The Vital Role of Regulatory Strategists, Biostatisticians, and Clinicians in Protocol Development

Recently, there’s been a growing focus on using single-arm trials as primary evidence for drug authorization in the European Union (EU). Given this, the role of regulatory strategists in shaping the trial protocol has gained significant importance. These strategists help ensure the trial design and execution provide the right evidence needed for drug approval.

This post sheds light on the crucial roles of regulatory, clinical, and statistical experts in formulating the protocol for single-arm trials. We’ll particularly reference the guidance provided by the European Medicines Agency (EMA) concerning single-arm trials as pivotal evidence for drug authorization in the EU.

Earlier this year, a guidance document was released. It underscores the essential role of regulatory strategy in making sure that single-arm trials comply with all regulatory standards and guidelines.

When Are Single-Arm Trials Utilized?

The EMA recently initiated a public review of this guidance document. This is a landmark move for medicine regulators, marking the debut of a guidance document offering a detailed look into the factors and hurdles linked with this kind of clinical trial.

Randomized clinical trials (RCTs) stand out as the benchmark for producing evidence that regulatory bodies require to evaluate the effectiveness and safety of a new medicine. In RCTs, patients get randomly placed into either the treatment group or the control group. These trials involve a substantial number of participants to deliver strong data on a treatment’s success.

But there are specific sectors, like rare diseases and particular rare cancers, where the target audience for new drugs is limited. In these scenarios, some marketing authorization applications presented to the EMA have clinical data from single-arm trials as their core evidence.

The Emergence of Single-Arm Trials

Single-arm trials are specialized clinical trials where every participant undergoes the same treatment, typically a drug under investigation. These kinds of trials come into play mainly when there’s no known effective standard of care, or the existing standard doesn’t work well.

While single-arm trials offer insightful details on the safety and efficiency of new medications, they also introduce distinct complexities in both their design and the analysis of their data.

The Critical Role of Regulatory Strategists in Protocol Development

The recent guidance from the EMA underscores the essential role regulatory strategists play in shaping the protocol for single-arm trials. It stresses that the expertise of regulatory professionals in designing the protocol is paramount. This ensures the trial design is suited to the specific drug under examination and aligns with all regulatory standards and guidelines. Their involvement guarantees that the conducted trial generates the vital evidence needed for a drug’s approval.

Key Challenges in Single-Arm Trials

One primary obstacle in single-arm trials is the lack of a control group. This absence complicates determining the genuine impact of the drug under scrutiny.

Regulatory strategists can offer solutions to this problem. They might suggest designing single-arm trials that integrate alternative types of controls, like historical benchmarks or simultaneous observational studies. By doing so, these controls can augment the evidence stemming from the single-arm trial, thus bolstering the trustworthiness of its outcomes.

Bias presents another hurdle in single-arm trials, given that both the patients and the researchers know the treatment being given. Using blind protocols can help mitigate this bias, enhancing the dependability of the findings.

EMA Guidelines on Single-Arm Trials

The EMA’s guidelines suggest that single-arm trials implement a solid statistical analysis plan, one that aptly tackles the heightened uncertainty inherent in single-arm studies. With the expertise of biostatisticians, these plans can be crafted and carried out, ensuring the results are statistically significant and apt for backing drug approval.

To interpret the results of single-arm trials (SATs) accurately, knowledge from general disease data or clinical evidence is essential. The guidelines underscore the need to detail the use of such external data in the study’s protocol beforehand.

It’s also vital to limit bias throughout the various phases, from the trial’s design and conduct to analyzing and reporting its outcomes.

Trial sponsors are encouraged to refer to multiple guidance documents when shaping these trials. This includes the International Council for Harmonisation (ICH) directives on clinical experiments, statistical principles, and selecting a control group for clinical trials. The EMA’s human medicines committee, CHMP, took on board the reflection paper, with insights from other committees.

Both US and EU regulatory bodies are now open to endorsing drugs based on single-arm studies in certain specific scenarios. For instance, Novartis’s Zolgensma secured approval in the EU, backed by single-arm studies and real-world evidence. In the US, several approvals for specific cancer treatments in 2021 hinged on non-randomized, single-arm trials with interim endpoints.

Although the FDA promotes randomized clinical trials when giving expedited approval to new cancer treatments, it acknowledges the value of single-arm trials in select contexts. Stakeholders have until September 30 to provide feedback on the EMA’s reflection paper, and this input will shape the final document anticipated in 2024.

Ensuring Quality and Adherence in Single-Arm Trials

Maintaining quality and ensuring adherence to regulations are pivotal when conducting single-arm trials. Quality and compliance services play a central role in making certain that trials are in line with regulatory stipulations and that the gathered data stands up to the highest standards. This encompasses conducting the study in accordance with Good Clinical Practice (GCP) directives. Moreover, it’s essential to have rigorous quality control procedures set up to curb mistakes and bias in the data.

For a deeper understanding of how MMS can bolster your single-arm trials via regulatory strategy, protocol creation, data management, and quality plus compliance services, kindly explore our website or reach out at info@mmsholdings.com.

Authored by: Luther Sampson, Principal Regulatory Strategist.