Barriers to Confirmatory Trial Enrollment Present Unique Hurdles for Accelerated Approvals

There can be no legitimate debate regarding the importance of well-designed and conducted clinical trials in defining the optimal cancer care delivery paradigm. Oncologists are encouraged in their training to consider patients for such research studies, and survey data have indicated a high level of interest for participation among patients.

Published studies have also suggested that participation in clinical trials may be associated with more favorable clinical outcomes, but objective interpretation of such research efforts is difficult due to the inherent selection bias associated with restricted study entry eligibility criteria.¹

Despite these favorable comments and interest in clinical trials, the objective fact is that a distressingly low percentage of patients with cancer, in the range of 2% to 4%, are enrolled in clinical investigative efforts. Further, it is increasingly recognized that cancer study participants are, in general, poor representatives of the real-world population of individuals who may receive the therapeutic should it leave the realm of investigative medicine and enter routine clinical practice.^2,3 Thus, one may reasonably question the objective success of a core tenant of clinical research in the cancer domain, the development of generalizable data.

Further, there has been concern expressed by individuals, including governmental regulators and several academics, regarding the status of requirements to enter patients into mandated studies. A recently published commentary in the Wall Street Journal captures this issue.⁴ The article highlights efforts by the FDA to ensure pharmaceutical companies with agents that achieve accelerated approval complete mandated follow-up studies in a timely manner. The article reports that “nearly half of the drugs given accelerated approval through the end of 2020 had yet to prove their benefit, according to a study published in the BMJ medical journal last year.”^4,5

As a result, the FDA has put additional requirements on the companies for confirmatory trials, which are generally randomized studies. In 1 case cited in the article a representative from the company said the FDA required full enrollment before the accelerated approval was granted.⁴ Unfortunately, absent from this discussion was the question of why patients should agree to participate in such studies if their sole purpose is to fulfill a regulatory requirement, when in fact, the patient and the treating physician may believe sufficient evidence already exists regarding clinical benefit to justify use of the agent.

In a commentary published more than 30 years ago in the New England Journal of Medicine by the eminent oncologist, Samuel Hellman, MD, the dilemma of physician encouragement of patients with cancer to participate in a randomized therapeutic trial is clearly articulated.⁶ The title of the manuscript, “Of Mice but Not Men: Problems of the Randomized Clinical Trial,” provides a simple and powerful summary of the critically relevant perspective.⁶

Hellman writes, “The physician, by entering into a relationship with an individual patient, assumes certain obligations, including the commitment always to act in the patient’s best interests…. The role of the scientist is quite different—ie, determining the validity of [a] formally constructed hypothesis. Such scientific information, it is presumed, will benefit humanity in general…. What the physician thinks, suspects, believes, or has a hunch about is assigned to the ‘not knowing’ category, because knowing is defined on the basis of an arbitrary but accepted statistical test performed in a randomized clinical trial. Thus, little credence is given to information gained beforehand in other ways or to information accrued during the trial but without the required statistical degree of assurance that a difference is not due to chance. The randomized clinical trial requires doctors to act simultaneously as physicians and as scientists. This puts them in a difficult and sometimes untenable ethical position….If the physician has no opinion about whether the new treatment is acceptable, then random assignment is ethically acceptable…. If the physician has no preference for either treatment (is in a state of equipoise, then randomization is acceptable. If, however, he or she believes that the new treatment may be either more or less successful or more or less toxic, the use of randomization is not consistent with fidelity to the patient.”⁶

And in the setting of a previously granted accelerated approval for a novel antineoplastic agent even the FDA has agreed there is sufficient evidence of clinical benefit to justify the drugs delivery outside the confines of an investigative study.

From the perspective of a patient with cancer who finds themself in a life-threatening situation, the bureaucratic language surrounding the regulatory structure of a confirmatory trial may not unreasonably be considered pure gibberish. Why should they be required to participate in such a study and potentially be randomized when existing data suggest the inferiority of a standard-of-care study arm?

Finally, it is appropriate to inquire: If there is sufficient evidence for the FDA to grant accelerated approval to permit patients to potentially benefit from an antineoplastic drug’s administration, then what is the ethical justif ication for delaying the approval process until accrual into a confirmatory trial is complete? Perhaps it is time for the FDA to provide more clarity on the process requirements for agents on the pathway.

As I noted in a commentary published 20 years ago, there will always be an understandable natural tension between an oncologist who serves the role of a patient’s personal physician but who also performs the function of a clinical investigator.⁷ Occasions that may hinder these relationships include opportunities to author a peer-reviewed article or present the results of a study at a regional, national, or international meeting; receive an academic promotion; complete a required component of a research grant; or even receive direct financial renumeration for entering patients into trials. At both a personal and organizational level, potential conflict of interests must be recognized and guarded against.

It appears we must add to this list the willingness of a physician to ask, or even strongly encourage, a patient to agree to become a research subject in a regulatory-mandated confirmatory trial, despite sufficient objective evidence of clinical benefit already reported to permit designation of accelerated approval.

Maurie Markman, MD, is president of Medicine & Science at Cancer Treatment Centers of America, a part of City of Hope.

References

1. Engelbak Nielsen Z, Eriksson S, Schram Harsløf LB, et al. Are cancer patients better off if they participate in clinical trials? A mixed methods study. BMC Cancer. 2020;20(1):401. doi:10.1186/s12885-020-06916-z
2. Abi Jaoude J, Kouzy R, Mainwaring W, et al. Performance status restriction in phase III cancer clinical trials. J Natl Compr Canc Netw. 2020;18(10):1322-1326. doi:10.6004/jnccn.2020.7578
3. Hershman DL, Wright JD, Lim E, Buono DL, Tsai WY, Neugut AI. Contraindicated use of bevacizumab and toxicity in elderly patients with cancer. J Clin Oncol. 2013;31(28):3592-3599. doi:10.1200/JCO.2012.48.4857
4. Whyte LE. FDA takes a tougher line. Wall Street Journal. December 5, 2022. Accessed January 13, 2023. bit.ly/3ZAhSnZ
5. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898. doi:10.1136/bmj.n1898
6. Hellman S, Hellman DS. Of mice but not men. Problems of the randomized clinical trial. N Engl J Med. 1991;324(22):1585-1589. doi:10.1056/NEJM199105303242208
7. Markman M. The needs of science vs the needs of patients: ethical concerns in cancer clinical trials. Cleve Clin J Med. 2003;70(12):1008-1016. doi:10.3949/ccjm.70.12.1008