It Takes a Village to Conduct a Clinical Trial
At a minimum, two parties are necessary to conduct a clinical trial: a principal investigator (PI) and a subject. However, contributions from a multitude of individuals, organizations, institutions, and regulatory agencies are needed for a clinical trial to be executed both successfully and ethically.
This chapter will summarize the roles and responsibilities of the various parties involved in the clinical trial process, including the subjects, PI and staff, sponsors, institutional review boards, contract research organizations, site management organizations, and regulatory agencies.
Subjects
Without study subjects, clinical research would not be possible. The specific composition of the subjects (ie, gender, age, disease state) will be dictated by the study protocol. In some cases, the inclusion criteria may be broad (eg, anyone who has psoriasis). In other cases only a select group of patients may be allowed to participate (eg, Caucasian females between 35 and 45 years old with uterine cysts, who have never smoked, taken oral contraceptive pills, or have had cancer).
Investigators and Staff
A PI is the person at the site who is in charge of all aspects of the clinical trial execution and administrative management, including legal, logistical, and financial obligations. This person has the ultimate responsibility, but may hire support staff to provide assistance. The actual efforts involved in conducting the trial, including managing subjects, performing assessments, and recording results are carried out by the PI and any associated staff at the site.
Sponsors
A clinical trial sponsor is any individual, organization, or company that takes responsibility for the initiation, management, monitoring, and financing of a clinical trial. A common example of a sponsor is a pharmaceutical company, but many small studies are sponsored by a single physician or group practice that seek to answer a specific clinical question. Other examples of study sponsors include medical institutions, medical foundations, and federal governments (eg, National Institutes of Health, Department of Defense). However, the same rules regarding ethical conduct and regulatory requirements apply, regardless of the type or size of the sponsor.
Institutional Review Boards (IRBs)/Research Ethics Committees (RECs)
IRBs (in the United States) and RECs (in Europe), also known as independent ethics committees or ethical review boards, are groups that have been formally designated to review and monitor clinical trials. These boards have the authority to approve or reject a clinical trial protocol, or require modifications, and are a mandatory component of clinical trial execution in the United States and elsewhere. IRBs/RECs also perform clinical oversight functions for clinical research to ensure that the studies hold scientific merit and are ethically conducted.
Academic institutions and medical facilities usually have their own IRBs/RECs, but, increasingly, IRB/REC reviews are being conducted by independent, for-profit institutions. These companies are known as central or commercial IRBs/RECs and are held to the same standards as institutional IRBs/RECs. In the United States, the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) approves all IRBs, both academic and commercial. In the European Union (EU), the creation of RECs as independent bodies in each of the member states has been directed by the European Medicines Agency (EMEA). In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) ensures that Good Clinical Practice (GCP) is practiced in the conduct of clinical trials to ensure that human research is ethically conducted.
The European system differs from that in the United States, with the involvement of coordination centers. Coordination centers are academic professional research organizations belonging to a network of international clinical research centers intended to improve the quality of clinical studies and further develop competence in this sector. The coordination centers provide support to institutions and clinical centers that are planning single- or multi-center clinical trials within different European countries in developing detailed, standardized treatment protocols across Europe, monitoring plans, statistical analysis plans, and validation plans specifying the data collection needs and systems (database) support according to the principles of GCP. Moreover, their staffs are responsible for arranging contacts to study centers, industrial partners and experts, providing support in preparing and financing studies, and training study personnel (physicians, study nurses, physiotherapists, monitors, statisticians) to reach a consistent level of study performance according to the principles of GCP.
Contract Research Organizations (CROs)
CROs are generally defined as independent contractors that perform one or more of the obligations of a sponsor. Responsibilities that may be delegated to a CRO include design of the protocol, central laboratory services, evaluation of reports, or preparation of materials to be sent to regulatory agencies. Contracts between CROs and sponsors are explicitly government regulated, and CROs are legally liable for the obligations they assume. The benefit of a CRO is that the sponsor does not have to hire staff for assignments that are only viable for the length of the trial, and CROs are considered a form of outsourcing. Not all sponsors utilize the services of a CRO.
