Principles and Practice of Clinical Research, Second Edition (Principles & Practice of Clinical Research),   ISBN:9780123694409

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PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH, 2nd ed., contains 29 chapters and is 430 pages long. Each chapter is by a different author(s). Surprisingly, only the introductory chapter is authored by one of the two editors of the book. The book is of moderate size. It too long to be called, "Clinical Studies in a Nutshell," and too short to be used as a resource for experienced clinical study monitors when they need expert advice.

Chapter 6, entitled Data and Safety Monitoring Boards, is by Lawrence Friedman. This chapter is first rate. We learn several reasons why clinical trials have a Data Monitoring Committee (DMC). One reasons is that trials are double blinded and the investigator must also remain blinded. The DMC is the party to view the unblinded data. Second, where trials are held at multiple centers this makes monitoring by a single investigator difficult. The DMC is the party to monitor the multiple sites. Third, to avoid undue bias for wanting to halt a trial, or wanting to prolong a trial, a DMC is useful. Fourth, to ensure that any changes to a protocol that are made are made by an investigator that is kept unaware of the direction that the data are trending.

Dr.Friedman provides some concrete, real-life examples of what a DMC can recommend. First, the DMC can suggest to drop a subgroup from the trial, for example, a subgroup that is found to do worse than the group receiving the standard of care. Second, the DMC can recommend sending a letter to all subjects warning them of a newly discovered adverse event, or even recommend that a new informed consent form be prepared and signed by all subjects. Third, the DMC can recommend that a trial be stopped early because of efficacy of the study drug (this is good news). Fourth, the DMC can recommend that a trial be halted for futility, that is, for failure to work, or for too many adverse events.

Chapter 7, "Data Management in Clinical Trials," discloses the nuts and bolts of any clinical trial. We learn about the site initiation visit, where the sponsor manages eligibility criteria, randomization, blinding, study procedures, study agent administration, adverse event (AE) recording, and the Case Report Form (CRF) and data entry. In this practical chapter, we also learn about Serious Adverse Events (SAEs), and that they include life threatening events, events that cause or prolong hospitalization, events that cause persistent or significant disability, and birth defects. Regarding SAEs, we also learn that the investigator must report SAEs to the FDA and to the sponsor, and that the sponsor must provide FDA and all investigators with an IND Safety Report. Chapter 7 provides sample forms and sample tables, e.g., inclusion criteria, registration form, and a randomization form. The strong point of Chapter 7 is that it provides examples of actual forms that are filled out. Chapter 7 is too short. This important chapter could easily be 2 or 3 times as long.

Chapter 8 by Stephen Starus consists of a single, 20-page anecdote. This 20-page anecdote concerns adverse events (AEs) from a potential anti-viral drug (fluoroiodo-arabinosyl-cytosine; FIAC). Chapter 8 is remarkably candid, and therefore remarkably useful. We read, "As these exciting early results were emerging from the FIAU trial, a few storm clouds appeared on the research horizon . . . patients . . . developed progressive liver failure from which they eventually died."

We learn that, during a clinical study trial, it was noticed that the drug produced small accumulations of fat in the liver, and eventually death. This effect was found to be due specifically to inhibition of a mitochondrial enzyme, the mitochondrial DNA polymerase. To view the writing, "It seemed as if FIAU had injured mitochondria. Only in time could we presume to understand why . . . electron microscopy provided a key piece to the puzzle . . . ultramicrographs of liver sections from our patients showed . . . mitochondria lacking their normal internal scaffolding of membranes . . ."

Chapter 8 is a good teaching device for those interested in DNA polymerases, and for those interested in mitochondrial metabolism. But more to the point, Chapter 8 is an exquisite lesson for safety monitors having the task of capturing adverse events (AEs) and relaying them to FDA. Chapter 8 is absolutely excellent.

This book also has some remarkable shortcomings. A vital part of every Clinical Study Protocol (CSP) is the disclosure of endpoints and surrogate endpoints. However, this book (Chapter 8) contains very little information on surrogate endpoints. In fact, this chapter dismisses surrogate endpoints as something that causes problems. Moreover, the book appears not to have any information on a related topic, stratification criteria. The issue of endpoints, surrogate endpoints, and stratification criteria deserves an entire chapter of its own.

Chapter 21 concerns scoring methods for measuring quality of life. This 7-page chapter lists a number of scoring methods, but fails to include a table disclosing an actual scoring chart. For example, it might be helpful to include an ECOG scoring chart and a Karnofsky scoring chart. But these are not to be found in this odd chapter.

Chapter 23 concerns patents. There is nothing whatsoever in Chapter 23 about patent term extension (the only aspect of patent law specifically relating to clinical trials). The most important issue that connects clinical study trials and patents is patent term extension. Patent term extension is disclosed in Chapter 2700 of the MANUAL OF PATENT EXAMINING PROCEDURE (MPEP). The MPEP is a handbook used, almost on a daily basis, by every patent attorney and agent in the U.S. But the book being reviewed fails to disclose anything about patent term extension. Patent term extension deserves a chapter of its own.

Another problem with Chapter 23 is that it spends nearly a whole page on 35 U.S.C. 101, the statute in the U.S.Code dealing with the requirement for utility for allowing claims in a patent. But 35 U.S.C. 101 (utility) is relevant only in the very, very early stages of developing a small molecule drug or a drug based on a nucleic acid sequence. For example, a claim for a small molecule can be rejected for lack of utility because the patent application failed to include any data showing that the molecule (or nucleic acid) has any biological effect.

By the time a drug has past the pre-clinical (animal) stage, and by the time a clinical trial is in the planning stage, this statute (35 U.S.C. 101) is not likely to be of any relevance to a company's patent portfolio. By this time, a company will have filed subsequent patent applications that claim methods for stimulating physiology, or methods for treating disorders. Hence, it is not really appropriate for this book to spend a page (or even one paragraph) on 35 U.S.C. 101. Generally, Chapter 23 is just a thumbnail sketch of patent law. It does not even acknowledge special issues that may crop up during a clinical trial, for example, claims to unique drug formulations, claims to methods of administration or for assessing response to a drug, or how to get allowed claims to methods of medical treatment in Europe (in Europe this type of claim is not allowed, but there are ways around it).

Chapter 24, which is entitled, "Writing a Protocol," is a little perplexing. This chapter is only 5 pages long. But clinical study protocols are generally 50 to 100 pages long. Chapter 24 does a disservice to this fascinating and central issue in clinical trials -- the Clinical Study Protocol.

The shortcomings of the book are further evident by the fact that the INDEX does not contain the terms, "pharmacokinetics" or "pharmacodynamics." Data on these two subjects are usually required by the FDA, where a clinical trials concerns a drug. Persons involved in clicical trials will want to know the difference between these two things.

Hopefully, when the time comes, a third edition of PRINCIPLES AND PRACTICE OF CLINICAL RESEARCH will overcome the above-disclosed deficiencies.

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It's a good collation on the practice of clinical research. Great learning examples to move forward.