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What Canada, the EU, and United States are doing to update their compassionate use regulations.
All medicinal products introduced on the market are the result of lengthy and costly R&D conducted by pharmaceutical and biotech companies.
Compassionate use programs facilitate patient access to promising medicinal products at an early stage in the drug development process, when the information already gathered for the drug benefit/risk profile suggests that patients will not be exposed to safety hazards.
This article reviews the relevant legislative framework in Canada, the EU, and United States, and highlights the applicable regulatory agencies' efforts to provide more efficient programs by revising their current regulation on compassionate use.
Drugs under investigation must undergo highly regulated nonclinical and clinical research to prove their quality, efficacy, and safety in the target population before they can be made commercially available. Additionally, pricing, reimbursement, and distribution discussions might delay the availability of the product in some countries even after a medicinal product has been successfully reviewed and approved by the local regulatory agencies.
Thus, the major challenge for industry is to market their product with as short a delay as possible in order to recuperate the huge financial sums invested during the R&D phase. In comparison, the hopes and expectations of the patient community are even greater, as they could possibly have at their disposal a new therapeutic arm to fight against fatal illness or seriously debilitating conditions.
All in all, the overall process for getting a drug on the market can take up to 10 years. This delay is far too long, especially for patients suffering from a seriously debilitating disease/condition and who lack efficacious treatment. Even when suitable treatment exists, the timely intervention of new and more satisfactory treatment could markedly improve the quality of patients' lives.
Although opportunities exist for patients to benefit from experimental or nonmarketed drugs—for example, by entering clinical trials or by importing the drug for personal use—they account for only a small number of cases. The actual need for access to such treatment is considerable and has brought about effective and transparent initiatives on the part of health authorities and regulatory agencies.
Authorities have set standards concerning the minimal data that is necessary to corroborate a marketing authorization application. At the same time, they have introduced exceptions to allow patients in need to benefit from a promising experimental treatment prior to completion of full testing or prior to its launch onto the market.
Resources for Monitoring Compassionate Use Information
This exception, often referred to as compassionate use of medicinal products, is in force in many countries and has been warmly welcomed by patients, patient organizations, and activists but has unexpectedly raised many issues for pharmaceutical companies unable to deal with and satisfy the increasing demands and who face more and more difficulties in recruiting patients for clinical trials. In an effort to meet all parties' expectations and adapt to growing needs, compassionate use and related legislation/guidelines have or are being revamped in the major regions (i.e., the EU, United States, and Canada).
The origins of compassionate use in the EU can be traced back to 1989, when the possibility for Member States to allow the supply of unauthorized medicinal products "in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health care professional and for use by his individual patients on his direct personal responsibility" was introduced in Directive 89/341/EEC.1
The Directive introduced a legal framework for the development of national programs for compassionate use of medicinal products for individual patients in the 12 EU Member States at the time. France was among the countries that took up the initiative. The French Health Products Agency introduced the Temporary Authorisation for Use (ATU) regulation in 1994 as a derogated, exceptional, and temporary measure to permit the use of medicinal products not yet holding a marketing authorization in France, outside the known context of a clinical trial.2 The Directive stated that only individual patients should benefit from compassionate use. However, in France, authorizations for both individuals and groups were set up (nominative and cohort ATUs). This program has been exercised for more than a decade and has allowed the dispensing of unauthorized drugs for the treatment of HIV, cancer, and neurological disorders as well as orphan drugs.
Article 5 of Directive 2001/83/EC, as amended, is the current legal basis for compassionate use programs.3 The Directive had to be transposed into national legislation by local authorities, but there was no coordination between the regulatory agencies concerned. This gave rise to a variety of different programs at different points in time and with distinct characteristics. There was clearly room for improvement as far as this complicated situation was concerned, and a great opportunity to harmonize procedures presented itself with the 2004 EU enlargement, where an increased number of countries could immediately benefit from new legislation.
