Build Patient-Reported Outcomes Into Cancer Drug Dose Optimization, US FDA Says
Executive Summary
In exploratory FDA analyses, PRO data appeared more sensitive at detecting an exposure-toxicity relationship for an oral small molecule cancer drug than clinician-reported data; Project Optimus representative dispels industry concerns that FDA wants firms to find the 'mythical' optimal dose.
Adding patient-reported outcomes data to clinician-reported adverse events in early cancer drug trials could better inform dose selection and optimization, US Food and Drug Administration officials said at a recent meeting on optimizing dose selection strategies.
PROs often are included only in late-stage or registrational cancer trials, but it is both feasible and advantageous to measure such outcomes during the dose optimization stage, said Vishal Bhatnagar, associate director for oncology patient outcomes at the FDA’s Oncology Center of Excellence.
In addition, exposure-response analyses for safety and tolerability using a combination of clinician-reported data and rich PRO data may be useful in characterizing such relationships for safety as well as tolerability specific to key adverse events, said Jeanne Fourie Zirkelbach, a clinical pharmacologist team lead in the FDA’s Division of Cancer Pharmacology II.
The combination approach also 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 cancer drug development programs, she said.
The meeting, which was cosponsored by the American Society of Clinical Oncology, was part of the Oncology Center of Excellence’s multidisciplinary initiative, known as Project Optimus, aimed at spurring cancer drug companies to do more work earlier in the development process to optimize dose.
Inadequate Dose Optimization For PI3Ks
The issue of dose optimization, or lack thereof, for targeted cancer therapeutics has received heightened attention in recent months due to the safety woes of the phosphatidylinositol 3-kinase (PI3K) inhibitor drug class, which has seen the withdrawal of accelerated approval indications for four drugs. (Also see "PI3K Inhibitors: Overall Survival, Adverse Events And Dose Optimization Top US FDA’s Concerns" - Pink Sheet, 19 Apr, 2022.)
The FDA has said that adverse overall survival trends in randomized studies of the PI3K inhibitors indicate a safety issue resulting from extensive drug-related toxicities, and that sponsors of approved drugs in the class have done a poor job in identifying the optimal dose.
In April, the agency’s Oncologic Drugs Advisory Committee voted to require that further approvals of PI3K inhibitors for hematologic malignancies should be supported by randomized, rather than single-arm, studies. (Also see "PI3K Inhibitors For Hematology Indications Need Randomized Data, FDA Panel Says" - Pink Sheet, 21 Apr, 2022.)
The FDA used the ODAC meeting to publicly spell out its expectations for dose optimization studies under Project Optimus, including more comprehensive dose escalation studies with more patients and longer periods of observation, to be followed by randomized, parallel dose response trials and, potentially, inclusion of multiple doses as a part of a registration trial. (Also see "US FDA Uses PI3K Inhibitor Experience To Spell Out What It Wants In Dose Optimization Studies" - Pink Sheet, 29 Apr, 2022.)
Exposure-Response Analysis With PRO-CTCAE
It is clear the FDA also would like to see PROs incorporated into the dose optimization process, particularly to provide information about drug tolerability for patients.
Zirkelbach presented results from an exploratory evaluation of use of PRO and pharmacokinetic data for exposure-response analysis for a previously approved, oral cancer drug.
Developed by the National Cancer Institute, the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is an electronic-based system for patient self-reporting of symptomatic adverse events. It is derived from the CTCAE, which is a clinician-reported outcomes instrument. (Also see "Oncology Patient-Reported Outcomes Tool May Lead To Comparative Tolerability Claims" - Pink Sheet, 1 Feb, 2016.)
For several years now the FDA has been encouraging incorporation of the PRO-CTCAE into cancer clinical trials as a way to assess drug tolerability and side effects. The agency has tried to assuage industry concerns about how it will interpret the data in the context of a regulatory filing. (Also see "Compliance Concerns Slow Industry Uptake Of Cancer Patient-Reported Outcomes Tool" - Pink Sheet, 5 May, 2017.)
In June 2021, the FDA issued draft guidance aimed at better standardizing PRO assessments in cancer drug registrational trials, recommending that sponsors collect and separately analyze five core types of data. (See sidebar for story.)
However, the agency also believes PRO data should be collected throughout a drug development program, including in early studies where information on tolerability could inform the selection of doses to be examined in later-phase trials.
The aim of the retrospective analysis presented by Zirkelbach was to explore whether the PRO-CTCAE may be used to complement a standard exposure-response analysis for safety based upon clinician assessment using the CTCAE.
In a registration trial of an oral small molecule drug with 750 patients, the most common adverse event was diarrhea, and there was a significant exposure-response relationship between clinician-assessed diarrhea using CTCAE and drug exposure.
The exploratory analysis was based on a subset of 120 patients who had PRO-CTCAE, CTCAE and PK data, which allowed for an analysis comparing exposure-response relationships for diarrhea using both patient-reported and clinician-reported data, all within the same cohort.
While the CTCAE data were collected every three weeks through week 18, PRO-CTCAE data were collected weekly. This frequency provided three times more power to assess adverse events using the PRO-CTCAE versus standard clinician visits for safety follow-up, Zirkelbach said.
Zirkelbach showed separate exposure-response relationship plots for probability of diarrhea based on the CTCAE and the PRO-CTCAE results. Although there was an exposure-response relationship in both cases, the slope of the relationship was steeper, and the strength of the association appeared stronger, for the PRO-CTCAE data relative to the CTCAE data.
