The drug development process encompasses a series of phased clinical trials, typically categorized as phases 0 (optional), 1, 2, 3, and 4. Phases 0, 1, and 2 primarily serve for premarket assessment, while phase 4 focuses on post-marketing evaluation. Phase 1 and 2 trials are often referred to as 'early phase trials,' while phase 3 trials are known as 'late phase trials,' 'pivotal studies,' or 'confirmatory trials.' Notably, the Code of Federal Regulations (Title 21 pertaining to the FDA) does not explicitly describe each phase of clinical trials. Instead, it mandates 'adequate and well-controlled investigations' to substantiate effectiveness. The Code of Federal Regulations does require the specification in IND application form "Identification of the phase or phases of the clinical investigation to be conducted."
The reliance on phased clinical trials can lead to significant delays and cost escalation in the drug development process, potentially impeding timely access to innovative therapies for patients. To address this challenge, incremental innovations, such as adaptive (seamless) clinical trials and cohort expansion designs, have been explored to streamline clinical trial procedures.
The FDA's guidance for industry titled "Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence" acknowledges the evolving landscape. It emphasizes that confirmatory evidence regarding effectiveness may not solely derive from clinical trials but can also encompass other sources like natural history evidence, real-world data, and evidence from expanded access programs. In certain scenarios, the conventional phased approach to clinical development may not be universally applicable. Embracing a phaseless clinical development process may offer a more pragmatic and suitable alternative in specific contexts.
Phased Clinical Trials
In a previous discussion, we delved into the realm of phased clinical trials, exploring the sequential stages denoted as Phases 0, 1, 2, 3, and 4.
Seamless (phases) Clinical Trials
The concept of seamless phases in clinical trials involves the integration of two distinct phases, such as seamless phase 1/2 trials or seamless phase 2/3 trials. It's worth noting that the FDA's guidance document titled "Adaptive Designs for Clinical Trials of Drugs and Biologics" has evolved beyond the specific term "seamless design." Instead, it incorporates seamless elements within the broader framework of "Adaptations to Treatment Arm Selection." This approach encompasses not only dose selection but also the confirmation of efficacy for the selected dose within a single study.
When registering clinical trials on ClinicalTrials.gov, it is necessary to specify the phases of the trial. Categories such as "Phase 1/Phase 2" and "Phase 2/Phase 3" are utilized to denote seamless designs, reflecting the integration of multiple phases within a single trial protocol. There is no option for "Phase 1/Phase 3" and 'Phase 1/2/3'.
The utilization of expansion cohorts design has gained significant traction within oncology drug development and is now widely recognized as a specialized variant of seamless design. Pioneered by Merck and described in NEJM paper by Prowell et al. in 2016, this approach has garnered attention for its potential to streamline the development process for oncology drugs.
In 2022, the FDA released guidance specifically addressing the use of expansion cohorts, titled "Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry." This guidance outlines best practices for incorporating expansion cohorts into early-phase clinical trials, with the aim of accelerating the development of oncology therapies.
Studies employing expansion cohorts design may be categorized as "Phase 1/Phase 2" or "Phase 1/Phase 3" trials, depending on the primary objectives of the expanded cohorts. If the focus is on assessing anti-tumor activities, the study may be labeled as a "Phase 1/Phase 2" trial. Conversely, if the expanded cohorts are intended to evaluate efficacy endpoints, the study may be classified as a "Phase 1/Phase 3" trial.
In their 2018 paper "Advancing Clinical Trials to Streamline Drug Development," Bates et al. introduced a notable departure from the traditional clinical trial progression. Instead of adhering to the sequential phases of safety evaluation in Phase 1, efficacy assessment in Phase 2, and comparative efficacy testing in Phase 3, they advocated for the adoption of expansion cohorts. This innovative approach created what they termed a "continuum" or "phaseless" trial model, characterized by the seamless integration of various trial components through the use of protocol amendments and ongoing discussions with the FDA.
By embracing expansion cohorts and the phaseless trial concept, the drug development process could expedite the delivery of new therapies to patients. Moreover, this approach showcased the FDA's willingness to embrace flexibility and innovation in regulatory practices.
A particularly intriguing aspect of this "continuum" expansion cohort model is its circumvention of the conventional drug development paradigm and the intricate regulatory framework that often poses challenges for both investigators and regulators. This departure from the norm represents a significant shift towards a more agile and patient-centric approach to drug development, potentially opening avenues for greater efficiency and accessibility in the advancement of medical therapies.
Phaseless Drug Development Process
In certain contexts, traditional phased clinical trials may not be applicable, particularly in the development of therapies for ultra-rare diseases or in the realm of gene therapy. This divergence from the traditional paradigm has led to the emergence of the term "phaseless" to signify scenarios where the sequential numbering of clinical trial phases becomes less relevant.
There are two primary scenarios where the phaseless approach is observed:
Single-Trial Clinical Development: In this scenario, the entire clinical development program revolves around a single clinical trial, regardless of whether it would conventionally be labeled as phase 1, 2, or 3. Regulatory approval, such as a New Drug Application (NDA) or Biologics License Application (BLA), may rely on the data from this singular study, which can be supplemented by various other types of evidence outlined in FDA guidance documents.
An example of this approach is seen in the development of the first CRISPR-Cas9 gene-edited therapy by Vertex/CRISPR Therapeutics for severe sickle cell disease (SCD). FDA approval for this product was based on a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study.
Seamless Phase 1/2/3 Trials: Alternatively, a phaseless approach can involve the integration of all three traditional phases into a single seamless clinical trial. Pfizer/BioNTech's COVID-19 vaccine study serves as an illustrative example of this approach. Their study, labeled as phase 1/2/3, encompassed a randomized, placebo-controlled, observer-blind, dose-finding investigation to identify preferred vaccine candidates and dose levels in phase 1, followed by an expanded cohort and efficacy assessment in phase 2/3.
Phases of clinical trials become vague nowadays and there is a growing sentiment that the reliance on the numbered phases of clinical trials may become outdated and potentially misleading in the era of innovative trial designs. Instead, regulatory drug approval processes should prioritize the totality of evidence, which can stem from a combination of exploratory and confirmatory trial designs, as well as other sources such as natural history data, real-world evidence, expanded access studies, and animal models. In this context, the numbering of clinical trial phases becomes less crucial, emphasizing the need for a more holistic and adaptable approach to evaluating the efficacy and safety of medical interventions.
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