22.Dec.2012

OCT submitted an application for orphan status designation for antitumor drug to EMA

This December 2012 OCT made a Common EMEA/FDA application for orphan medicinal product designation. The product is an orally administered small molecule for the treatment of hepatocellular carcinoma.

This December 2012 OCT made a Common EMEA/FDA application for orphan medicinal product designation.

The product is an orally administered small molecule for the treatment of hepatocellular carcinoma. There are approximately 30,000 U.S. and 45,000 E.U. annual cases of this disease, with an overall survival rate of only 15%.

The drug developer is a Russian pharmaceutical company established in a joint venture between a Russian fund and US company, who are engaged in developing and marketing innovative and effective anti-cancer drugs in these countries. Currently a multi-center Phase I trial is ongoing in the Russian Federation.

Orphan drug designation is for medicines to be developed for the diagnosis, prevention or treatment of rare diseases that are life-threatening or very serious. In the European Union, a disease is defined as rare if it affects fewer than 5 in 10,000 people across the EU.

The sponsor of the drug (here: an active substance currently authorized for another indication) decided to seek orphan designation of its product from the European commission in accordance with Regulation (EC) # 141/2000 of 16 December 1999 and commission regulation (EC) # 847/2000 and from the United States Food and Drug Administration (FDA) in accordance with section 526 of the Federal Food, Drug, and Cosmetics Act (FDCA) (21 U.S.C. 360bb). The sponsor through OCT applied for orphan designation in the EU jurisdiction and by itself in the US jurisdiction by using the common application form for its submissions to the European Medicines Agency (EMEA) and the FDA.

The application has been submitted in accordance with the provision that prevalence of the disease / condition is below the statutory threshold. The proposed orphan designation is for the treatment of primary hepatocellular carcinoma, a life-threatening condition that affects 0.366 /10,000 people in the EU.

No scientific advice has been given by the CHMP (the Committee for Medicinal Products for Human Use) for the product. However, the sponsor intends to seek protocol assistance for its medicinal product in May 2013.

It took 2 months to organize a pre-submission meeting, submit "Intent to Submit" notification to COMP (the Committee for Orphan Medicinal Products, responsible for reviewing applications from persons or companies seeking “orphan medicinal product designation”), appoint COMP/EMA coordinators by COMP, submit draft application to COMP, conduct the pre-submission meeting by means of a teleconference and make the application. Due to our expectations, in 2 months COMP will review the application, make the validation of the application, and take 90 days as a maximum to make the final decision since the review started. OCT hopes the decision will be positive and no need to appeal will arise. The planned submission of the marketing authorization application for the orphan indication is within 5 years.

In general, COMP exams an application for orphan medicinal product designation and determines whether the sponsor has established that the designation criteria are met, i.e.:

  • the life-threatening or debilitating nature of the condition;
  • the medical plausibility of the proposed orphan indication;
  • that the prevalence of the condition in the European Union is not more than five in 10,000;
  • that it is unlikely that marketing the medicinal product in the European Union, without incentives, would generate sufficient return to justify the necessary investment;
  • that no satisfactory method of diagnosis prevention or treatment exists, or if such a method exists,
  • that the medicinal product will be of significant benefit to those affected by the condition

The evaluation process takes a maximum of 90 days, without any clock stoppage and cannot be prolonged for any reason.

Sponsors notify the EMA of their intention to submit an application as early as possible (at the latest two months prior to the planned submission date). The EMA strongly recommends sponsors to request a pre-submission meeting prior to filing an application. Pre-submission meetings for orphan designation are free of charge and are held mostly via teleconference. Two coordinators (1 COMP member, 1 Agency scientific administrator) are appointed for each application. Sponsors submit the application on a CD or DVD with a signed cover letter. In parallel they submit the complete application directly to the address of the appointed COMP coordinator.

If an application has not been submitted in the US before, the EMA encourages the sponsor to seek orphan designation from both the EMA and the FDA in parallel using the common orphan application form. If an application has not been submitted to the Japanese authorities before, the EMA also encourages the sponsor to seek orphan designation from the Ministry of Health, Labor and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA). If more than one indication is applied for the same product, separate applications should be submitted for each orphan indication. In this regard, 'treatment' and 'prevention' of the same condition are considered as two separate indications and should be the subject of two separate applications for orphan designation.

