March 2003

Orphan Medicinal Product Regulations In The EC: The Story So Far

ERA News
Biomedical science has made immense progress in the discovery of new targets for improving the prevention, diagnosis and treatment of a great number of diseases. Despite this progress, countless diseases and conditions exist for which there are still no satisfactory diagnostic tools or medical therapies. Some of these are life-threatening or chronically debilitating, affecting relatively few people and generally considered rare in occurrence and distribution. This month, Lincoln Tsang, Of Counsel at law firm Arnold & Porter in London, provides a brief overview of the historical and current developments of the regulations governing the designation of orphan products in the EC. Comparative references are also made to the US regulatory framework, with a particular focus on the latest legislative changes.

The Orphan Drug Act introduced an incentive system for the development of orphan products in the US in 1983. Orphan diseases are defined In the legislation as those affecting fewer than 200,000 individuals in the US and include conditions such as Huntington's disease, amyotrophic lateral sclerosis, Tourette syndrome, Crohn's disease, cystic fibrosis and Duchenne muscular dystrophy.

Before congress passed the Orphan Drug Act, only 38 drugs existed to treat rare diseases. Since the law was enacted, offering tax credits, seven years' market exclusivity and other incentives, the US Food and Drug Administration (FDA) has approved more than 200 treatments for orphan Indications as defined in the Act. There are another 800 potential new drugs In the research pipeline. This is an important initiative to motivate research into orphan drugs and an example of how government can use the legislative framework to stimulate the progression of treatments, working in partnership with stakeholders to produce drugs that might not otherwise have been developed.

The FDA's Office of Orphan Products Development was set up to encourage the development of drugs, biologics, medical devices and medical foods for rare conditions by offering financial incentives to product sponsors. Since 1984, the programme has funded more than 300 grants geared towards clinical research into orphan product development. It has been reported elsewhere that the appropriations for this programme have remained virtually static for the last decade while running costs have escalated.

Following the introduction of the US Orphan Drug Act, a number of developed countries and regions built a regulatory framework designed to provide incentives for companies to develop products for orphan diseases which would not normally justify R&D or marketing thanks to their poor financial return. Apart from the EC, countries such as Japan, Australia and Singapore have developed their own regulatory frameworks to encourage development of products for orphan diseases. The Japanese Ministry of Health and Welfare, for example, is responsible for granting orphan drug status following scientific examination by the expert sub-committee of its Medicinal Products committee, based on criteria such as estimated size of the affected patient population and the development protocol. Australia established Its orphan drug policy in 1997 and the Therapeutic Goods Administration is responsible for its administration.

...European regulation

Almost 20 years after the introduction of the US Orphan Drug Act, the EC, within the regulatory framework of the single market, enacted two legal Instruments, namely European Parliament and council Regulation 141/2000[1] and commission Regulation 847/2000.[2] Since the Regulations came into operation over two years ago, more than 120 products have been granted orphan drug status.

Some of these orphan medicinal products have already been approved through the European centralised procedure. The first two were authorised as replacement therapy for Fabry's disease. Products have also been authorised for the treatment of acute promyelocytic Leukemia and chronic myeloid leukemia. Most recently, the EC commission granted authorisations for carglumic acid and miglustat, indicated for the treatment of hyperammonemia and type-1 Gaucher's disease, respectively.

The aim of the enabling Regulation 141/2000 is to establish a Community procedure for designating orphan medicinal products and to introduce incentives for R&D and marketing by granting exclusivity rights for 10 years. In contrast, the US and Australia offer seven and five years, respectively, whereas Japan also grants 10.

Under Article 4 of Regulation 141/2000, a Committee for Orphan Medicinal Products (COMP) was established to examine applications for the designation of a medicinal product, advise the Commission on orphan drug policy for the EC, assist the Commission in liaising with patient support groups and international bodies on related matters and draw up detailed guidelines.

