No Excuses: US FDA Wants Early, Thorough Dosage Optimization For Cancer Drugs
Executive Summary
Breakthrough therapy designation is not a sufficient reason to avoid identifying an optimal dosage prior to submitting a marketing application, agency says in draft guidance under Project Optimus. Guidelines also emphasize randomized comparisons of multiple dosages and exploration of tolerability issues.
Development of an oncology drug under one of the US Food and Drug Administration’s expedited regulatory programs is no excuse for failing to identify an optimal dosage prior to marketing approval, the agency says in a new draft guidance.
The guidance, “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,” emphasizes the need for more thorough dosage characterization earlier in development, including randomized trials to compare multiple dosages and better assessment of dose-related tolerability, such as through patient-reported outcomes.
Guidance Definitions
-
Dose – Quantity of the drug
-
Dosage – Dose and schedule, such as the recommended interval between doses and duration of treatment
-
Optimal Dosage – Dosage that can maximize the benefit-risk profile or provide the desired therapeutic effect while minimizing toxicity
The guidance was prepared by the Oncology Center of Excellence, Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research. It reflects OCE’s push under Project Optimus for sponsors to do more work up-front in optimizing cancer drug dosing, and to move away from the traditional “maximum tolerated dose” (MTD) approach. (Also see "US FDA’s ‘Project Optimus’ Will Encourage Move Away From Conventional Dose-Finding For Modern Cancer Therapies" - Pink Sheet, 26 May, 2021.)
These efforts have been evident in several public meetings and Oncologic Drugs Advisory Committee reviews in the past two years. For example, in April 2022 the agency used an advisory committee on safety concerns with phosphatidylinositol 3-kinase (PI3K) inhibitors to spell out its dose optimization expectations under Project Optimus – expectations that align with the recommendations in the guidance. (Also see "US FDA Uses PI3K Inhibitor Experience To Spell Out What It Wants In Dose Optimization Studies" - Pink Sheet, 29 Apr, 2022.)
Moving Away From MTD
MTD involves a step-wise evaluation of increasing doses in a small number of patients until a prespecified rate of severe or life-threatening toxicities is observed. This approach was developed for cytotoxic chemotherapies but has less relevance for targeted agents, such as kinase inhibitors and monoclonal antibodies, that demonstrate different dose-response relationships compared to chemotherapy.
“The traditional MTD paradigm often does not adequately evaluate other data, such as low-grade symptomatic toxicities (i.e., grade 1-2), dosage modifications, drug activity, dose- and exposure-response relationships, and relevant specific populations (defined by age, organ impairment, concomitant medications or concurrent illnesses),” the guidance states.
“Dose-finding trials that investigate a range of dosage(s) and select the dosages to be further investigated based on clinical data and an understanding of dose- and exposure-response, represent a more informed approach to identify the optimal dosage.”
The guidance includes recommendations on:
-
Collection and interpretation of clinical pharmacokinetic, pharmacodynamic and pharmacogenomic data;
-
Trial designs to compare multiple dosages;
-
Safety and tolerability;
-
Drug formulations; and
-
Subsequent indications and usages.
The document does not address selection of the starting dosage for first-in-human trials, or dose optimization for radiopharmaceuticals, cell and gene therapy products, microbiota or cancer vaccines.
Emphasis On Premarket Assessment
The guidance suggests the agency does not want to hear excuses from sponsors about why the appropriate dosage optimization work was not done prior to approval.
“Dosage optimization prior to approval is recommended because delaying until after approval may result in large numbers of patients being exposed to a poorly tolerated dosage or one without maximal clinical benefit,” the FDA said. “Furthermore, conducting clinical trials to compare multiple dosages may be challenging to complete once a drug is approved for a given indication.”
“Sponsors should note that development of a drug under an FDA expedited program (e.g., breakthrough therapy designation) is not a sufficient justification to avoid identifying an optimal dosage(s) prior to submitting a marketing application.”
Dosages selected for use in a clinical trial should be adequately supported by data appropriate to the stage of development for each indication and usage. This includes relevant nonclinical and clinical data, as well as dose- and exposure-response relationships for safety and efficacy.
“An approach where a dosage is chosen for a trial without adequate justification or consideration of relevant data may not be acceptable because FDA may determine that patients are exposed to unreasonable and significant risk, or there is insufficient information to determine risk, or the design of the trial is deficient to meet its stated objectives,” the agency said.
Sponsors, including those holding designation under the breakthrough therapy program or other expedited regulatory pathways, should plan their development programs so that identification of the optimal dosage can occur prior to, or concurrently with, establishment of the drug’s safety and effectiveness.
“Sponsors should note that development of a drug under an FDA expedited program (e.g., breakthrough therapy designation) is not a sufficient justification to avoid identifying an optimal dosage(s) prior to submitting a marketing application,” the guidance states. “FDA is available to discuss strategies to determine the optimal dosage(s), and sponsors are strongly encouraged to discuss their plans for dosage optimization with FDA at relevant milestone meetings.”
In fact, dose optimization is one area that FDA and oncology drug sponsors have identified for more interactions under the breakthrough therapy program. (Also see "Oncology ‘Beyond Breakthrough’ Takes Shape: FDA Project Will Create Benefits ‘Menu,’ Rescission Process" - Pink Sheet, 26 May, 2021.)
