Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Orphan Drugs and rare diseases

Dr. Elke Bertram-Neis (Abschlußjahr: 2001)

Summary

In which region is the research on these drugs most attractive for the Pharmaceutical Industry?

In recent decades, medical science research have made remarkable progress in saving lives, extending life expectancy and ridding the world of a number of diseases. However, this refers seldom to rare diseases. Pharmaceutical products for treatment of rare diseases are commonly referred to as orphan drugs. Currently, there are a lot of publications about orphan drugs and rare diseases in journals, internet and on TV. The term "orphan drug" implies that it lacks sponsorship due to an low expectation of economic value. Marketing managers and accountants, however, want to analyse sales potential before an investment in the product would be authorised. Therefore, it seems that the needs of patients who suffer from orphan diseases are met unsatisfactory, not only because of a lack of treatment, but also because of a shortage of knowledge about the causes, prevention, and diagnosis of these diseases. It has been estimated that there are more than 5.000 identified rare disorders affecting more than ten million people throughout the world. 4.000 of these diseases appear to be linked to genetic factors. A large number of these diseases affects children and new-born infants. A lot of orphan medicinal products are developed by biotechnology but not all. Many are ordinary chemical entities. Some statistics show that 82% of orphan products are for treatment of serious or life-threatening diseases.

The U.S. American solution to the orphan drug problem has had world-wide impact. The incentives established by the United States Orphan Drug Act in 1993 initiated significant changes within the pharmaceutical industry. In consideration of the success of the American legislation and of comparable legislation in Japan and Australia, the European Commission introduced similar Regulations for the European Union. Patient groups in Europe convinced the European Commission to understand that orphan drug incentives are good for everyone because they will create jobs, especially in new companies, they will generate taxes, increase exports and, most of all, help patients. Legislation on orphan medicinal products came into force in the European Union in April 2000. This was welcomed by clinicians, academics, patient support groups, industry and, above all, by the patients themselves. Additionally, patient groups try to press the government's representatives to improve the legislation and demanded further incentives. They hope that these can influence the attitude of pharmaceutical companies which otherwise would continue their development of "me-too" diet pills, anti-depressants, anti-hypertension drugs, and baldness medicines, as the pharmaceutical industry, just like any industry invests its resources where the most profit is assumed.

The international research community is now challenged to develop suitable trial designs required for marketing approval of orphan drugs. Like any drug, orphan designated products must be proven safe and effective before the authorities can approve them for marketing. They undergo the same review process as a non-orphan product. The parameters for approving the drug to treat a rare disease are not compromised. The clinical testing requirements are designed to determine the effectiveness of the drug and its safety to patients. Unfortunately, most of the standard double-blind study designs are well suited for greater patient groups and are not easy to carry out in smaller populations. However, the limited number of patients available for clinical trials, the fact that no other treatment may be available for patients other than the study drug and also the life-threatening nature of many orphan diseases impair the research and present obstacles to investigators. But nevertheless, there are unique study designs that have been developed around orphan drug treatment or orphan drug use. Additional new creative statistical methods are needed for this specific purpose. Some authorities provide sponsor assistance in order that studies are adequately controlled to show safety and efficacy, even with small numbers of patients.

Another specific aspect is worth mentioning: many positive results originate from the close relationship between patients and the physicians treating them. Rare disease studies lead to publications in journals that are read and disseminated world-wide. Sometimes companies decide that they are no longer interested in developing a useful product, then certain orphan product committees or patient organisations try to find a company which is interested in proceeding the research. Even so in the course of a clinical trial on rare diseases but not in case of emergency treatment of a single patient, a possible attraction of patients allows the physician to observe greater numbers of them with the disease. Consequently, the investigators are able to understand influencing factors that may contribute to the disease and increase the knowledge about the drug being studied.

Patient organisations are usually founded by the patients themselves, or by their parents, relatives or friends, who want to help a loved one. Therefore, these organisations are sometimes called "self-help" groups because they are governed by people with a direct interest in the disease. Patients express their needs, e. g. to be informed as soon as there is a development in rare diseases. They believe that the government of social societies has an obligation to take care for their inhabitants affected with rare diseases and should implement the required laws and incentives. It is obvious, that generally the pharmaceutical companies cannot take care for individual problems. Only small or medium sized companies have to be satisfied with the smaller markets at which orphan drugs are aimed. The innovative biotechnology companies will develop the needed treatments for genetic diseases because they are willing to take higher risks, especially in areas where no satisfactory therapies are existing.

Market exclusivity and tax credits seem to be the most important attraction points of the legislation for the industry. Yet, other measures like fast track review processes, fee waivers, and clinical trial protocol assistance are of interest as well.

In order to accelerate access to market for orphan medicinal products, foremost investigators need special guidelines that define and develop new processes, while preserving appropriate guarantees for safety and efficacy. Both requirements could be met by options available before marketing authorisation is granted, e. g. compassionate use programmes. Other options should be available at the stage of application review, e. g. priority review, marketing authorisation approval under special circumstances or approvals which are granted on a temporal basis. Like any common drug, orphan drugs must be used responsibly and very cautiously. An early access implies certain restrictions, e. g. limited delivery and special labelling on warnings. Safe use of orphan drugs during timely limited authorisation might be enhanced by supplementary means, e. g. patient's name has to be entered into a registry and patients have to answer questionnaires regarding efficacy and safety matters, periodically.

The similarity of the orphan drug rules in the U.S., EU and Japan is conspicuous but a few points are weighed differently. The recent EU legislation defines a "rare disease" as one that affects less than one per 2.000 people in the community. In the United States, a prevalence figure of 200.000 (1:1325) is stated which is roughly twice the 50.000 total patient population required to qualify for orphan designation in Japan (1:2500). The most restrictive requirement refers to Australia. Australia chose the lowest population figure with 1.1 per 10.000 people. But according to some publications the bulk of the rare diseases would be covered by most of the criteria, whether it is 4 (Japan), 5 (EU) or 7.5 (USA) per 10.000 people. In a few years, it will be interesting to compare which diseases have qualified under the orphan drug rules in the three ICH-regions and which one would be left out under the Australian Regulation.

After a consolidation period in Europe, perhaps next year, it should be exciting to determine which region will be the most attractive one for the pharmaceutical industry to develop orphan drugs, not only theoretically but after conducting a concrete project, because the regulations seem to be quite similar.

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