Patients’ Voices Largely Absent From FDA Reviews of New Cancer Drugs – Renal and Urology News

More and more clinical trials of cancer drugs involve assessments of patients’ views on how treatments are affecting them. The US Food and Drug Administration (FDA) encourages the gathering and reporting of these patient-reported outcomes (PROs), which offer insight into the patient experience without biased interpretation by investigators. Still, PROs for cancer drugs are frequently absent from marketing approval requests submitted to the FDA, or they are inadequate. Recent studies have found that the FDA approves many novel cancer drugs without PROs, so these medications reach the market without patients’ perspectives on how these products influenced their quality of life.

A study presented at the American Society of Clinical Oncology’s 2023 annual meeting by investigators at Howard University in Washington, DC, revealed that less than half of 420 pivotal trials leading to FDA cancer drug approvals from 2006 to 2022 included PRO assessments.¹ Another study, published in 2023 in Supportive Care in Cancer,² showed that of 59 unique cancer drugs approved from 2013 to 2022 via the FDA’s accelerated approval pathway, only 59% included PRO assessments in the clinical trials. The investigators concluded that “PRO measurements are inconsistently utilized in trials leading to initial accelerated approvals of oncology drugs, and there seems to be a lack of harmonization of different PRO measurement tools across trials.”

In another study, investigators who reviewed transcripts from 27 meetings of the FDA’s Oncology Drugs Advisory Committee (ODAC) from 2016 to 2021 found that PRO-related topics were mentioned in only 12, according to a report in JCO Oncology Practice.³ Of those, ODAC reviewers were satisfied with PRO assessments in only 2.

“During ODAC meetings, committee members and FDA reviewers expressed frustration at the lack of PROs captured in clinical trials for cancer treatments,” authors Ari Gnanasakthy, MBA, MS, and colleagues concluded.“Less than half of evidence packages for cancer treatments submitted for FDA review included PROs. Even when PROs were included in evidence packages, the PROs were rarely deemed adequate for benefit-risk assessments.”

They added: “Lack of credible PRO data in oncology clinical trials prevents regulators from making comprehensive and accurate assessments of the benefits and risks of new cancer treatments. Clinicians and patients, therefore, are forced to choose among treatment options without understanding the experiences of patients who were treated with these options.”

Influence on Formularies

Lack of PROs could adversely affect decisions about which medications are placed on health plan formularies and thus covered by insurance. A survey of health plan representatives (90% pharmacists, 56% pharmacy administrators) found that 78% of the 106 respondents thought PRO evidence is useful for providing additional context for safety of oncology therapies. In addition, 47% suggested that formulary reviews would be at least somewhat influenced by a lack of PRO evidence from oncology clinical trials.

“US payers view PRO evidence from both clinical trials and real-world studies as useful for supplementing traditional clinical trial data when making oncology formulary decisions and for refining treatment pathways and care delivery models,” investigators Gary Oderda, PharmD, MPH, and coauthors concluded in a 2022 paper in the Journal of Managed Care & Specialty Pharmacy.⁴ “Manufacturers of oncology therapies should collect and consider leveraging PRO evidence from both settings when engaging with US payers.”

Primacy of Objective Data

Although PROs, which are subjective, can provide FDA reviewers with additional information to consider, objective data must be the foundation for evaluating a drug except in cases in which a drug’s effectiveness can only be evaluated using PROs, said Peter Lurie, MD, MPH, President and Executive Director at the Center for Science in the Public Interest in Washington, DC, and former Associate Commissioner for Public Health Strategy and Analysis at the FDA.

For example, in clinical trials of pain drugs, investigators have to rely on PROs to gauge effectiveness because changes in pain perception in response to treatment are subjective. This is not the case with diseases such as cancer for which objective measures are available, Dr Lurie said. Those measures, and not patient opinion, must provide the basis for approval. Cancer drugs “should not be coming onto the market because the majority of patients think the drugs work for them,” he said.

Dr Lurie asserted, “Encouraging assessment of PROs is definitely a good idea; making it a required part of the primary assessment of safety and efficacy probably is not.”

The American Society of Clinical Oncology said in an emailed statement that it “recommends that trialists consider including attributes of accessible and equitable research, such as patient-reported outcomes, in the design and conduct of all clinical trials, as understanding how patients are affected by a therapy is paramount.”

FDA’s Efforts

Through its Patient-Focused Drug Development initiative established in 2012, FDA has been working to improve data collection and reporting in clinical trials. As part of that effort, the agency issued 2 guidance documents in November 2023: “Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory” and “Submitting Patient-Reported Outcome Data in Cancer Clinical Trials.” The primary goal is to incorporate the patient’s voice in the drug development and evaluation.