Seeking Diversity In PK/PD Studies
Dose-finding trials should include pharmacokinetic sampling and an analysis plan to ensure that PK data are of sufficient quality and quantity to allow an adequate characterization of the PK, including linearity, absorption and elimination, following administration of multiple dosages. The PK sampling and analysis plan also should be sufficient to support population PK and dose- and exposure-response analyses for efficacy and safety.
Following completion of dose-finding trials, dosages should be selected for further evaluation based upon population PK, exposure-response analyses, anti-tumor activity, safety and tolerability data.
“Clinical trials should enroll an appropriately broad population to allow assessment of the dosage(s) across relevant subpopulations.”
“Clinical trials should enroll an appropriately broad population to allow assessment of the dosage(s) across relevant subpopulations,” the FDA said, citing its various guidance documents aimed at encouraging clinical trial diversity in terms of race, ethnicity, eligibility criteria and concomitant conditions. “Population PK data should be evaluated to identify specific populations (e.g., defined based on weight, age, sex, race and ethnicity, or organ impairment) in which the PK demonstrate clinically meaningful differences in exposure.”
When justified, simulated exposure metrics may be used to conduct exposure-response analyses to evaluate alternative dosages in relevant subpopulations. Alternative dosages for subpopulations should be incorporated into registration trials when feasible.
Comparing Multiple Dosages
To decrease uncertainty with identifying an optimal dosage in a marketing application, sponsors should compare multiple dosages of a drug in clinical trials designed to assess activity, safety and tolerability.
The agency prefers these trials be randomized, parallel, dose-response studies, and it includes some recommendations for making this approach more feasible.
“The trial should be sized to allow for sufficient assessment of activity, safety, and tolerability for each dosage. The trial does not need to be powered to demonstrate statistical superiority of a dosage or statistical noninferiority among the dosages,” the guidance states. “An adaptive design to stop enrollment of patients to one or more dosage arms of a clinical trial following an interim assessment of efficacy and/or safety could be considered.”
In addition, multiple dosages may be compared prior to, or as part of, a registration trial by adding more dosage arms, the FDA said, providing recommendations for statistical design of such studies.
“If safety and efficacy data from multiple dosages will be used to support a marketing application, this approach should be discussed with FDA early in clinical development.”
Safety And Tolerability
The agency wants to see various safety and tolerability parameters compared across multiple dosages, including: duration of exposure; proportion of patients who were able to receive all planned dosages; percentage of patients that required dose interruptions, reductions or discontinuations due to adverse reactions; and percentage of patients with serious adverse reactions.
“Safety monitoring rules should be prespecified for trial designs that include dosages associated with a high percentage of dosage modifications or serious adverse reactions,” the guidance states. “The protocol should clearly state what action will be taken if the percentage of dosage modifications or serious adverse reactions is too high. Such actions may include pausing the trial so the safety monitoring committee can review these events, changing the starting dosage for future patients, and/or discontinuing the trial.”
The guidance emphasizes monitoring not just for serious adverse reactions, but also tolerability issues.
Symptomatic but less severe adverse reactions, such as Grade 1-2 diarrhea, may significantly affect a patient’s ability to remain on drug for extended periods of time, the guidance states. “The frequency and impact (i.e., the frequency of drug discontinuation, or paused/reduced dose) of such reactions should be carefully assessed and considered in selecting the dosage(s) for subsequent clinical trials.”
OCE has been very public in its concerns about the tolerability of cancer drugs, be they investigational or approved, in the context of large percentages of dose discontinuations and modifications in clinical trials. (Also see "US FDA Oncology Center Makes Dose Optimization Personal" - Pink Sheet, 21 Mar, 2022.)
The agency recommends that sponsors consider including patient-reported outcomes to enhance the assessment of tolerability in early-phase dosage finding trials.
FDA officials previously have said that adding PRO data to clinician-reported adverse events may aid more efficient dose selection by identifying safety signals with higher sensitivity and providing early reliable data on tolerability, even for single-arm dose escalation trials in expedited development programs. (Also see "Build Patient-Reported Outcomes Into Cancer Drug Dose Optimization, US FDA Says" - Pink Sheet, 9 May, 2022.)
Formulations And Subsequent Indications
The guidance also includes considerations for drug formulation and the data need to support subsequent indications.
“Perceived difficulty in manufacturing multiple dose strengths is an insufficient rationale for not comparing multiple dosages in clinical trials.”
Various dose strengths should be available so that multiple dosages can be evaluated in clinical trials, the agency said. “Perceived difficulty in manufacturing multiple dose strengths is an insufficient rationale for not comparing multiple dosages in clinical trials.”
For oral drugs, the size and number of tablets or capsules required for an individual dose should be taken into consideration when selecting a final dosage form and strength. For parenteral drugs, the concentration and volume to be administered should be considered.
Different dosages may be needed in different disease settings, and applicable nonclinical and clinical data should support the proposed dosage to be evaluated in a registration trial for a subsequent indication and usage.
“Strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage, especially for oncologic diseases not adequately represented in completed dose-finding trials or for new combination regimens,” the guidance states. “If sufficient rationale for choice of dosage cannot be provided, additional dose-finding should be conducted.”