Top critical review
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A fine introductory book, but lacking in depth or examples.
on July 26, 2009
Biologics Development: A Regulatory Overview, by Mark Mathieu is a 330 page book, containing 15 chapters. The paper is a off-white. There are about ten tables and flow charts, and reproductions of two forms, FDA Form 356h and the MedWatch form. This is a review of the second edition (but the currently available edition is still very short, around 350 pages).
Overall, the book is a walk-through that takes us along various rules in Title 21 of the CFR. The book is useful, in that it teaches a pharma or biotech employee things that management might not have time to teach. This book fills a niche, in that other books on clinical trials generally fail to disclose back and forth communications between the sponsor and FDA. But for the price charged for this book, the book does not go far enough. It is only an overview or introduction.
We learn that CBER has an office called OCTMA that provides guidance on how to go about filing an IND. We learn that the IND must be submitted using Form 1571, and that INDs include the Investigator's Brochure and Clinical Study Protocol (pages 64-66) to be used in the Phase I study, and that the CSP must be accompanied with the Consent Form. We learn that Institutional Review Board (IRB) approval is not needed for submitting an IND, but IRB approval is required before carrying out the actual study.
We learn that the Chemistry, Manufacturing, and Control Data (CMC) part of the IND includes drug substance, drug product, placebo (page 67), labels, and environmental analysis requirements sections, and that the Pharmacology & Toxicology Data section includes animal studies, in vitro studies, previous human experience, studies.
After an IND is approved, we learn that subsequent submissions include a revised IB, amendments to the CSP, information amendments, and IND safety reports (these report only AEs that are serious and unexpected, and must be submitted within 10 days after the sponsor's receipt (page 75).
Attention is devoted to the Clinical Hold and partial clinical hold (pages 72, 95, 99, 100, 105), to Informed Consent forms (pages 61, 145, 152-155), and to the label for the drug container and package insert (pages 170-172, 208, 223, 226, 280).
We learn how CBER is organized--its offices include Therapeutics (cytokines, cellular & gene therapies, hematologics, monoclonals), Vaccines, Blood Products, Office of Establishment Licensing & Product Surveillance, Office of Compliance, Office of Communication, and Office of Management. We learn about the time-line followed after submitting the IND, where the decision tree is to proceed (occurs automatically at 30 days after receipt of IND), to call the sponsor about minor deficiencies, or to impose a clinical hold.
An overview is provided of Phase I, Phase II, Phase III, and Phase IV clinical trials (page 107), and we learn about Expedited Development and Accelerated Approval. We are provided with a number of other concepts, but these are only named, and there are no examples (comparison group, multicenter trials, randomization, blinding, Data Safety Monitoring Committee, Endpoints and Surrogate Endpoints). It would have been nice to be provided with a disclosure of how these things are handled differently in oncology versus infectious diseases, but we're left in the dark.
We learn of the responsibilities of the Sponsor (selects investigators, ensures monitoring of trials, to ensure that requirements set forth by IRB and by Consent Forms are followed (page 145), to ensure that investigators understand the IB (page 145).
After the IND is filed, and after the clinical study is completed, a subsequent step is licensing. We are provided with the history of biologics approval, at least as it applies to licensing. We learn that the Establishment License Application (ELA) was implemented early (in 1902), because it was easy to monitor and control manufacturing steps, but that Product Licensing Application (PLA) came much later (in 1944), because it was not until this time that analytical methods became good enough to do quality control on the biologics product. We learn that in 1996, CBER combined the PLA and ELA, where the combination was called, BLA (BLA applies only to plasmids, peptides of 40 or fewer amino acids, monoclonals, and somatic cell therapy) (page 160, 233)
Examples and case histories would be a welcome addition to this book. For example, I would have liked to see a reproduction of a Consent Form, an example of a Synopsis from a Clinical Study Protocol, an example of an FDA Form 483 Warning Letter, a time-line of all milestone documents that are sent to the FDA with commentary disclosing what event triggers the submission of each of these documents, and information of additional FDA documents. I would like to see examples of an Information Request letter and an Advice letter (page 100). We are told of these letters but have no idea of their content.
We are told about INDs, BLAs, PLAs, ELAs, and CSPs, but certainly there are other major documents. Perhaps the following documents were not available at the time of the edition of the book being reviewed, but at the present time (2009), these other documents include a Fast Track Application, a Briefing Document, Statistical Analysis Plan, Change Control Form, and Special Protocol Assessment (SPA).
What is also missing is information about the European equivalent of the FDA, that is, European Medicines Agency (EMEA). I would have also liked to see two or three case histories, for example, disclosing conversations occurring during a pre-IND meeting. An excellent example of cases histories can be found in Data Monitoring in Clinical Trials: A Case Studies Approach by DeMets, et al. In my opinion, the DeMets book is a glorious, no holds barred, well-written treatise, on one aspect of clinical trials (data and safety monitoring committees). If Mark Mathieu's book was less expensive (in the range of $30-$40) it might deserve five stars.