Article 3 of 141/2000 sets out the criteria for the designation of an orphan medicinal product based on:
  • the prevalence of the disease in the Community which is not more than five in 10,000 persons; or
that there Is Insufficient financial return to market the product without Incentives; and
  • that there is no satisfactory method of prevention, diagnosis or treatment of the condition or, if such a method exists, that the medicinal product will be of significant benefit to the affected individuals.
In order for a product to be eligible for designation it should, first of all, meet the definition of a medicinal product as set out in Article 1 of Directive 2001/83/EC[3] (see Article 2(b) of Regulation 141/2000). For novel biotechnology products, such as gene-transfer and cell-based products, reference should be made to the existing guidelines already developed by the Committee for Proprietary Medicinal Products (CPMP) that set out the working definition for a gene-transfer medicinal product[4] and a human somatic cell therapy medicinal product.[5] The working definitions take into account the Commission Communication 98/C 229/03 regarding the scope of the medicinal products derived from biotechnology. In this sector, the COMP has granted orphan status to the following:
  • a recombinant adenovirus containing a herpes simplex virus thymidine kinase gene used in conjunction with ganciclovir for the treatment of high-grade glioma;
an autologous renal cell tumour vaccine for the treatment of renal cell carcinoma; and
  • a murine retrovirus containing a gene insert coding for gamma-c for the treatment of severe combined immunodeficiency (SCID) diseases.
Secondly, for a given medicinal product that has not previously been designated, the COMP will consider the epidemiology of the disease to be treated. The relevant population for the purpose of prevalence is the population of the EC. When there Is a satisfactory existing method of treatment, the orphan designation is based on assumption or plausible evidence for the purpose of significant benefit over the existing medicinal product(s).

'Significant benefit' is defined in Article 3 of Commission Regulation 847/2000. A new or alternative treatment would generally be considered of significant benefit if the product provided a clinically relevant advantage or a major contribution to patient care. It should be emphasised that, at the time of orphan designation, significant benefit should be based on well-justified assumptions and demonstration of this benefit is not required. But assumptions of potential benefits should be plausible and based on sound scientific argumentation. The COMP may take into account the potential availability of a medicinal product to patients when assessing whether it will be of 'significant benefit'.

Once an orphan medicinal product designation has been granted, the applicant can, and is often encouraged to, apply for protocol assistance and advice from the European Medicines Evaluation Agency (EMEA).

Article 6 of the Regulation sets out the legal provision for seeking protocol assistance from the EMEA and the CPMP for conducting the various tests and trials necessary to demonstrate the quality, safety and efficacy of the product concerned. To this end, on 27th February 2002, the EMEA Issued a guidance note for companies wishing to request protocol assistance.[6] The requests, as set out in the guidance, should be related to prospective questions concerning quality, pre-clinical and clinical aspects for the future development of the product within the scope of the designated indications. The CPMP's Scientific Advice Review Group addresses the scientific issues that fall within the scope of protocol assistance, including follow-up pursuant to Article 5(10) of Regulation 141/2000.

As mentioned, once an orphan medicinal product is approved it is entitled to a market exclusivity period. Market exclusivity should be read in the context of Article 8 of Regulation 141/2000 that defines the rules for a competitor to break the exclusivity of an authorised orphan drug for a given indication. In addition to other incentives, such as fee waivers and protocol assistance, it is this prospect of obtaining market exclusivity for a certain period that provides the strongest inducement to industry to develop orphan drugs.

Market exclusivity can only be broken if the second applicant can demonstrate that its product is different from the originator's, that is to say that it is not similar. The definitions of a similar medicinal product and a similar active substance are provided in Article 3(3) of Commission Regulation 847/2000, which states:

"(b) 'similar medicinal product' means a medicinal product containing a similar active substance o[r] substances as contained in a currently authorised orphan medicinal product and which is intended for the same therapeutic indication;

(c) 'similar active substance' means an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism."

