The use of drug products to manage diseases and improve patients’ quality of life is increasing as more effective and safer agents become available. Research to develop these agents is occurring in health system practice settings throughout the world. The credibility of this research and the protection of human subjects is a major responsibility of all health professionals involved.
ASHP believes pharmacists should play a pivotal role in the management of drugs used in the conduct of clinical research.1–3 Pharmacists have become essential components of health system infrastructures supporting clinical research with both approved drugs and investigational drugs.a,b Pharmacists’ roles in clinical research generally fall into one of two categories: (1) drug storage, preparation, and record keeping, frequently through an investigational drug service, and (2) serving as a principal investigator or a subinvestigator, manager, or coordinator within a research team that may include other health care professionals, research sponsors, monitors, contract research organizations, institutional review boards (IRBs), and institutional administrators.
The purposes of this document are to (1) outline the principles of clinical research, (2) describe the roles of participants in clinical research, (3) define pharmacists’ roles in the use of drugs in clinical research, and (4) provide guidance to pharmacists and others responsible for the medication management component of clinical research. ASHP believes these guidelines are applicable to clinical research conducted in any health-system practice setting. These guidelines are an interpretation of federal laws, regulations, and standards for pharmacy practice in health systems. They should be used in conjunction with the applicable federal and state laws and regulations, not as a substitute for them. This document uses the term shall when the content is based on law or regulation and the term should for advice based on other guidelines, professional judgment, or expert opinion.
The United States has benefited from a system for researching and marketing drug products that is codified in federal and state laws and regulations. The federal Food, Drug, and Cosmetic Act and its amendments4 regulate drug product quality, safety, and effectiveness. The Food and Drug Administration (FDA) is the federal agency charged with enforcing the act and promulgating regulations for its implementation. FDA regulations concerning the conduct of clinical research with drug products of particular relevance for health-system pharmacists include Title 21 Code of Federal Regulations (CFR) Part 50, Protection of Human Subjects; Title 21 CFR Part 56, Institutional Review Boards; and Title 21 CFR Part 312, Investigational New Drug Application. Also applicable are the Department of Health and Human Services regulations in Title 45 CFR Part 46, Protection of Human Subjects. Requirements for and guidance on compliance with regulations are provided in FDA Information Sheets.
FDA has also published the Good Clinical Practice Consolidated Guideline5 that was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The guideline offers a unified standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects in the United States, Japan, and the European Union. In particular, the guideline provides a clearer understanding of behavioral and compliance standards for regulated drug research.
The institutional components and practice settings of health systems participating in clinical drug research shall develop mechanisms, generally in the form of policies and procedures, for the approval, planning, and implementation of protocols. Good clinical practices, consistent with national and international standards, are the cornerstone of drug research in humans. Principles consistent with good clinical practices include the following:
- An organization participating in human drug research studies shall ensure that such studies contain adequate safeguards for human subjects, its staff, and the scientific integrity of the study. There shall be written policies and procedures for the approval, management, and control of research involving investigational (not FDA-approved) drugs and post-marketing studies of FDA-approved drugs used in a research protocol. All research team members shall be fully informed about and comply with these policies and procedures.
- The clinical trial shall have adequate prior information to justify use of human subjects, have a clearly defined protocol, and have received IRB approval before implementation.
- All drug studies shall meet accepted ethical, legal, and scientific standards and be conducted by appropriately qualified investigators. Investigator qualifications, such as prior training and experience in research and with certain disease states, are required to be reviewed by IRBs, study sponsors, and FDA if the research will be submitted under an investigational new drug application (IND).
- Every member of the research team shall be qualified by experience or training to perform his or her respective role.
- All subjects must freely provide informed consent (documented in writing) before treatment with study drugs is begun. Accurate and complete information about the study’s objectives, risks, and benefits must be provided before consent is obtained from the subject or his or her legally authorized representative. No unreasonable inducements (i.e., coercion or undue influence) shall be offered to subjects to encourage their participation in the study.
- All clinical trial data shall be recorded and the records stored in such a way that the subject’s rights of privacy and confidentiality are protected. All records shall be managed in a way that permits accurate reporting, verification, and retrieval after archiving.
- Qualified pharmacists and other nonphysicians may serve as principal investigators as long as medical decisions made for the subjects are always the responsibility of a qualified physician or dentist.
The health system should have processes for the administration of research that ensure that the aforementioned principles are upheld and the following responsibilities are met.
1. The health system shall be able to review and approve a protocol in the context of federal, state, and local laws and regulations. The health system should consider whether its own sponsored research or intellectual property development of drugs requires an IND for drugs not commercially available and approved drugs for unlabeled uses. An IND may be required if proposed research on the use of a marketed drug is intended to support the sponsor’s change in drug labeling, advertising, or indications for use; a significant increase in risk; or a change in dosage level or route of administration. The health system should consult FDA for guidance.
