May 1, 2004 marked the deadline for implementing new clinical trial rules across the 25 member states of the European Union. As member states begin to introduce legislation and guidelines to comply with the Clinical Trial Directive of the European Commission, concerns over their far reaching impact on clinical research in Europe and the ripple effect in the pharmaceutical industry in the United States continues to grow. The new rules are expected to result in increased legal and administrative burdens and costs and it is feared that they may have a chilling effect on strategic alliances between drug manufacturers and clinical research organizations ("CROs") in the European Union.
The full title of the Clinical Trial Directive, - "Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use,"1 - conveys the principal objectives of the legislation. The Directive was the result of years of discussion within the European Commission based upon a determination that there existed significant inconsistencies among the national rules concerning how clinical trials in Europe are undertaken and controlled. The European Commission (the EU's principal administrative body) began drafting a directive in the late 1980s and, after numerous revisions by the EU Council of Ministers (the representatives of the member states' government) and the European Parliament, agreement on the final version of the Directive was reached in February 2001. The Directive was published on May 1, 2001, giving each member state three years to enact its own national legislation, rules and guidelines to implement the Directive.2 It remains to be seen how all of the member nations will interpret the Directive in their specific legislation but it is certain that, regardless of the individual specific enforcement provisions, the Directive will change the way clinical trials are conducted in Europe and that these changes will impact the cooperative efforts between CROs and US pharmaceutical companies in developing and managing clinical programs.3
Strategic alliances between CROs and pharmaceutical companies have become an important component of global clinical research. Faced with an avalanche of federal and state legislation over the last ten years and an increasing need to launch products out of the pipeline into the market more quickly, many US companies have turned to outsourcing their clinical development programs to global service companies in the CRO industry. As a result, the CRO market has expanded exponentially, with revenues of approximately $50 million in the late 1970s to about $10 billion this year alone.4 Today, there are over one thousand CROs worldwide, with the largest number existing in Europe, followed by North America and Japan.5 According to an analysis by the United States Department of Health and Human Services' Office of the Inspector General, the number of foreign clinical investigators that conducted drug research under US investigational new drug applications increased from 41 in 1980 to 271 in 1990, and 4,458 in 1999.6 Thus, it is apparent that European CROs have a large stake in maintaining their status in the pharmaceutical industry as flexible organizations that can deliver greater efficiencies in the planning and management of clinical programs on a global basis. With the adoption of the Directive and the implementing national legislations, European CROs are at risk of losing this position, as the cost of doing business with US pharmaceutical becomes exorbitant.
The emphasis of the Directive is on ethics, government oversight, and quality assurance. Specifically, the major provisions of the Directive are:
Protection of clinical trial subjects. While the Directive reiterates the basic requirements of informed consent already existing in patient care guidelines, it introduced two new areas of patient protective measures that will have practical implications for clinical trial teams. First, the Directive and the relating guidelines published by the EC increase the amount of information to be given to clinical trial subjects. Subjects will have the right to know such information as the name and address of the sponsor, the institutional affiliation of the investigator, the financial ties between the investigator and the sponsor, the source of finance for the study, and contact details of all personnel involved in the trial. Secondly, the Directive specifically outlines what protection must be accorded to children and adults incapable of giving legal informed consent. The Directive also clarifies existing general safeguards on subjects' privacy and protection of personal data to provide that subjects should be informed as to who will have access to clinical trial data, the procedure for handling any retained identifiable biological samples, and plans to de-identify or destroy samples after analysis.
Ethics Committees. The Directive requires that the member states take measures to establish and operate ethics committees. Ethics Committees are, in principle, the functional equivalent of US Institutional Review Boards, which are designated under the Food and Drug Administration regulations to review and monitor biomedical research involving human subjects, including the authority to approve, require modifications in (to secure approval), or disapprove research. Under the Directive, Ethics Committees will be charged with giving opinions on, among other things, the relevance of the trial and its design, evaluations of the benefits, risks and conclusions of the trial, and any other issues requested. No trial may be commenced by the sponsor prior to receipt of a favorable opinion of the local Ethics Committee.
Databases. The Directive requires that the member states enter into a centralized clinical trials database (known as "EUDRACT"), which will be accessible only to the authorities of the member states having jurisdiction, the Commission and the European Agency for the Evaluation of Medicinal Products. The database will facilitate communication between regulatory authorities to enable them to improve their oversight of trials and provide for enhanced protection of patients. The sponsors of clinical trials must register with the EUDRACT database (via the Internet) and then obtain a EUDRACT identifier number.
Inspection. Member states must appoint inspectors that will inspect all clinical trial sites and facilities of manufacturers of investigational medicinal products (IMPs). Investigation reports will be recognized by all member nations.
Training. Principal investigators of trials will be required to provide information concerning their qualifications and any prior GCP training or clinical trial experience to their local Ethics Committee for opinion on their suitability to conduct clinical trials.
Facilities. Sponsors of clinical trials will be required to submit to their local Ethics Committee an evaluation of the quality of the facilities (including the availability of adequate resources, personnel, and laboratory facilities) in which they plan to conduct a clinical trial.
