Although the author of a clinical protocol must ultimately deal with individuals and committees within the organization to review and approve a protocol before it can be submitted to external investigators, Institutional Review Boards (IRBs), and regulatory agencies [e.g., the Food and Drug Administration (FDA)], a number of principles are initially described that review some of the issues relating to this area.

Marketing and sales professionals may request that their medical colleagues modify a protocol or design it in a certain way. These requests are often the result of market research or direct customer contact in which the end-user physician has asked questions or raised issues that the conduct of the trial will help address. The most general type of pressure is a request to evaluate a specific topic, such as comparing two or more drugs on (a) efficacy, (b) safety, (c) quality-of-life issues, or (d) pharmacoeconomics. More specific requests may be made. For example, a marketing group may desire to have specific drugs and doses compared with the company’s drug within a clinical trial or may ask that certain endpoints or measures be used in the trial, possibly as secondary endpoints. As another example, marketing may request to have certain investigators participate in a multicenter trial because of their reputation or for other reasons. The value of such trials depends on the quality of the protocol, the importance of the trial objective(s), and the phase in which the trial is conducted. While some types of Phase 4 trials (e.g., seeding studies) have been strongly criticized in recent years, the designs and validity of these trials vary greatly.

The clinical trial requirements specified by regulatory authorities for investigational drugs often differ from those specified for marketed drugs. In some countries, every protocol for investigational drugs must be approved by regulatory authorities before that phase of the trial can be started (e.g., Canada, Italy). In others, every protocol must be submitted to regulatory authorities, but after the first protocol is approved, no special permission is needed to initiate the trial, although the regulatory authority may force the sponsor to stop the trial or modify the protocol at any time (e.g., United States). In a third scenario, protocols are initiated after initial approval is obtained but are not submitted to the government until the regulatory dossier is completed. Regulatory influences on a protocol’s design may be felt if the protocol is submitted either prior to or after the trial is conducted. The FDA sometimes requires a clinical trial design to be modified despite its being approved by an IRB or EC and even being underway for weeks or months. The author is aware of several cases where this action has not been based on ethical issues but on the study design or measurements made. The FDA‘s comments, requests, or requirements may be based on safety, trial design, or any issue that is important to them at the time.

Even though most types of epilepsy are not rare diseases, certain forms of this condition do meet the criteria for a rare disease (e.g., Lennox-Gastaut syndrome). Protocols for treating patients with investigational drugs for rare diseases are a separate category in a few countries with special statutes. While regulations do not state that lower standards (i.e., fewer data, lower quality data) may be used, regulatory authorities are willing in most cases to accept clinical data from a smaller number of patients to approve such drugs. Nonetheless, it is usually not in a sponsor’s interests to test these drugs with less rigorous protocols, unless agreed to by the most important regulatory agency(ies).

A crossover design used in a 1980 to 1982 trial of cinromide (Spilker et al. 1983) required extensive discussions with the FDA before the FDA agreed that the prerequisites of a crossover design would most likely be met. After the FDA accepted this trial design and the trial was conducted successfully, the agency became enthusiastic about recommending the design in appropriate situations.