FDA OCE response on dose individualization


April 21, 2020

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).

Here is the text of my Jan 20 letter to Rep. Pramila Jayapal. FDA’s April 20 response may be found on page 1 of this post.

January 20, 2020

Congresswoman Pramila Jayapal
1904 3rd Ave Suite 510
Seattle WA 98101

Dear Congresswoman Jayapal:

FDA’s Oncology Center of Excellence (OCE) currently presents an ambiguous posture toward dose individualization in clinical trials, undermining innovations I endeavor to promote. May I request your help to encourage OCE to resolve this uncertainty publicly?

As a scientific and statistical consultant living and working in WA-07, I have for the past 3 years labored to develop and promote a methodologic framework for patient-centered dose individualization in cancer drug trials.1–7 I have carried out this effort as a private-sector innovator, but in a public-spirited manner. While receiving no public funds, I have released all developed software and algorithms into the public domain. Although my framework has attracted genuine interest in industry and academia, widespread apprehension about FDA’s stance on dose individualization remains a formidable barrier to implementation. 

It may surprise you to learn that the vast majority of cancer drugs are dosed in a 1-size-fits-all manner, lacking the clinical titration patients normally experience with drug dosing for so many other common conditions: hypertension, hypothyroidism, pain, diabetes. Remarkably, medical oncology’s sister field of radiation oncology is practically defined by the art of individualizing radiation delivery for each patient. Yet in medical oncology, 1-size-fits-all dosing remains the rule—eroding the efficiency of drug discovery,4 the ethics of clinical trials,7 and the equitable and humanistic delivery of cancer care.2,3

Motivating my efforts is the basic premise that dose individualization during early-phase clinical development of cancer drugs is a necessary and sufficient condition for achieving dose individualization in clinical practice. So it is specifically regarding the design of ‘phase 1’ dose-finding studies that I seek clarification of FDA OCE’s posture. Space does not allow me to document fully the extent and origins of the uncertainties engendered by FDA in this regard, but most notably a series of 3 FDA-AACR Oncology Dose-Finding Workshops (2015–2017) concluded without seriously contemplating the prospect of dose individualization.8,9 More proximately and urgently, speaking this past summer at an international conference, an Assoc. Branch Chief from our National Cancer Institute (NCI) defended 1-size-fits-all dose-finding methods primarily on the grounds that “regulators want a single dose” on drug labels.10

From time to time, ‘FDA Myths’ require debunking,11 and I sincerely believe the above notion belongs in this category. But even if OCE does in fact harbor residual prejudice against dose individualization, this might swiftly be rectified by FDA’s new Commissioner Stephen M. Hahn, MD, who himself hails from the field of Radiation Oncology mentioned above.

I wish to stress that this appeal to you is not an exercise in rent-seeking. I am not seeking an FDA endorsement or Fit-for-Purpose designation for my own ‘DTAT’ methodology. I seek only a clear public statement to reassure my potential collaborators from industry and academia that OCE welcomes dose-individualization designs. Several venues seem available for such a statement, including an imminent Feb 5 #OCEProject2025 Public Workshop. Would you be willing to bring my concerns and this request to the attention of Commissioner Hahn?


David C. Norris, MD
Precision Methodologies, LLC
Seattle, WA  98102

1. Norris DC. Dose Titration Algorithm Tuning (DTAT) should supersede ‘the’ Maximum Tolerated Dose (MTD) in oncology dose-finding trials. F1000Research. 2017;6:112. doi:10.12688/f1000research.10624.3

2. Norris DC. Costing ‘the’ MTD. bioRxiv. August 2017:150821. doi:10.1101/150821

3. Norris DC. Costing ‘the’ MTD: What Is the Economic and Human Cost of 1-Size-Fits-All Dose Finding in Oncology? Conference Poster presented at the: 8th Annual American Conference on Pharmacometrics (ACoP8); October 19, 2017; Ft. Lauderdale. doi:10.7490/f1000research.1114988.1

4. Norris DC. One-size-fits-all dosing in oncology wastes money, innovation and lives. Drug Discov Today. November 2017. doi:10.1016/j.drudis.2017.11.008

5. Norris DC. Precautionary Coherence Unravels Dose Escalation Designs. bioRxiv. December 2017:240846. doi:10.1101/240846

6. Norris DC. Costing ‘the’ MTD … in 2-D. bioRxiv. July 2018:370817. doi:10.1101/370817

7. Norris DC. Ethical Review and Methodologic Innovation in Phase 1 Cancer Trials. JAMA Pediatr. April 2019. doi:10.1001/jamapediatrics.2019.0811

8. Jänne PA, Kim G, Shaw AT, Sridhara R, Pazdur R, McKee AE. Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(11):2613-2617. doi:10.1158/1078-0432.CCR-15-2643

9. Emens LA, Bruno R, Rubin EH, Jaffee EM, McKee AE. Report on the Third FDA–AACR Oncology Dose-Finding Workshop. Cancer Immunol Res. 2017;5(12):1058-1061. doi:10.1158/2326-6066.CIR-17-0590

10. Norris DC. Missed opportunities at Phase 1 Manchester. July 2019. https://precisionmethods.guru/2019/07/25/missed-opportunities-at-phase-1-manchester/.

11. Blumenthal G, Prowell T. Top 10 Myths About FDA’s Office of Hematology and Oncology Products. ASCO Post. January 2015. https://www.ascopost.com/issues/january-25-2015/top-10-myths-about-fda-s-office-of-hematology-and-oncology-products/.