The sub-paragraphs of Article 3(3)(c) set out what constitutes 'similarity' for active substances with varying degrees of structural complexity. It is noteworthy that the definition of 'similar' is close in wording to the US Code of Federal Regulations Title 21 § 316.3 with respect to 'sameness' (see also 62086 Federal Register Vol. 57 Number 250 of 29th December 1992).

In the EC legislation, the definition of 'similar' has been broadened to provide a satisfactory level of protection to the originator and has therefore been strengthened to protect against other substances in the same class of products or biologicals with minor structural variations. It should be noted that 'similarity' in the context of data protection of an orphan medicinal product is distinguishable from, and wider than, 'essential similarity' under Article 10(1)(iii) of Directive 2001/83/EC.[7] The latter is tied In with the provision of the necessary data to prove safety, quality and efficacy, which would suggest a tighter definition of 'essential similarity" to ensure the generic medicinal product meets quality standards.

Indeed, this point has been elaborated In an opinion given by the Scientific Steering Committee's[8] Scientific Committee on Medicinal Products and Medical Devices, issued on 21st October 1998. Furthermore, the Committee was of the opinion that the definition of 'product similarity' should include the biological properties of substances.

This opinion will be of particular interest in defining similarity for products that cannot be defined chemically and should be defined in terms of biological activity (see Part 2A, paragraph 3.1 of Annex 1 to Directive 200l/83/EC). Article 3 of Commission Regulation 847/2000 is silent on the extent to which similarity should be defined for substances which are not amenable to physico-chemical characterisation alone. Perhaps, in this case, the mere fact that the two drug substances act via the same mechanism is sufficient to class them as 'similar'.

Alternatively, a second applicant, although developing a medicinal product containing an active substance with a chemical structure similar to the originator's, may still break the market exclusivity for a given indication provided it can demonstrate 'clinical superiority'.

Article 3(3)(d) defines 'clinically superior'. It means that a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that obtained from an authorised orphan medicinal product with respect to efficacy or safety or, in exceptional cases, the product offers a major contribution to diagnosis or to patient care. For example, in order to demonstrate greater efficacy, it is necessary to provide evidence on comparative efficacy using appropriate end-points, including surrogate end-points, which should be appropriately validated.

It is particularly interesting in this context to note that the scope of the protocol assistance on study design includes the need to demonstrate clinical superiority over a similar orphan medicinal product authorised for the same Indication. The EMEA states: "Such [a] request for advice on clinical superiority over similar orphan products authorised for the same indications is also possible for non-designated orphan drugs through the usual scientific advice procedure." However, the protocol assistance does not provide a pre-evaluation of data for submission for regulatory approval.

…other initiatives

Article 9(1) of Regulation 141/2000 sets out other incentives made available by the Community and by the Member States to support research into, and the development and availability of, orphan drugs. Aid for research for small and medium-sized companies under the auspices of the European framework programmes is available, administered under the Directorate-General Research. A Decision adopted by the European Parliament and Council[9] in 1999 provides for a Community action programme on rare diseases including genetic conditions. The budget was set at €6.5 million. Both the Commission's Fifth and Sixth Research Framework Programmes will provide further impetus directly or indirectly for research into rare diseases.[10]

The Commission has published a report entitled Inventory of Community and national Incentive measures to aid research, marketing, development and availability of orphan medicinal products.[11] This report recognises that incentives available at the Community level have to be implemented by national initiatives, particularly in areas such as fiscal incentives and national research projects.

Most notable in the report are the ongoing strategic activities undertaken by the governments of France, Germany and the Netherlands. The French government, for example, is encouraging the application of genomics to R&D into orphan medicinal products, offering tax incentives and subsidies, as well as simplifying the procedure for placing on the market.

On 1st October 2002, the US House of Representatives passed two Bills to promote research into treatments for orphan diseases affecting fewer than 200,000 individuals in the US. This was In recognition of the fact that rare diseases and disorders deserve still greater emphasis in the national biomedical research enterprise, despite the success of the Orphan Drug Act.

