Oncology Drug Regulation Faces an Uncertain Future

Oncology Live®Vol. 22/No. 22
Volume 22
Issue 22

Maurie Markman, MD, discusses how agency leaders should be encouraged to improve regulatory science, include a patient’s perspective in approval decisions, reduce unnecessary bureaucracy and costs associated with the conduct of trials, and accelerate the overall review process for drug approval.

Maurie Markman, MD

Maurie Markman, MD

The stunningly successful rapid development of safe and effective vaccines to combat COVID-19 sends an encouraging message that industry, sometimes with the support of government agencies, can quickly create agents that are of unquestionable benefit for mankind. The message underscores the potential for pharmaceutical developments in a wide range of human illnesses.1

The basic, translational, and clinical science activities conducted over the past 2 years that led to the development of the vaccines and potentially novel medications to treat active COVID-19–related illness must be lauded. However, formidable challenges ahead also must be acknowledged. Perhaps most concerning is that scientists are being attacked across the globe for stating their views regarding the evolving evidence related to the pandemic.2

It has been widely reported that Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases received death threats that resulted in a security detail being assigned to Fauci and his family.2 In a survey of more than 300 scientists conducted by Nature, 15% reported receiving death threats.2 The potential negative effects associated with social media–generated activity on open scientific discourse cannot be overstated.

Further, the political atmosphere in the United States has made essential coordinated efforts by public health agencies problematic. For example, it is more than 9 months into the new presidential administration and a permanent director for the FDA still has not been appointed.

This may have contributed to less-than-optimal timely review of critical COVID-19–related decisions, impaired public communication efforts, and confusing regulatory decisions, such as the widely disputed approval of the Alzheimer disease drug aducanumab (Aduhelm).3

Changing the Status Quo

The FDA will be confronted with major challenges in the coming years, including some that the agency has internally identified. Examples include evidence that the magnetic fields of smartphones and smartwatches may interfere with pacemakers and cardiac defibrillators4 and concerns that clinical trials of innovative surgical tools being explored in cancer care (eg, robotically assisted surgical devices for mastectomy) may not adequately examine essential issues of patient safety.5

The FDA Oncology Center of Excellence Scientific Collaborate is working to focus the efforts of the agency on both current and future needs of patients with cancer and on maintaining awareness of the rapidly evolving and often increasingly complex science.6 Particularly noteworthy are defined plans in precision oncology, pediatric cancers, rare cancers, oncologic safety, patient-focused drug development, and innovative trial designs.

The FDA will need to continue to confront the reality that treatment is being increasingly based on defining relevant driver molecular pathways rather than the site of origin of the cancer or the histological subtype. For example, if a drug with molecularly inhibitory effects demonstrates high clinical activity in resistant metastatic tumors from the breast, will investigators need to demonstrate the same degree of clinical activity of the agent in a clinical trial for other tumors with the identical resistant cancer phenotype?

Similarly, it is likely that molecularly defined resistance mechanisms rather than site of origin–based treatment programs will comprise a major component of pharmaceutical anticancer agents up for regulatory approval. Apart from the widely recognized mechanisms of resistance, the FDA also will need to consider efficacy outcomes against smaller subsets of well-characterized resistance mutations (eg, rare EGFR mutations).7

What's Next for the FDA?

The FDA will need to consider the future of several areas of clinical trial design. These include the requirement of an objectively meaningful study control arm, the potential need to permit crossover from the control to the investigative regimen at the time of disease progression, and relevant or acceptable study end points for regulatory approval. Additionally, the agency should recommend the enrollment of individuals who represent appropriate patient populations with the malignancy—elderly patients, patients with common clinically relevant comorbidities, and patients from varied socioeconomic and ethnic groups. In terms of safety analysis for investigational and maintenance therapies, investigators should evaluate the effect of low-grade adverse events on patient quality of life until documented disease progression.

Finally, it is relevant to note the pushback the FDA faces from those who challenge the current approach to trial design leading to regulatory approval,8 and also to note the clinical value of examining real-world outcomes vs the typical nonreal-world participants whom are often enrolled in cancer clinical trials.9

As cancer becomes treated in a number of settings as a serious but chronic condition, the objective of investigators to demonstrate an improvement in overall survival becomes increasingly problematic. In this clinical scenario, patients may receive several therapies after experiencing disease progression, 1 or more of which may favorably affect an individual’s survival.

Despite the complexity of the task, the role of the FDA in the cancer arena has never been more relevant. Agency leaders should be encouraged to improve regulatory science, include a patient’s perspective in approval decisions, reduce unnecessary bureaucracy and costs associated with the conduct of trials, and accelerate the overall review process for drug approval.


  1. Barda N, Dagan N, Ben-Shlomo Y, et al. Safety of the BNT162b2 mRNA Covid-19 vaccine in a nation-wide setting. N Engl J Med. 2021;385(12):1078-1090. doi:10.1056/NEJMoa2110475
  2. Scientists under attack and weird viruses – the week in infographics. Nature. Published online October 15, 2021. Accessed October 20, 2021. https://www.nature.com/articles/d41586-021-02817-8
  3. Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA approval of aducanumab. N Engl J Med. 2021;385(9):769-771. doi:10.1056/NEJMp2110468
  4. Seidman SJ, Guag J, Beard B, Arp Z. Static magnetic field measurements of smart phones and watches and applicability to triggering magnet modes in implantable pacemakers and im-plantable cardioverter-defibrillators. Heart Rhythm. 2021;18(10):1741-1744. doi:10.1016/j.hrthm.2021.06.1203
  5. Update: caution with robotically-assisted surgical devices in mastectomy: FDA safety communica-tion. FDA. August 20, 2021. Accessed October 22, 2021. bit.ly/3aZJxH9
  6. Schneider JA, Gong Y, Goldberg KB, et al. The FDA Oncology Center of Excellence Scientific Collaborative: charting a course for applied regulatory science research in oncology. Clin Cancer Res. 2021;27(19):5161-5167. doi:10.1158/1078-0432.CCR-20-4429
  7. Cho JH, Lim SH, An HJ, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multi-center, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol. 2020;38(5):488-495. doi:10.1200/JCO.19.00931
  8. Shen C, Ferro EG, Xu H, Kramer DB, Patell R, Kazi DS. Underperformance of contemporary phase III oncology trials and strategies for improvement. J Natl Compr Canc Netw. 2021;19(9):1072-1078. doi:10.6004/jnccn.2020.7690
  9. Boyle JM, Hegarty G, Frampton C, et al. Real-world outcomes associated with new cancer medicines approved by the Food and Drug Administration and European Medicines Agency: a retrospective cohort study. Eur J Cancer. 2021;155:136-144. doi:10.1016/j.ejca.2021.07.001
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