“PROs play an important role in assessing the patient experience with a medical product, and can provide valuable evidence for regulators, payers, and health system administrators,” the agency said in an email. “FDA is working collaboratively to increase appropriate use and increase the value of PROs as evidence in regulatory decisions and for other, non-FDA purposes.”

The agency added, “In premarket studies, the patient perspective and experience are often complementary to clinical and other biological measures when evaluating the safety and effectiveness of candidate medical products.”

In the agency’s view, PROs are already having a positive impact on the product approval process. “The existence of well-established and researched PROs has benefited the ability to make regulatory decisions directly related to patient impact,” the agency wrote. “The development and continued research on PROs facilitated through FDA guidance efforts benefits FDA’s ability to include patient’s perspectives in meaningful ways.”

Studies demonstrate an increase in PRO assessments in clinical trials. The proportion of clinical trials registered with the ClinicalTrials.gov website that included use of 1 or more PRO measures rose from 14% during 2004-2007 to 27% in 2007 to 2013, according to separate studies.^5,6 A review of PRO assessments in phase 1 oncology clinical trials registered in the same website found that the proportion of trials using 1 or more PRO measures rose from 0.6% of trials initiated prior to 2000 to 3.4% of trials initiated from 2015 to 2019, investigators reported in Oncology.⁷

PRO Reporting Issues

Amid the rise in PRO assessments in trials, shortcomings in PRO data reporting, such as delays in publication, have become apparent, as demonstrated in a review of 40 pivotal clinical trials leading to the approval of 40 genitourinary (GU) cancer drugs from February 2007 to July 2022. PRO data was published for 27 trials (67.5%). Of these, 4 (15%) included preliminary PRO results in the primary publication of clinical data, a team led by Jad Chahoud, MD, MPH, of H. Lee Moffitt Cancer Center in Tampa, Florida, concluded in a 2024 paper published in eClinicalMedicine.⁸ For 23 studies, PRO results were reported in a secondary dedicated paper. The median time from primary publication of results to publication of the corresponding secondary PRO data was 10.5 months.

Moreover, the investigators identified problems with the quality of PRO reporting as assessed using the PRO Endpoint Analysis Score (PROEAS), a scale with 24 items describing some aspect of PRO reporting and analysis. A score of 1 is assigned to an item that is clearly reported, and a score of 0 is assigned to an item that is unclear or not reported. Of 30 randomized controlled trials in the study’s dataset, 20 reported PRO data in a dedicated secondary manuscript. The median PROEAS score for the 20 trials was 11.1 out of 24.

“Low overall PROEAS score and delays in PRO data publication in GU cancer drug trials conducted in the past decade emphasize the need for improvement in quality of design and conduct of PRO endpoint in future trials and accelerated publication of PRO endpoints, using standardized analysis, and prespecified hypothesis driven endpoint,” Dr Chahoud and colleagues wrote.

PROMIS

Many of the PRO measures used in clinical trials in recent years are products of the Patient-Reported Outcomes Measurement System (PROMIS) initiative launched in 2004 by the National Institutes of Health to develop and strengthen PRO measures for use in research and clinical settings. PROMIS has developed more than 300 measures of physical, mental, and social health designed to be relevant across all conditions for the assessment of symptoms and functions. “PROMIS is now the gold standard for patient-reported outcome (PRO) measurement,” Edward Haksing Ip, PhD, of Wake Forest University in Winston-Salem, North Carolina, wrote in a 2021 editorial accompanying a special edition of Psychometrika focusing on lessons learned from PROMIS.

PROs Not Always Appropriate

Despite the potential usefulness of PROs in the drug approval process, efforts to assess them might not be relevant or appropriate for all clinical trials. “PROs have an important role and should be considered in most drug trials, but may not be appropriate in every setting,” medical oncologist Tomasz M. Beer, MD, who has participated in numerous clinical trials, said in an interview. He added that “while PROs are an invaluable tool to better understand the patient experience, like any important outcome measure, they should be used when clinically and scientifically indicated. That is often, but not always.”

He pointed out that PRO assessments may be unwarranted when a trial is of insufficient size (as with a small pilot study) to enable meaningful measurement of PRO end points, or when the PRO effect of a particular drug treatment has been robustly evaluated and is well understood. “These are circumstances where a requirement for PROs may not add value,” said Dr Beer, Chief Medical Officer for Multi-Cancer Early Detection at Exact Sciences in Madison, Wisconsin, and adjunct professor of medicine at Oregon Health & Science University’s Knight Cancer Institute in Portland.

Another consideration is limited resources. “It is also important to remember that adding elements to studies increases the burden on participants, study staff, and costs to sponsors,” Dr Beer explained. “We have a responsibility to be thoughtful about when an element adds value and when it does not add meaningful value. Adding cost, complexity, and burden can have undesirable consequences that are not always visible, for example, fewer resources for other important features of the study, for outreach, or even smaller study sample sizes than might otherwise have been possible.”