Here is the text of FDA’s April 20, 2020 response to a query submitted on my behalf Jan 22 by the office of Congresswoman Rep. Pramila Jayapal. (Advance to page 2 of this post to see the text of my Jan 20 letter to Rep. Jayapal.)
The following is a response to the request that Rep. Pramila Jayapal received from Dr. David Carl Norris regarding dose individualization in clinical trials, specifically in the area of oncology trials.
The Food and Drug Administration (FDA) Oncology Center of Excellence (OCE), authorized by the 21st Century Cures Act, was established as FDA’s first Inter-Center Institute in 2017, to facilitate the development and clinical review of oncology products by uniting scientific experts across FDA’s product Centers to conduct a coordinated review of drugs, biologics, and devices. The OCE has successfully collaborated with other FDA Centers to develop over a dozen Guidances for Industry regarding various topics on the clinical aspects of oncology drug development and is known for regulatory flexibility. The OCE has encouraged developers to consider novel trial designs that better serve the needs of patients with cancer, including various types of master protocols, including those with common control arms, “umbrella” trials, and “basket” trials, as well as novel clinical trial endpoints, such as metastasis-free survival in non-metastatic castration-resistant prostate cancer and minimal residual disease in hematologic malignancies.
As Dr. Norris noted in his letter, in this same spirit, the Center for Drug Evaluation and Research’s Office of Oncology and Hematology Products and the OCE held three workshops in 2015-17 in conjunction with the American Association for Cancer Research (AACR) to identify best practices for optimizing dosing across the entire life cycle of product development. Although individualized patient dosing was not discussed in detail during these meetings, the OCE is supportive of drug development programs evaluating individualized patient dosing based on clinical signs, laboratory findings, or therapeutic drug monitoring measured by an accurate and reliable test method. The results of population pharmacokinetic analyses, exposure-response and exposure-toxicity modeling, information on drug interactions and food-effects (for orally administered products) result in individualization of starting doses for all oncology drugs. Subsequent individualization of dosing is typically based on tolerability and toxicity. However, in contrast to the diseases and conditions mentioned in Dr. Norris’ letter (e.g., hypertension, hypothyroidism, diabetes), currently there is no rapidly measurable clinical or laboratory pharmacodynamic measure (e.g., blood pressure, TSH, glucose) that would allow individualization of dosing in patients with various cancers based on pharmacodynamic effects on tumors that have been scientifically validated to predict clinical outcomes. Please note that FDA has encouraged the development of pharmacodynamic biomarkers that may assist in drug development, including through exploratory INDs and through participation in FDA’s Biomarker Qualification Process.
Finally, we caution that every investigational drug product development program is evaluated on its own merits. As a result, FDA cannot make a blanket statement that we would either accept or reject any particular dose optimization method or trial design. Such alternative dosing strategies can only be evaluated in the context of the cancer type and stage, the patient population, the information available regarding the investigational drug, the information available regarding the biomarker to be used to guide an individualized dosage regimen, and the details of the trial design.
Thank you for your interest in this topic. Below, we provide links to potential additional resources for your constituent:
Oncology Center of Excellence – (https://www.fda.gov/about-fda/fda-organization/oncology-center-excellence) This is FDA’s main website for OCE and includes contact information by which constituents may reach FDA staff.
Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle – (https://www.ncbi.nlm.nih.gov/pubmed/27250931).