2. The health system should have a mechanism for review and approval of the financial aspects of drug research, whether the study is sponsored by government agencies, foundations, or the pharmaceutical industry or is not sponsored.6 Financial aspects may include contractual agreements stipulating cost recovery for resources, intellectual property agreements, insurance provisions, indemnification terms, and conflict-of-interest statements. Cost identification, allocation, and recovery mechanisms are imperative items for review and approval.
3. As required by federal regulation, clinical research shall be reviewed and approved by an IRB or equivalent committee (21 CFR 56.109). This committee shall evaluate each proposed clinical research study in terms of human subject protections and compliance with recognized ethical, legal, and scientific standards. No clinical study may be initiated unless approved in writing by the committee. Spoken IRB approval may be granted in emergency situations for a single subject’s access to an investigational drug, but emergency use shall be reported to the IRB within five days; subsequent use requires full IRB review. Studies on the use of drugs in emergency or critical care settings do not in themselves qualify for single-subject approval and emergency exemption. Specific regulations govern research in the emergency setting and should be consulted in preparing protocols, IRB submissions, and consent procedures.c,7
Treatment IND protocols are also subject to IRB review and approval. These protocols permit patient access to investigational drugs through a special program established by a sponsor. The physician and patient must agree that use of the agent may be in the patient’s best interest and must document this agreement on a consent form.
The IRB shall monitor approved studies to ensure that they are carried out appropriately and that the protocols are reassessed at least annually. Health system policies and procedures shall provide guidance on the conversion of human subjects to other therapies in the event that approval of an existing protocol is withdrawn by the IRB. The investigational-drug pharmacist, pharmacy director, or pharmacy director’s designee should be a member of the IRB and should be consulted by the committee whenever drug studies are reviewed.
4. Investigational drugs shall be used only under the supervision of the principal investigator or authorized subinvestigators, all of whom shall be members of the professional staff. The determination of qualifications for investigators is the responsibility of the sponsor, IRB, and FDA when appropriate. Properly qualified pharmacists with experience and training in research may serve as principal investigators or subinvestigators.
5. The principal investigator or designee is responsible for obtaining informed consent from each subject who is eligible for participation in the study (i.e., meets inclusion and exclusion criteria).c The informed consent process shall conform to current federal and state regulations. IRB approval of the consent form (and assent form for minors) is required. Review by legal counsel may be desirable. The following points shall be included in the consent document and in an accompanying oral explanation by the investigator:
a. That the trial involves research.
b. The nature and purpose of the study and its expected benefits and foreseeable risks or discomforts. The name and telephone number of the principal investigator and persons to contact for questions about the study or drug.
c. A balanced description of the alternative treatments available, including their respective risks and benefits.
d. A general description of the study procedures, identification of any procedures that are experimental, expected length of therapy with the drug, and the subject’s responsibilities. The name(s) of the investigational drug(s), including brand and generic names of commercial products.
e. A statement that (1) participation is voluntary, (2) the subject may withdraw from the study at any time, (3) refusal to participate in or withdrawal from the study will involve no penalty or loss of benefits to which the subject is otherwise entitled, and (4) the principal investigator may remove the subject from the study if circumstances warrant. The investigator shall supply any new information that may affect a subject’s desire to continue in a study.
f. The name and signature of the subject (or his or her legally authorized representative), the name and signature of the principal investigator or subinvestigator, and the name and signature of the person presenting the consent form, with lines for each to personally date the signature.
g. A statement of who will have access to any study records that contain subject identifiers, including monitoring personnel from the study sponsor or FDA who may inspect the records to assess compliance with the study protocol and all regulations, or institutional personnel auditing the quality of clinical research or financial transactions.
h. Compensation or treatment available for a research-related injury.
i. Anticipated payments to subjects, pro rata terms, or expenses subjects may incur. Any costs for which the subject will be responsible.
The consent form shall be as detailed as is practical, with the goal of minimizing the amount of information that must be presented orally yet enabling comprehension by most persons reading the form. For non-English-speaking subjects the consent form shall be in the subject’s own language when feasible, or adequate interpretation shall be provided. For children able to read, an assent form shall be used to document their participation in the research process. The subject (or his or her representative) must have adequate time to read the consent form before signing it and shall receive a copy of the signed and dated form, along with any amendments to it. The subject shall retain a copy of the consent form. Additional copies of the consent form shall be kept on file as required by the sponsor, the IRB, the individual health system, and the medical records department.
Under certain protocols, patient drug or medical information may be collected from existing medical or pharmacy records. Pharmacists and investigators should consult the IRB to determine protocol-review and informed-consent requirements for any proposed studies.
6. The principal investigator is responsible for the proper maintenance of case report forms and all other study records required by the health system, the sponsor, and FDA.
7. The health system’s medication-use system shall contain the following elements concerning drugs used in clinical research:
a. Drugs shall be properly packaged in accordance with all applicable federal and state laws, regulations, and standards (e.g., FDA, The United States Pharmacopeia and The National Formulary [USP–NF], and the Poison Prevention Packaging Act).
b. Drugs shall be labeled properly to ensure their safe use by the research and institutional staff and the subject.
c. There shall be a mechanism to ensure that sufficient supplies of the drugs will be always available for the duration of the study.