One Bill (HR 4014), sponsored by Congressman Foley, would increase the authorised funding from $12 million (€11.2 million) to $25 million a year for the FDA's Orphan Products Development Grant Program. This is a substantial injection of money into the FDA compared with the budget of $500,000 allocated when the Agency set up its Office of Orphan Products Development in 1982 and the woefully inadequate budgets allotted in the subsequent 20 years.

The other related Bill (HR 4013) was sponsored by Congressman Shimkus, seeking to establish by law an Office of Rare Diseases at the National Institutes of Health (NIH) with annual authorised funding of $4 million to fiscal year 2006. The NIH Bill would create centres of excellence to offer training facilities where new investigators could conduct more targeted and organised research into the causes and treatment of orphan diseases. The centres would capitalise on the existing academic research facilities and hospitals in the locality of the NIH, carry out clinical studies end accept referrals from clinicians who needed help with diagnosis or treatments.

…what next?

The regulation of orphan medicinal products in the EC is relatively new compared with its counterpart In the US and, by and large, adopts the US legislative framework, However, within a very short space of time, since the establishment of the COMP, it has achieved a remarkable record In the granting of orphan designation. Some of these products have been authorised via the European centralised procedure. Advances in molecular genetics and ongoing research into decoding human genomes Into biological functions will undoubtedly create opportunities to identify new molecular targets for the development of novel therapeutics or diagnostics for orphan diseases.

As indicated above, Member State governments are doing a great deal to foster new technology. Further, in conjunction with the regulatory strategies to deal with orphan medicines, the Commission's Sixth Research Framework Programme has set aside €17.5 billion to fund research projects Into new technology like genomics. In order to promote a coherent and transparent policy in the global development of orphan medicines, there should also be continued dialogue between regulatory agencies, patient groups and industry at an international level. In its statement of 14th March 2002, the FDA's Office of Orphan Products Development indicated that it had consulted interested EC legislators, as well as the COMP and other foreign official bodies in order to investigate new product development strategies for orphan diseases and conditions.

In October 2002, the EMEA organised a one-day workshop on the methodology of clinical trials In orphan diseases and in children. Dr. Marlene Haffner, director of the Office for Orphan Products Development at the FDA, also attended.

This is an initiative to stimulate debate about alternative clinical trial designs and statistical methods for the evaluation of efficacy of medicines where patient recruitment is limited - such as with orphan diseases. Forums of this kind will allow the free exchange of information and the opportunity for the agencies and their advisory committees to share experiences. Since Its inception, the COMP has organised meetings with healthcare professionals, patient interest groups and industry to exchange views on, and expectations of, development and access to medicines produced in the orphan drug field. 

[1] Commission Regulation (SC) No 141/2000 of the European Parliament and of the Council of 16th December 1999 on orphan medicinal products. OJL 18/122nd January 2000.

[2] Commission Regulation (SC) 847/2000 of 27th April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and the definition of the concepts 'similar medicinal product' and 'clinical superiority'.

[3] Directive 2001/83/EC of the European Parliament and of the Council of 6th November, 2001 on the Community code relating to medicinal products for human use. OJL311/67 28th November 2001.

[4] Committee for Proprietary Medicinal Products Note for Guidance, on the quality, pre-clinical and clinical aspects of gene-transfer medicinal products CPMP/BWP/3088/99.

[5] Committee for Proprietary Medicinal Products Points to Consider on the manufacture and quality control of human somatic cell therapy medicinal products CPMP/BWP/41450/98.

[6] EMEA Guidance for Companies Requesting Protocol Assistance Regarding Scientific Issues 27th February 2002 EMEA/H/238/02.

[7] OJL311/67 28 November 2001.

[8] The Scientific Steering Committee, established by Commission Decision 97/404/EC, shall assist the EC Commission in obtaining the best scientific advice available on matters relating to consumer health.

[9] Decision 1295/1999/EC of the European Parliament and of the Council of 29th April 1999. OJL155/1 22nd June 1999.


[11] Under Article 9(3) of Regulation 141/2000.
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