1. Compassionate use programs and the European regulatory system Filip Josephson M.D., Ph.D. Clinical Assessor

2. The European Medicines Agency (EMA) and the Committe for Medicinal Products for Human Use (CHMP) The European Medicines Agency is a decentralised agency of the EU, located in London, and is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the EU. The CHMP is the ultimate scientific decision-making assembly at the EMA. It consists of representatives from each EU national agency The decisions of the CHMP are based on assessments and recommendations generated by national agency assessors

3. The responsibilities of EMA/CHMP and that of the national agencies Decisions concerning the approval, conditions for approval, and post-approval follow-up of new antivirals are taken by the CHMP. CHMP decisions pertain to the entire EU Decisions on clinical trial applications are taken by the national agencies alone (or cooperatively through VHP procedures) and pertain to the area of jurisdiction of each national authority Decisions on the approval and implementation of compassionate use programs (and other forms of ”early access” such as availability on a named-patient basis) are principally the responsibility of national agencies in accordance with national legislation.

4. Forms of early access (treatment prior to drug approval Clinical trials Expanded access programs (understood as clinical trials with primarily a safety endpoint) Compassionate use programs Named patient basis

5. Compassionate use programs Compassionate use programmes can only be put in place for medicines that are expected to help patients with life-threatening, long-lasting or seriously disabling illnesses who currently cannot be treated satisfactorily with authorised medicines, or who have a disease for which no medicine has yet been authorised. The compassionate use route may be a way for patients who cannot enrol in an ongoing clinical trial to obtain treatment with a potentially life-saving medicine.

6. General limitations on knowledge when deciding on compassionate use At this stage in the development of the medicine, what is known of the medicine’s safety may be limited. Generally, toxicology studies will have been completed and analysed, and early pharmacokinetics studies will have been completed. There may still be uncertainties about the best way to give the medicine to patients, such as the exact dose to use, and the dose frequency, and the medicine’s safety profile is not yet fully established.

7. The role of the EMA concerning compassionate use (article 83) 7

8. The objectives of article 83 To facilitate and improve the access of patients in the European Union to compassionate use programmes To favour a common approach regarding the conditions of use, the conditions for distribution and the patients targeted for the compassionate use of unauthorised new medicinal products, To increase transparency between member states in terms of treatment availability.

9. Compassionate use by EC article 83 Medicinal use to be made available to: patients with a chronically or seriously debilitating disease or a life- threatening disease, and who cannot be treated satisfactorily by an authorised medicinal product in the European Union. The medicinal product is either the subject of a marketing application or is undergoing clinical trials, and would be approved through the ”centralised procedure” (applicable for all new antiviral substances). The compassionate use program is intended for ”a group of patients” (as opposed to Named Patient Basis). “Group of patients” can be interpreted as any set (i.e. more than one) of individual patients that would benefit from a treatment for a specific condition. 9

10. Article 83 versus member state authority The CHMP may adopt an opinion on the conditions for use, distribution and patients targeted CHMP opinions are not binding on MS; however, ”MS shall take account of any available opinions” The recommendation complements national legislation, which it does not replace The recommendations are optional, and are only implemented by the MS that wish to use them for their patients 10

11. Request for a CHMP opinion according to article 83 When a MS envisages the need to make a medicinal product available for compassionate use, the national agency of that MS should notify the EMA Companies should not directly contact the EMA for CHMP opinion Companies may, at their own initiative, inform the EMA of compassionate use in MS(s) Article 83 has hitherto only been implemented for i.v. oseltamivir and i.v. Zanimivir (for treatment of influenza in severely ill patients) 11

12. Principal requirement for compassionate use Access to documentation about the drug Access to the drug European regulators have no legal provision to force a company to provide early access through compassionate use 12

13. The European Medicines Agency 13