“This suggests that the PRO data may be more sensitive to identify this known exposure-response relationship for diarrhea in a small, 120-patient dataset compared to CTCAE diarrhea,” Zirkelbach said. She noted this could be due to the larger amount of data available with the PRO-CTCAE within the same treatment timeframe, or because patient responses have more range, particularly with the lower-grade events.
This small analysis showed that the PRO-CTCAE appeared more sensitive to detecting an exposure-toxicity relationship than the CTCAE for the same symptoms, she said. “This holds promise that the PRO data may be used to complement standard exposure-response analyses and potentially assist in dose selection decision-making through improved characterization of symptomatic AEs.”
A Call For Patient Preference Studies
Gregory Friberg, VP for medical affairs at Amgen, Inc., described the CTCAE as a “a fairly blunt instrument” primarily aimed at trying to determine if hospitalization is needed or if there is a potentially life-threatening toxicity, but which is relatively poor at distinguishing what is really going on with lower-grade adverse events.
These lower grade events can be incredibly bothersome to patients, impacting drug tolerability and leading to dose reductions and discontinuations.
Patient preference studies “is something that I think that we, as an oncology community, have to spend much more time understanding and incorporating.” – Medical oncologist Mace Rothenberg
In early-stage studies, such PRO data could be useful not just for gauging diarrhea over time, but also vision impacts, fatigue, asthenia, shortness of breath, or other adverse events that impact a patient’s independence or activities of daily living, Friberg said.
Mace Rothenberg, a medical oncologist and independent board member at Tango Therapeutics, Inc., Surrozen Inc. and Aulos Bioscience, Inc., said although the FDA’s exploratory analysis showed discordance between patient-report diarrhea and related distress, and physician grading of that adverse event, it is difficult to evaluate this finding in isolation absent a better understanding of how a patient views this side effect relative to others that may have a different impact on activities of daily living.
“I’ve been really surprised that we haven’t seen another measure of patient-centered effects, and that’s patient preference studies,” Rothenberg said. “This is something that I think that we, as an oncology community, have to spend much more time understanding and incorporating.”
Not Targeting The ‘Mythical’ Optimal Dose
Rothenberg raised some concerns about the agency’s push for early and more thorough dose optimization studies in cancer drug development.
He suggested stratifying the urgency for dose optimization based upon a drug’s therapeutic index, mechanism of action, class, urgency and unmet medical need, such that for potentially transformational drugs it would be acceptable to have some information gaps regarding optimal dose that could be filled in later.
However, Mirat Shah, a medical oncologist and clinical lead for Project Optimus, noted that OCE’s “Project Beyond Breakthrough” is looking at how dose optimization can be incorporated into development programs for breakthrough therapy drugs. (Also see "Picture Is Worth 1,000 Meetings: ‘Snapshots’ Could Support ‘Breakthrough’ Dialogue At US FDA" - Pink Sheet, 27 Sep, 2021.)
The agency also is developing guidance on cancer drug dose optimization.
Atik Rahman, FDA director of the Division of Cancer Pharmacology II, said a postmarketing requirement for dose optimization studies should not be considered as an option going forward.
“Conducting such trials is challenging, takes years to complete, doesn’t fully benefit the patients getting treated with the drug,” he said. “Generated information is sometimes inconclusive, and most of all it shows our failure in not progressing dose optimization in the preclinical setting and subjecting patients to unnecessary toxicity because of an inadequate dose.”
Rahman said the FDA looks forward to engaging with sponsors to facilitate dose optimization during drug development. The agency has met with sponsors at the pre-IND stage and developed a journalized questionnaire and points of view to share with sponsors as they embark on first-in-human trials evaluating PK and safety, he said. Every cancer drug development program should have a dose finding and optimization plan from the start, he added.
“We’re not trying to set some type of impossible standard to meet. We think therapies need to be more tolerable to patients when they get to the clinic. We think more dose characterization and dose optimization needs to happen up front.” – FDA’s Mirat Shah
Rothenberg also suggested that integrating dose optimization early in cancer drug development will be challenging because it will take longer than simply determining enough information exists to conclude that a dose has benefit-risk relationship that is acceptable, although perhaps not “optimal.”
The industry veteran said he was trained to study the fewest number of patients in Phase II that is necessary so that if a drug proved not efficacious, its development could be quickly halted with as few people as possible exposed to an ineffective dose.
“Now we have to recognize that we’re now whip-sawing the field to say, ‘No, more patients would be better, longer time would be better to allow us more certainty that we really nailed the optimal benefit-risk relationship when it goes into Phase III,” Rothenberg said.
Shah distinguished the agency’s focus on dose optimization from “an optimal dose.”
“It makes it seem like there’s this mythical pie in the sky, an optimal dose” for every drug that is the same for every patient, she said. “We’re not trying to set some type of impossible standard to meet. We think therapies need to be more tolerable to patients when they get to the clinic. We think more dose characterization and dose optimization needs to happen up front, and we do believe that we can achieve that without thousands and thousands of patients in Phase II clinical trials.”
“We think that by using the tools that we have, the science that we have, and making some modifications to the way we’re looking at how we select doses for oncology drugs, this is achievable, and it’s achievable before drugs get to the market,” Shah said.