In May 2004, Regulation 726/2004 entered into force and set forth the need for a common approach to the criteria and conditions for the compassionate use of new medicinal products under Member States legislation. The term compassionate use was defined as making a "medicinal product...available to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who can not be treated satisfactorily by an authorised medicinal product."4
Although the implementation and coordination of compassionate use programs remains a Member State's prerogative, the Regulation assigned the EMEA and the Human Medicinal Products Committee (CHMP) a key role in the harmonization of compassionate use programs and allowed the CHMP to adopt opinions on the criteria relating to the conditions of use and distribution in the target population. Detailed guidance on the steps to be followed by concerned Member States, CHMP, and companies is provided in a guideline recently adopted by the EMEA in July 2007.5
The scope of the legal text is limited to medicinal products that are eligible for the centralized procedure (Articles 3(1) and 3(2) of Regulation (EC) No 726/2004) and that are undergoing clinical trials or the process of a marketing authorization application. It applies to groups of patients (cohort programs) suffering from a chronically/seriously debilitating/life-threatening disease who cannot be treated satisfactorily by currently available medicinal products.
EMEA plans to publish and update opinions adopted for compassionate use to provide transparent information to patient and patient organizations on the availability of drugs before they get approved.
Although one does not come across the term compassionate use in U.S. regulations—"compassion should be and is an element of all drug investigation activities"—FDA commonly refers to it as the program that allows the use of an experimental drug to answer individual patients' requests, whereas larger use patient requests usually occur under treatment Investigational New Drugs (INDs).6
Programs allowing the use of investigational drugs to treat serious or immediately life-threatening disease conditions—treatment INDs, single patent INDs, and protocol exemption provisions—were introduced together with other programs directed toward expediting drug development through accelerated approval and expanded access in the late 1980s, when HIV patients lacking appropriate drug therapies campaigned to obtain immediate use of promising experimental drugs before they had received official approval.
FDA rules, codified in 21 CFR Part 312.34, establish that investigational drugs can be used for treatment use when the drug is intended to treat a serious or immediately life-threatening disease and in the absence of comparable or satisfactory alternative drugs or therapies. The drug is usually under investigation in a controlled clinical trial or all clinical trials have been completed and the sponsor is actively pursuing marketing approval of the investigational drug.7
21 CFR Part 312.36 also introduced a provision applying to the supply of investigational drugs for individual patient treatment use in emergency situations. However, clear guidelines on criteria or requirements to be met is lacking.
Whenever a drug company agrees to dispense its unapproved drug to a patient, the FDA reviews the patient's request and verifies that there are no safety concerns and that the patient has no proven treatment options available before making a decision. Agency decision making on individual patient treatment use has been criticized for not being a transparent process (guidance is missing)—the major concern being that there is unfair and disparate access to treatment use for different types of patients and diseases.
There also has been concern that access to investigational drugs for treatment use has focused primarily on cancer and HIV-related conditions, and patients with other types of serious diseases or conditions have not had comparable access to appropriate treatment use of unapproved drugs.
In December 2006, the FDA published a proposed rule with the aim of improving access to investigational drugs for patients with serious or life-threatening diseases/conditions who lack other therapeutic options and may benefit from such therapies. Under this proposal, which significantly amends 21 CFR Parts 312.34 to 312.36, investigational drugs would be available for treatment use to individual patients (including in emergencies), intermediate size patient populations, and larger populations under a treatment protocol or treatment IND.8
Furthermore, a proposal to revise the current regulation with regard to manufacturers' recovery of costs for experimental drugs has also been published for comment.9 Information on the ongoing process should be monitored throughout the year.
Legislation was established in 1966 to permit the sale of nonmarketed drugs in emergency situations. This legislation was introduced as a consequence of the thalidomide disaster when concerns for using experimental and potentially harmful drugs were running high. It was an attempted compromise: It embraced these concerns, while at the same time it tried to provide a solution to unmet medical needs.