Site Management Organizations (SMOs)
SMOs assume one or more of the regulatory obligations of a clinical investigator, which differs from CROs that perform the functions of the sponsor. They may serve as the single contact for multiple sites, may handle centralized functions, such as document development, and may also provide administrative and clinical staff to a site. Tasks may include preparing and maintaining case histories, ensuring compliance with IRB/REC review, or adverse event reporting, among others. Like CROs, the responsibilities of SMOs are contractually delegated, but unlike with CROs, contracts are between the SMO and the clinical investigator. Furthermore, SMOs are not legally liable for the investigator obligations they assume.
Regulatory Agencies
The largest pharmaceutical markets can be found in the United States, the European Union, and Japan. Each of these political jurisdictions possesses its own system of regulating the pharmaceutical industry and its governance of clinical trials.
United States Food and Drug Administration (FDA)
The FDA is the scientific, regulatory, and public health agency that oversees most food products (other than meat and poultry), human and animal drugs, therapeutic agents of biological origin, medical devices, radiation-emitting products for consumer, medical, and occupational use, cosmetics, and animal feed in the United States. The FDA is an agency within the Department of Health and Human Services, and consists of 8 centers/offices with different responsibilities. Of these, the Center for Drug Evaluation and Research (CDER) is responsible for the approval of new drugs, biologics/vaccines, and in addition the CDER has the responsibility for ensuring the safety of the nations’ blood supply.
The process of drug approval begins with the initial identification of a potential new product. Drug sponsors must submit an investigational new drug (IND) application to the CDER before initiating any human trials. Approval of the IND is based on preclinical studies. Once the pivotal clinical trials have been completed, the drug sponsor submits a new drug application (NDA) to the CDER. Only after the CDER has approved the NDA can a product be marketed in the United States. After a drug has been licensed, the CDER continues to monitor its safety and reviews marketing materials produced by the drug manufacturer for truthfulness and fair balance. The CDER will also follow up on any complaints related to the drug, including medication errors, drug shortages, and ineffectiveness or toxic effects.
The FDA currently consists of more than 9,000 employees, including chemists, pharmacologists, physicians, microbiologists, veterinarians, pharmacists, and lawyers, among others. With a budget of close to $2 billion, the FDA evaluates applications for new human drugs and biologics, complex medical devices, food and color additives, infant formulas, and animal drugs. The FDA also monitors the manufacture, import, transport, storage, and sale of about $1.5 trillion worth of products annually. In addition, the FDA investigates/inspects more than 16,000 facilities a year and arranges with state governments to help increase the number of facilities checked.
European Medicines Agency (EMEA)
The EMEA is a decentralized body of the European Union, with its headquarters in London. The function of the EMEA is to evaluate and supervise medicines for human and veterinary use in the EU. The Committee for Medicinal Products for Human Use (CHMP) is the division of the EMEA responsible for preparing opinions regarding medicinal products for human use, and employs one of two approaches for approving new medicinal products: a centralized approach and a decentralized approach. In the centralized or “Community” procedure, the CHMP conducts the initial assessment of medicinal products for which marketing authorization is sought for all member states simultaneously. Medicinal products that must be reviewed under the centralized procedure include those for human and animal use derived from biotechnology and other high-technology processes, as well as all human medicines intended for the treatment of HIV/AIDS, cancer, diabetes, or neurodegenerative diseases, and for all designated orphan medicines intended for the treatment of rare diseases. With the decentralized or “mutual-recognition” procedure, an applicant goes directly to a single member state and, once the drug is approved by that authority, seeks to have other member states recognize the approval and grant their own marketing authorizations. In the decentralized procedure, the CHMP arbitrates in cases where there is a disagreement between member states concerning the marketing authorization of a particular medicinal product. The CHMP also acts in referral cases in response to concerns regarding the protection of public health or where other community interests are jeopardized. Those drug classes not mandated by the centralized system can be reviewed via the decentralized procedure. In addition, the CHMP is responsible for several postauthorization and maintenance activities, including the assessment of any modifications or extensions to the existing marketing approval.
