5.1 Protocol Design and Implementation

The study protocol should explicitly state the rationale for studying the drug in the disease of interest. The source and chemical nature of the compound, its pharmacology and toxicology, and the data obtained in previous clinical investigations must be present in appropriate detail. All study protocols must be approved by the appropriate regulatory authorities. The objectives of the study must be clearly stated and appropriate methodology employed to ensure that these are met. The study treatment schedule should define the drug administration (dosage, strength, route of administration, the blinding process, packaging and labeling) in sufficient detail.

The inclusion and exclusion criteria, baseline, pre- and post-treatment measurement and evaluation visits and procedures for reporting adverse events and treatment overdoses must be clearly specified.

A study discontinuation procedure is defined in the event of lack of efficacy, intolerable side effects, poor patient compliance or the occurrence of a treatment endpoint.

Detailed definitions of the statistical analysis, data management procedures, administrative structure of the study and insurance and liability requirements are also necessary.

The protocol should contain a description of the background information that is provided to the patient and the informed consent document. For the patient's protection, lay language must be used. Diary forms and informed consent papers must be translated into the patient's primary language.

Once a protocol has been developed, an appropriate study administrative structure should be organized. An executive (steering) committee is constituted, which is responsible for the strategic aspects of conducting the trial. Usually other committees are organized to oversee the operational aspects of the trial, to monitor the safety of participants, and to adjudicate key outcomes.

The selection of the investigators for clinical research will depend on the nature of the drug and the phase of the investigation. Experts in clinical pharmacology are selected for Phase I and II studies; experts in medical practice or medical specialties will usually be selected for Phase III and IV studies. The principal investigator in each center is responsible for the study in accordance with the protocol and for the accurate and complete reporting of the results: he or she must sign a formal statement of agreement for the study and its commitments and provide copies for the sponsor and government authorities. Investigators are selected on the basis of several criteria, including their past record in peer-reviewed medical research, their current interest in the proposed study and available time to participate. Appropriate on-site hospital or private clinic facilities with adequate space, equipment, safe drug storage, assistance from a research nurse and access to a certified laboratory are essential prerequisites for participation in clinical trials. The laboratory must be able to conduct the study according to the guidelines of good laboratory practices (GLP) adopted by the FDA in 1978. In addition, the investigators should be able to make an estimate of the number of study subjects available at their centers so a recruitment projection can be derived. The investigators must agree to have their facility and data audited at any time by the sponsor's representatives or by the regulatory authorities (FDA or HPB).