In 1992 the US FDA established the accelerated approval pathway for drug development as treatment options for serious or life-threatening conditions like cancer based on the effect the drug has on surrogate measures or an intermediate clinical end-point that could predict the real endpoint. However, these investigational drugs are subjected to post-approval confirmatory studies which would assess their actual clinical benefits [1, 2]. More recently, the FDA established the success of this pathway as only 5% of accelerated drug approvals were revoked or had been withdrawn over the last 25 years [3].
A range of trial designs have been used to supplement the accelerated approval for therapeutics though single-arm trial (SATs) designs have commonly been used in oncology. However, more recently per the US FDA, randomized control trials (RCTs) have demonstrated significant benefits over SATs as their use would address challenges that may have led to delays in confirming the clinical benefits of the therapeutic, thereby reducing clinical uncertainty for patients. RCTs may also address some of the limitations that are associated with SATs.
Limitations of SATs
Surrogate measures in oncology include progression-free survival, disease-free survival, time to tumor progression, response rate etc. Though the latter can easily be interpreted in SATs for monotherapy oncology drug regimens, there are certain limitations that are associated with SATs for supporting accelerated drug approval [4]. These include:
- Small safety databases preventing the detection of rare and potentially serious adverse events (AEs)
- Common time-to-event efficacy endpoints such as survival & tumor progression; the FDA considers these endpoints as inadequate for measuring efficacy in SATs
- Low-magnitude response rates, such as immunotherapy, may not predict clinical benefit
- Challenges in determining the effect of individual components of combination therapies/regimens
- Cross-trial comparisons to previous trials when determining if the effect of the observed treatment represents any improvement compared to available therapy. This is challenging as there may be differences in design, conduct, study population etc across trials which may not be easily discerned leading to inaccurate conclusions.
These are some examples of limitations associated with SATs that can add uncertainty when determining the safety and effectiveness of an oncological therapeutic. However, a RCT may address the limitations associated with SATs.
Benefits of RCT
According to the FDA, when properly planned and carried out, RCTs offer a more thorough assessment of efficacy and safety and permit direct comparisons to a concurrent control arm.
In previous trials where the response rate for the standard-of-care treatment was not evaluated in a population of interest, assessing the new treatment compared to the available treatment, in the same trial, gave a more accurate safety and efficacy representation for the standard of care in the same population. A RCT also facilitates comparisons of study populations in situations where the treatment landscape has changed considerably upon completion of the trial for the available therapy. Trials for accelerated approvals have been conducted in patients with refractory disease. However, a RCT may enable new drug evaluation in an earlier disease setting which allows access to the new drug earlier in the disease that would benefit the patient more. Furthermore, a RCT may enable assessment of potential regional differences for trials that span several geographic regions and enrolling international participants [4].
FDA Recommendations for RCTs
Indeed, the US FDA released a guidance document that outlined recommendations to anti-cancer or biologic therapeutic sponsors that highlighted some of the considerations they must take when designing trials that are intended for accelerated approvals of these therapeutics. It highlights ways in which available data and trial design can be improved to facilitate accelerated drug approval. The document covers considerations for RCTs for two situations:
- Sponsors choosing to conduct 2 separate RCTs where one trial with an early endpoint would support accelerated approval and the second trial would support a longer-term clinical endpoint or overall survival to verify clinical benefit. The FDA requires the second trial to be well underway at the time of accelerated approval.
- Sponsors choosing to conduct one single RCT to support accelerated approval as well as for verifying the clinical benefit.
One-Trial Method for Accelerated Approval
According to the FDA, for the “one-trial” method, the trial needs to be carefully structured based on early data to make sure that the chosen endpoints can be assessed both short- and long-term to demonstrate therapeutic benefit in both stages.
An advantage of the “one-trial” method is that a separate confirmatory trial may not be required. However, sponsors choose a SAT for accelerated approval and the FDA requires a post-marketing trial to assess progression-free survival or overall survival, a separate RCT may be required. Essentially, a one-trial approach may not necessitate for separate clinical trials as longer- term follow-up in the same trial would fulfil post marketing requirements that are required to verify clinical benefit.
Conclusion
Accelerated cancer drug approval can affect public health in both positive and negative ways. It can speed up access to treatments that might save lives, but it also emphasizes the need for ongoing drug monitoring and could have financial repercussions for patients and healthcare systems. The accelerated approval process can reduce the time it takes for a new cancer drug to reach patients, which can be particularly beneficial for patients with limited treatment options, especially those that may have exhausted all available treatments and may be facing a poor prognosis, so the availability of a new drug can provide them with hope and potentially extend their life.
The use of RCTs has demonstrated significant benefits compared to SATs, particularly for “one-trial” RCTs in which a separate confirmatory trial may not be needed. This addresses some of the challenges associated with SATs in delaying verifying the clinical benefits for a given cancer therapeutic.
References and Further Reading:
[1] US FDA. Title 21 Part 601.41 Approval based on surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. United States Food and Drug Administration. 1992
[2] Kepplinger, Erin E. “FDA’s expedited approval mechanisms for new drug products.” Biotechnology law report 34, no. 1 (2015): 15-37.
[3] Beaver, Julia A., Lynn J. Howie, Lorraine Pelosof, Tamy Kim, Jinzhong Liu, Kirsten B. Goldberg, Rajeshwari Sridhara et al. “A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review.” JAMA oncology 4, no. 6 (2018): 849-856.
[4] US FDA. Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics. United States Food and Drug Administration. 2023