Once the application’s validation process (which takes maximum 3 months) is successfully completed, a timetable to start the procedure for the evaluation will be forwarded to the sponsor for information.

The oral explanation lasts around 1 hour and includes the COMP discussion with the sponsor. The outcome of the discussion will be communicated to the sponsor immediately after the Committee has reached a conclusion.

Before day 90, the COMP adopts its opinion (in English). The opinion may be obtained during a COMP meeting or exceptionally by written procedure. The COMP opinion, which may be favorable or unfavorable, is whenever possible reached by consensus. If such consensus cannot be reached, the opinion shall be adopted by a majority of two-thirds of all COMP members.

In the case of a negative verdict, the sponsor always has the option of submitting an appeal. The grounds for appeal must be forwarded to the Agency within 90 days of receipt of the verdict.

The decision will be adopted by the Commission, within 30 days of its receipt of the COMP opinion and forwarded to the sponsor. Upon a favorable decision by the Commission, the designated medicinal product shall be entered in the Community Register of Orphan Medicinal Products.

The sponsor may submit an application for orphan medicinal product designation to the Agency at any stage of development of the medicinal product.

The EU Regulation does not foresee recognition of orphan status granted in other regions. In addition, the criteria for orphan designation are not internationally harmonized. Orphan designation can only be granted in the EU, by the European Commission, once an application for designation has been reviewed by the Committee for Orphan Medicinal Products, in accordance with the procedure laid down in Article 5, Regulation (EC) No 141/2000 of 16 December 1999.

As for orphan drug status in Russia, we expect some changes in the main law On Medicines FZ-61. Ministry of Healthcare plans to determine the conception of the “orphan medication” and implement an accelerated registration procedure. However, such measures will not help, as we are still having problems in the country: poor orphan diseases’ diagnostics database / monitoring, no orphan patients’ registry, orphan status given not to all the rare diseases which are life-threatening and resulting in disability (only 24 from list of 230 diseases have been recognized by the MoH; for example, the most orphan drugs are needed for oncology patients in Russia, such as: acute lymphoblastic leukemia, polymyelocytic leukemia, chronic myelogenous leukemia and others, but nothing from hemaoncology diseases has been included into the list of drugs financed by the state), no treatment standards for such diseases, no special educational programs for doctor, no adequate financial support at the federal, regional and local levels, no efficient system of the state purchases of the drugs, no special committee responsible for orphan drug status designation. The development costs of orphan drugs are comparatively high due to the lack of population to be tested and due to the lack of sufficient market to cover these costs.

In the US Orphan Drug Act came into force in 1983, in EU the similar legislation was adopted in 1999. In the US the developers of orphan drugs to treat the maximum population of 200 000 in the country, receive 7 years exclusive selling rights and reasonable tax deductions; in EU they have 10 years of exclusivity. In both regions they have a special body responsible for orphan drug legislation’s control and improvement. Within the period of 1983-2010 353 orphan drugs have been registered and 2116 orphan drug statuses have been given. In comparison, during 10 years before 1983 there only 10 products have been launched on to the market.

There are special laws on orphan drugs in Australia, Singapore, and Japan. On the contrary, in Russia with 1.5-5m patients with orphan diseases regulatory authorities are still talking about changes in the law on medicines, but not developing the special legislation which is required. The term “orphan drug” has been implemented in Russia only in 2011 within the law on basics of the health protection of the citizens of the Russian Federation.

Russia does not suggest any initiatives, tax reduction for the companies which develop orphan drugs. This limits the opportunities for Russian biotech companies in comparison with the ones abroad which use many pluses from receiving orphan drug status in the kind of: In the US:
  • tax credits on clinical research
  • technical assistance during the elaboration of the application file necessary for marketing
  • approval as well as simplification of administrative procedures (reduction of the waiting period and reduction of the amount of registration fees)
  • marketing exclusivity of 7 years after the marketing approval
In Europe:
  • protocol assistance
  • access to the centralized authorization procedure
  • ten years of market exclusivity
  • fee reductions
  • grants

At OCT we hope that the situation will change extremely soon towards a positive direction. We will do our best to conduct clinical research of orphan drugs within the highest applicable standards.