Additional Provisions. The Directive contains other important guidelines including: standards for the manufacture, import and labeling of IMPs; quality assurance of clinical trials and IMPs; safety monitoring of patients in trials; and procedures for reporting and recording of adverse drug reactions and events.
The most significant problem facing pharmaceutical companies lies in the increased obligations which the Directive imposes on the "sponsor" of a trial. The Directive defines a "sponsor" as an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial. The Directive requires that there be a single sponsor for each clinical trial. Accordingly, a US pharmaceutical company that initiates a clinical study in an EU member state or provides management or financing of a clinical study conducted by a CRO in a member state will be responsible as the "sponsor" for all legal and financial responsibilities mandated by the Directive relating to clinical trials covered by the Directive regardless of the intent of the parties involved in the trial with respect to management, sponsorship, liability or similar issues. This responsibility may result in significant unexpected costs to the US pharmaceutical company. For example, the US pharmaceutical company which is considered a "sponsor" under the Directive will be responsible for paying for all drug and device costs (even the cost of routine non-investigational aspects of the treatment) while patients are involved in the study. In addition, sponsors will be required to pay fees to ethical committees and governmental authorities associated with the clinical trial. Variations in member states implementing legislation will likely compound these burdens or, at least, result in additional complexities in managing multi-national clinical trial programs. Moreover, the US pharmaceutical industry may not be willing to provide its products for noncommercial trials if this could be construed by the member states as a form of sponsorship of the trial.
The Directive was adopted to achieve harmonization and simplification of the administrative procedures regulating clinical trials in the member states. Given the discretion afforded the governments of each of the member states to interpret the Directive in implementing the member state's legislation, incompatible requirements and procedures will only increase the costs of conducting multi-jurisdictional clinical trials in the EU. Clinical trials which depend on collaborative relationships between US pharmaceuticals and CROs in the EU may be moved to other jurisdictions outside of the EU, such as Africa, to avoid the sweeping legislation and associated costs. This approach may not be a panacea, given the difficulties of conducting clinical trials in emerging markets with little track record of experience and no or inadequately established clinical trial infrastructure. Moreover, recent proposed rules by the FDA may restrict the ability of US pharmaceutical companies to move their clinical research programs to emerging markets. Under the proposed regulations, the FDA would revise its current position on acceptance of foreign clinical studies not conducted under an investigational new drug application ("IND") as support for an IND or marketing application for a drug or biological product. The proposed regulations would only permit acceptance of studies conducted in accordance with good clinical practice, including review and approval of the trial by an independent Ethics Committee. The stated purpose of the proposed rules is to update the standards for the acceptance of nonIND foreign studies and to help ensure the quality and integrity of data obtained from such studies.7 Given the current climate of scrutiny of the pharmaceutical industry, the proposed regulations stand a good chance of being adopted. If the proposed FDA regulations are adopted, US pharmaceuticals would be prevented from forming alliances with CROs or conducting their own clinical trials in countries without comprehensive regulatory measures such as those included in the Directive. Regardless of whether or not the proposed FDA regulations are adopted, it is clear that regulatory hurdles and national bureaucracies will continue to challenge US pharmaceutical companies and their strategic alliances with CROs.
1 European Parliament, Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 (European Parliament, Brussels, Belgium, 2001); http://www.europa.eu.int/eur-lex/en/search/search_lif.html
2 When the EC adopts a directive, the directive sets forth the objectives to be attained, but is not law. The directive only serves as a guideline to each member state with respect to the subject of the directive, and each member state has the responsibility to adopt, at its own national level, the precise legislative measures to attain the objectives. Directive 2001/20/EC is supplemented by more than 11 EC guidance documents, which do not have the force of law, and can be updated and modified as circumstances dictate. For a review of these documents see http://dg3.eudra.org/F2/pharmcos/dir2001/20ec.htm. A separate draft directive on good clinical practices was published by the EC on July 1, 2004 and comments were due to be submitted by July 31, 2004. This draft directive modifies Directive 2001/20/EC and may be finalized before the end of the year. One of the more significant clarifications in the draft directive is to recognize that non-commercial research, in which no pharmaceutical company is involved, may be excluded from certain of the provisions of the Directive.
3 As of September 20, 2004, the EC reported that 12 of the old member states had already implemented some form of legislation in response to the directive and had confirmation that 3 new member states have implemented legislation.
4 Progress and Potential: Evolution of the CRO Industry; Dennis Gillings, Aug 2, 2004, Act Clinical Trials.
5 Looking Back; Moving Forward: Industry in Evolution, Toby Jane Hindin, EdD, August 2, 2004, Act Clinical Trials.
6 United States Department of Health and Human Services, Office of the Inspector General, The Globalization of Clinical Trials, A Growing Challenge in Protecting Human Subjects, September 2001, OEI-01-00-00190.
7 Department of Health and Human Services, Food and Drug Administration, 21 CFR Part 312.
Lori J. Braender practices in the transactions group of Pitney Hardin LLP, where Ms. Braender is a Partner. This article represents only the author's opinions and does not necessarily reflect the views of Pitney Hardin or any of its clients. Questions concerning the article or Pitney Hardin's practice may be directed to Ms. Braender at (973) 966-8118.