The EMEA is headed by an Executive Director and has a secretariat of approximately 440 staff members at present. A network of 4,000 European experts from the various member states underpins the scientific work of the EMEA and its committees.
Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)
Japan’s PMDA was established in April 2004 with the purpose of improving the safety and efficacy of pharmaceuticals, medical devices, and related healthcare products. The agency also provides relief to those who have suffered adverse health effects from pharmaceuticals and biological products, such as from an adverse reaction to a medication.
Any foreign manufacturer intending to import drugs, quasi-drugs, or medical devices into Japan must be accredited by the Minister of Health, Labour, and Welfare (MHLW). The process is similar to what is required of Japanese manufacturers, which also must be licensed. The PMDA evaluates the efficacy, safety, and quality of pharmaceuticals and devices before granting approval for marketing in Japan. It provides advice regarding the conduct of clinical trials and performs on-site and document reviews of manufacturers to ensure drug quality and safety. In conjunction with the MHLW, the PMDA assesses safety after a drug has been granted approval.
The PMDA is led by an Executive Director and currently has more than 300 permanent staff members, of which almost 200 are part of the Review Division.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
The ICH is not a regulatory agency but was established in April 1990 by regulatory agency representation from the United States, EU, and Japan. The World Health Organization (WHO) Conference of Drug Regulatory Authorities (ICDRA) in Paris initiated the formation of the ICH in 1989. The purposes of the organization are several-fold: 1) to encourage more economical use of human, animal, and material resources; 2) to eliminate unnecessary delays in the global development and availability of new medicines while maintaining safeguards on quality, safety, and efficacy; 3) to maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, USA, and Japan; 4) to contribute to the protection of public health from an international perspective; 5) to monitor and update harmonized technical requirements leading to a greater mutual acceptance of research and development data; 6) to avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products; 7) to facilitate the adoption of new or improved technical research and development approaches that update or replace current practices; and 8) to facilitate the dissemination and communication of information on harmonized guidelines and their use to encourage the implementation and integration of common standards.
The ICH has created international guidelines for the conduct of clinical trials. Called Good Clinical Practice (GCP), these guidelines provide ethical and scientific quality standards for designing, conducting, recording, and reporting clinical trials. The purpose of the GCP is to provide a unified standard for the United States, EU, and Japan to facilitate drug approval and more rapidly supply medical products to patients in need around the world.
The ICH has also developed the Medical Dictionary for Regulatory Activities (MedDRA) to internationally standardize medical terminology. The importance of MedDRA is realized in the electronic transmission of adverse event reporting, both in the pre- and postmarketing areas, as well as the coding of clinical trial data. MedDRA has allowed important medical information to be more easily conferred among countries, expediting regulatory reviews and ensuring continued safety of approved medicinal products. It should be noted that MedDRA is only available to subscribers.
In addition, the ICH consists of several subgroups. For example, the Global Cooperation Group (GCG) promotes mutual understanding of regional harmonization initiatives by providing information about ICH to any country submitting a request.
The ICH consists of 6 Parties, 3 Observers, and the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). The 6 Parties are comprised of the founding members of the ICH and include the EU, European Federation of Pharmaceutical Industries and Associations (EFPIA), MHLW, Japan Pharmaceutical Manufacturers Association (JPMA), FDA, and Pharmaceutical Research and Manufacturing Association (PhRMA). The 6 Parties are directly involved in the operations of the ICH. The Observers are the WHO, European Free Trade Association (EFTA), and Canada (represented by Health Canada). The function of the observers is to act as a link with non-ICH countries and regions. The IFPMA provides the ICH Secretariat.
Summary
This review was not intended to be exhaustive regarding all of the contributors to a clinical trial. It is hoped that the information provides some perspective on the efforts that are involved in designing, executing, and then utilizing the data from a successful clinical study.
Resources
European Medicines Agency. Available at: www.emea.europa.eu. Accessed March 26, 2007.
Food and Drug Administration. Available at: www.fda.gov. Accessed March 26, 2007.
Pharmaceuticals and Medical Devices Agency. Available at: www.pmda.go. Accessed on March 26, 2007.