Sections C.08.010 and C.08.011 of the Food and Drug Regulations provides for the Special Access Programme (SAP), which gives discretionary authority to issue letters of authorization for the sale of drugs by manufacturers to practitioners.10
The SAP authorizes emergency access to nonmarketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable or unavailable. Since its establishment, the SAP has mainly dealt with cancer, HIV/AIDS, neurological disorders, blood disorders, and orphan diseases.
Requests for SAP access are considered by the regulatory agency on a case-by-case basis. It takes into consideration the nature of the medical emergency, the availability and efficacy of marketed alternatives, and the information provided in support of the request regarding use, safety, and efficacy of the drug.
In recent years, Health Canada has experienced increasing pressure from manufacturers, practitioners, and patients to provide access to products requested through the SAP. Many of these groups have pushed the boundaries of the Program's mandate into areas not covered or envisaged by the supporting Food and Drug Regulations. This has driven the Therapeutic Products Directorate, Health Canada's branch for regulating pharmaceutical drugs, to develop a guidance document to clarify the mandate, intent, and scope of the SAP within the regulatory framework and to outline the process to be followed when requesting a nonmarketed drug through the SAP.11
The document, addressed to industry and practitioners, is at draft status. Information about the ongoing process should be monitored throughout the year.
Compassionate use provisions are regulated programs to facilitate the availability of promising medicinal products to patients at an early stage in the drug development process or before the product is launched on the market, where there is already sufficient information on the drug benefit/risk profile to assure that patients will not be exposed to safety hazards.
A compassionate use program, either for a patient or group of patients, is usually initiated by a medical professional and involves several factors, mainly the drug manufacturer/MAH who volunteers to supply the drug, the local competent authority responsible for authorizing/notifying the application, hospitals for follow-up, and health insurers for cost recovery.
Handling a compassionate use program is a burdensome activity and the European pharmaceutical industry is calling for a standardization of procedures to avoid the duplication of tasks when running programs in different EU countries. The recent proposals for regulation amendment in the United States and new guidance release in Canada also aim to streamline the process and foster a more transparent approach when authorizing the supply of experimental/nonmarketed drugs.
Major changes or significant readjustments have occurred in the compassionate use in Europe this year and are expected across the United States and Canada, with interested parties providing input into the shaping of this regulatory landscape.
1. Council Directive 89/341/EEC amending Directives 65/65/EEC, 75/318/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products (May 3, 1989).
2. French Public Health Code (Code de la Santé Publique), Articles R. 5121-68 to R. 5121-76.
3. European Parliament and of the Council, Directive 2001/83/EC on the Community code relating to medicinal products for human use (November 6, 2001).
4. European Parliament and the Council, Regulation (EC) No 726/2004 laying down community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing the European Medicines Agency (March 31, 2004).
5. EMEA/CHMP, Guideline on compassionate use in the European Community pursuant to Article 83 and the Annex of Regulation (EC) No 726/2004 (July 19, 2007).
6. U.S. House of Representatives, Robert J. Temple, MD, Associate Director for Medical Policy, Center for Drug Evaluation and Research, statement before the Committee on Government Reform (June 20, 2001).
7. Code of Federal Regulations, Title 21, Part 312: Investigational New Drug Application (IND).
8. Department of Health and Human Services, proposed rule: "Expanded Access to Investigational Drugs for Treatment Use," Federal Register, 71 (240) 75147 (December 14, 2006).
9.Department of Health and Human Services, proposed rule: Charging for Investigational Drugs," Federal Register 71 (240) 75168 (December 14 2006).
10. Food and Drug Regulations, Part C—Drugs.
11. Health Canada, Draft Guidance for Industry and Practitioners: Special Access Programme for Drugs (January 31, 2007).
Rosanna Melchior, RPh, MS, is a regulatory online learning project manager at Thomson Scientific, email: firstname.lastname@example.org.