grant awards, waiving of application and user fees, or quid pro quo arrangements of other types.
Regulatory Authorities
These authorities are primarily motivated to improve and protect the public health of the community they serve through approval of effective and safe new drugs. This includes underserved patient populations, however small, and orphan drugs. Regulatory authorities are influenced by their perception of a drug’s medical value and their obligations to supervising legislatures.
Patient Associations
These groups typically focus primarily on one specific disease or type of disease process (e.g., inborn errors of metabolism, muscle disease, glycogen storage diseases, autoimmune diseases). Occasionally, they may serve as umbrella organizations for larger numbers of rare diseases, in order to achieve a critical mass required for advocacy purposes [e.g., the National Organization of Rare Disorders (NORD) in the United States]. Their motives include supporting initiatives that may stimulate the discovery and development of new treatments for their diseases of interest. Another important function of many of these groups is to provide patient information to their members, and often also to the public.
Pharmaceutical Companies
The motivation of these organizations is not solely profitorientated in most cases, as they usually accept social responsibilities for the patients they serve with their more profitable drugs (see previous text). In addition to the small amount of profit they may make on the majority of orphan drugs brought to market, there is an enhancement of the company’s image.
Trade Associations
Professional trade associations usually represent pharmaceutical companies or distributors. These are concerned with the image of the industry, as well as providing social benefits through publicizing the products of their members.
Patients and Families
The motivation of those with the disease or with affected relatives is clear—they want better treatments that are affordable and will improve quality of life for the patient.
Physicians and Other Healthcare Providers
The motivation of these people is also clear—they seek better treatments for their patients and are often willing to test new drugs in clinical trials.
Academicians
Orphan drugs offer research opportunities for scientists and academic clinicians, together with career enhancement opportunities.
SOURCES OF INFORMATION ON ORPHAN DRUGS
The FDA publishes an annual list of orphan drugs that have been either designated or approved for marketing. This is now available on the Internet (see www.fda.gov).
Most specific disease organizations, as well as umbrella disease organizations (e.g., the NORD), provide information of relevant diseases for members and sometimes for researchers, and the public. These groups may also provide current scientific information. Again, most of these organizations have websites that are easily located by commonly used search engines when the disease of interest is used as the search term.
DISCOVERY, DEVELOPMENT, AND MARKETING OF ORPHAN DRUGS
The process of discovering new orphan drugs is not different from that used to discover drugs for more common diseases, and the earlier chapters of this book are equally applicable to orphan drugs.
Development of Orphan Drugs
The overwhelming majority of processes used to develop orphan drugs do not differ from those used to develop drugs for more common diseases in terms of strategies created, methodologies used, and the criteria used to judge success. However, quantities of data required for marketing approval usually differ, sometimes by several orders of magnitude. If there are only 500 patients with a specific disease, it is usually impossible to design and conduct two randomized, well-controlled placebo trials. However, it is interesting to speculate whether NDA populations for orphan diseases might deviate from the general patient population less than for more conventional drug development programs. This lesser deviation is virtually certain when an NDA contains a greater proportion of all the patients for whom the drug is likely to be prescribed.
Some of the unique challenges often encountered with orphan drugs to treat rare diseases include:
How to find patients when there are very few around and they are spread out geographically. Two quite novel approaches have been to open sites where the patients were located and encourage the patient’s treating physician to become an investigator, and to send visiting nurses to the patients from a central location rather than asking the patient to travel to the medical facility for treatment. In some situations, a group of patients with a rare disease is brought to the National Institutes of Health, often periodically until the trial is completed.
How does one find investigators when there are almost none who specialize in the disease? This may take time and effort at professional meetings, interacting with patient associations or an umbrella group such as the NORD.
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