CLINICAL RESEARCH
Clinical Materials: Changes and Comparability
Jilla K. Boulas, MS
Senior Regulatory Consultant Complya Consulting Group, LLC
Submitted: 02/23/2015 Accepted for Publication: 02/26/2015
Boulas J. Clinical materials: changes and comparability. Pharm Outsourcing. 2015;16(2): 42-45.
Introduction
The development of a drug product is a long and costly journey which starts from basic research and moves down a path that requires much development, and takes turns at points where decisions have to be made. At the end of this path, one hopes to arrive at a safe and effective product for the treatment or prevention of a disease or condition. While commercialization of the product is one possible happy ending to this long journey, one also has to be prepared to reach a potential dead end where the “no go” decision has to be made. Moving along this path requires careful planning and the flexibility to convert potential hurdles into new opportunities. One area where such flexibility is important involves changes that have to be made. These changes may be to the clinical plans, financial arrangements, or they may be chemistry and manufacturing changes. Changes affect investigational drugs differently compared with those affecting approved products. The number of unknowns while in the investigational phase is higher than that when in the commercial phase. The manufacturing process is not yet fully developed, the knowledge of the potency, toxicity, and impurities is not complete yet, and the safety profile of the drug may have to be further improved. While considering changes to an approved drug, the sponsors have the option to consider the “no change” state, and this is not often feasible for drugs in clinical trials. The changes are either planned—in order to improve product safety and efficacy—or imposed as a result of factors beyond the sponsor’s control.
This article provides an overview of a strategy which has been applied to investigational drugs when dealing with inevitable Chemistry Manufacturing and Control (CMC) changes. The goal is to present 5 questions to be asked when assessing the risks associated with the implementation of a change. A brief discussion of the regulatory requirements is provided, followed by a case study to which the recommendations are applied.
A Discussion of Regulatory Requirements Both European Medical Association1
Administration (FDA)2,3
documents which describe categorization of changes to approved products. This is understandable, as approved drugs can reach a much larger patient population, hence the need to clarify regulatory expectations for reporting CMC changes to an approved application. While the regulatory documents provide clarity for assessing changes to an approved product, they do not address CMC changes to investigational drugs.
The FDA guidance document4 provides a thorough list of references to
help sponsors with the evaluation of changes and the assignment of a reporting category. The Committee for Medicinal Products for Human Use5
provides some guidance on changes which require notification
of the competent authorities, but it also notes that “…the Sponsor should decide on a case by case basis if an amendment is to be classified as substantial or not.” Another FDA guidance document6
provides a
short reference to clinical materials impacted by a change: “If a Sponsor can demonstrate comparability, additional clinical safety, and/or efficacy, trials with the new product will not be needed… FDA will determine if comparability data are sufficient to demonstrate that additional clinical study (ies) is (are) unnecessary.” In the same guidance document, FDA notes that the “the most important factor to FDA while assessing product comparability is whether the manufacturing changes can have a significant impact on the safety and efficacy of the investigational drug.” The sponsors of unapproved products are encouraged to consult with FDA when considering CMC changes before they are implemented.
The bottom line is that not all changes affect drug products in the same manner. Investigational products (pharmaceutical or biologics) have different characteristics. Some may be new chemical entities, with much uncertainty regarding the structure or mechanism of action. Some investigational products may have a simpler manufacturing process than others. There may be more historical data associated with some products that are not readily available/attainable for novel products.
and the U.S. Food and Drug have extensive requirements for addressing changes to approved products. There are additional guidance
Prior to implementing a change to investigational products, one has to assess the risk and impact on critical quality attributes, target product profile in addition to the financial state of the company. As mentioned above, the state of “no change” is often not an option. It is also a reality that performing additional nonclinical or clinical studies to demonstrate comparability of the “new” and “old” products presents a constraint on
Pharmaceutical Outsourcing | 42 | March/April 2015
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