Randomized clinical trials (RCTs) are widely recognized as the gold standard for clinical and regulatory decision-making. Indeed, RCTs would be required in most cases, in particular when modest activity/efficacy is expected or when there is a poor understanding of the safety profile. Other reasons include the disease's poorly understood natural course, high heterogeneity, suboptimal biomarker strategy, and the presence of effective therapies. However, RCTs may not always be feasible due to factors such as the rarity of the patient population, lack of equipoise after compelling early clinical trails results or difficulty in recruiting patients, especially when competitors are developing a similar medicinal product for the same small target population.
The traditional single-arm trial (SAT) with typically fewer than 100 patients may not always be a suitable alternative, particularly when isolating the drug's effect is challenging. The latter may occur in several circumstances. For instance:
When taking this concept to the extreme, certain, often rare, patient populations could remain underserved. This may happen either because obtaining comparative data would take an unreasonably long time or because single-arm data may not be considered direct evidence of clinical benefit. Such situation would be undesirable. However, necessity is the mother of innovation and even a quick internet search will reveal the plethora of alternative/innovative study design options and listings with pro- and con- considerations to each and everyone of them.
The common denominator of all advice is: know the product and the disease you want to study inside and out, define the study aim, plan the conduct of the study and data analysis far ahead and know where to find the right patients. That may sound easy but such knowledge should also be placed in the framework of regulatory requirements at set by e.g. FDA and EMA.
Both the FDA and EMA aim to provide guidance on the utilization of single arm trials for regulatory decision-making1 2. Importantly, in addition to understanding the concerns regulators have with single arm trials, getting insight into when a single arm trial would potentially be acceptable as pivotal evidence for regulatory decision-making is key for planning the overall drug development plan. Currently the FDA's draft guidance provides more comprehensive direction compared to the EMA draft reflection paper on this topic, even though both recommend consulting the respective agencies before initiating a pivotal SAT. A minimum result of the development of these guidance documents should be that the final versions are aligned on key considerations as to the role of SATs in regulatory decision-making3, which should best also include directions on the use of external control arms.
An article by FDA published last year analysing what role external control arms had and may have in regulatory decision-making concluded that such have not been accepted yet as a source for formal comparative data allowing for effect size estimation, but rather as a tool to provide context informing on the natural course of the disease or interpreting of the single arm trial results as being direct evidence of clinical benefit. General concerns limiting the use of such SAT data were related to methodological aspects, in particular the unquantifiable impact of unknown prognostic factors and selection bias4.
Various approaches can expand and strengthen SAT data. These pertain to replication of the SAT results with an independent, similar single arm cohort or conducting a confirmatory RCT in the same treatment setting. The latter should however be well underway at the time of marketing authorisation approval to maintain equipoise. For both strategies FDA and EMA precedents are available. Another alternative involves incorporation of more sophisticated methodological tools, such as the synthetic control arm, in which the external control arm is constructed based on weighted combination of groups used as controls to which the treatment group is compared. The acceptability of such approach for regulatory decision-making is much dependent on the validity and quality of trials, which need to be critically appraised beforehand5. Importantly, when done in a prospective manner this approach would gain impact significantly, as is also recognised by the EORTC6.
In addition to strengthening single arm trial data for regulatory purposes, the use of synthetic controls can also be used in combination with an unequal randomisation in favour of the experimental arm. This hybrid approach would enhance the feasibility of an RCT, increase the statistical power of a randomized controlled study, and thereby facilitate benefit-risk assessment, as well as health technology assessment, particularly in rare disease settings.
With such rapidly evolving opportunities, not even mentioning the impact which expanding utilisation of the digital health care space may bring about7, timely requesting regulatory advice on the best trial design option for your product and development plan is pivotal. This would best include as to what extent new technology and statistical methods can be of help in unleashing previously unexplored opportunities for data collection to support your drug development plan.
At ProPharma we continue to keep abreast of the latest global regulatory and scientific developments and look forward to working with clients to maximise opportunities in the rare disease space. By providing tailored support, our experts will not only streamline the path to approval but also champion the advancement of innovative therapeutic approaches with the potential to redefine the future of rare diseases.
Ready to explore innovative trial designs and navigate the future of clinical research? Join us at ProPharma and accelerate your path to success in rare disease therapies. Contact us today to learn more!