Clinical Development: The Clinical Trial Protocol

Dr Michael Silverman, principal at BioStrategics Consulting Ltd, initiates a discussion this week on the Clinical Trial Protocol. The protocol to test one’s product, to confirm or reject a specific hypothesis, is key in the Clinical Development Plan and in the overall development of the product with the goal of moving the science forward and preparing a product for market acceptance.

This week I would like to discuss a key aspect of the clinical trial protocol; the clinical trial objective(s). The clinical trial protocol is the experimental blueprint for a clinical study, and every activity and procedure it specifies should contribute to the efficient testing of the central hypothesis being examined.

The key Clinical Trial Protocol components include:

  • Product rationale; potential risks and benefits
  • Study objectives
  • Primary and secondary clinical end points
  • Study population; inclusion and exclusion criteria.
  • Study design
  • Investigational product
  • Study schedule
  • Procedures and Evaluations
  • Safety assessments
  • Clinical monitoring plan
  • Statistical analysis
  • Quality control and assurance
  • Ethics protection
  • Data handling and record keeping
  • Financing and insurance
  • Publication policy

If all aspects of the protocol are prepared thoughtfully and executed effectively then the clinical trial should realize its scientific goals.

Each protocol is grounded in scientific hypotheses regarding the new drug product. In fact, conducting a protocol that lacks a cogent hypothesis is not just wasteful of corporate resources, it is distinctly unethical because it exposes human subjects to an investigational substance without the expectation of generating knowledge that will potentially contribute to the ultimate benefit of patients. Thus, the statement of the protocol objectives is at the very center of protocol development.

The objectives, in turn, must be directed at gathering data that are absolutely required building blocks of the total registration dossier of the new drug. No drug can ever be completely investigated in one trial: the totality of the evidence in support of its safety, efficacy, and biological behavior is assembled from a series of trials that ask related but complementary questions.

Most protocols have more than one objective, because it is generally possible to study several closely related hypotheses in a single study. There is a limit to the number objectives that a protocol can have before the trials risk becoming so complicated that none of the objectives can be studied conclusively. Usually four or five objectives are sufficient. Similarly, it is necessary to designate no more than two or three of the objectives as primary, meaning that the scientific success of the trial is wholly dependent upon answering these questions. The other objectives, relegated to secondary status, represent questions that can also be answered under the conditions of the protocol but whose resolutions are not absolute requisites for success.

Several major categories of clinical trial objectives exist:

  • Dose-dependent objectives:
    • Safety and tolerability
    • Biological effect, pharmacodynamics, surrogate end points
    • Absolute efficacy (i.e., versus no treatment or placebo control)
    • Relative efficacy (i.e., versus an established comparative agent)
    • Pharmacokinetic behavior
    • Pharmacoeconomic outcomes
    • Effects in special populations (e.g., pediatric or renal impaired patients)
  • Non-drug-dependent objectives
    • Natural history of disease
    • Pilot data to guide the design of subsequent trials

Hopefully this gives you a sense of the importance and necessity of the Clinical Trial objective within the context of the Clinical Trial Protocol and its relation to the Clinical Development Plan. In next weeks blog, I will cover other aspects of the Clinical Trial Protocol, and if there is an area you are particularly interested in, let me know.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd., a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.



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For more information: go to my web site or send me an email at

Copyright © 2011 BioStrategics Consulting Ltd.


About BioStrategics Consulting Ltd

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical and biotechnology industries
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One Response to Clinical Development: The Clinical Trial Protocol

  1. Keep up the good work on this blog!

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