By Peter Embley, BSc. (Hons), Dip.Reg.Aff, FTOPRA INSEAD

Emerging biotech and biopharma companies spend precious time and money on discovering and rapidly building scientific evidence to support the safety and efficacy of their compounds. Such resources are somewhat limited and focused on near-term activities. In doing so, they are often unaware of or undervalue the importance of getting early regulatory guidance on long-range development strategies. The regulatory step maybe perceived as a compliance step rather than a mechanism to add value to the program. 

In the context of this article, a regulatory strategy (RS) is defined as the crucial issues that are required to be practically discussed with regulatory authorities to transpose the steps of the regulatory approval process into the product design and program milestones. It is prudent to develop an RS before clinical trials are initiated; companies first need to understand the regulatory landscape, such as identifying relevant local and regional guidelines, engaging with important stakeholders, considering emerging policies, and heeding the relevant precedents.

An RS can determine the fastest and/or greatest value path to market for the program and can be developed in one of three ways: an RS to focus on a specific region (e.g., EU), a sequential RS for each region, or a single, composite RS that considers all regulatory requirements and pathways of each region. The focus of this article is on the last scenario, where an RS may be aligned, effectively merged, to be applicable to at least two regions.

Achieving an aligned RS for two regions may be a challenge. Factors such as the complexity of product, epidemiology, and expected value/cost price may differ significantly between the regions. The degree of complexity may be considered at an early stage in the development of the RS, and the consensus may be to develop an independent RS for each region. However, a single aligned RS for two regions provides significant benefits to the developer in terms of cost/timelines and, ultimately, benefits more patients.

This article suggests an approach for aligning an RS for the U.S. and EU regions.

Approach To Alignment 

To reiterate, achieving an aligned RS for two regions may be a challenge. These steps undertaken in the following order chart a progressive approach:

1. Comparative regulatory guidance & precedence 
2. Regulatory authority engagement
3. Scientific advice 
4. Accelerated regulatory pathways 

1. Comparative Regulatory Guidance & Precedence 

A thorough review of the relevant (regional) guidance documents relating to the development of the sponsor’s specific product type is extremely important to ensure general alignment (on paper). This step ensures the respective regulatory landscapes, between the two regions are comparable, and that a single development program, for both,  appears feasible.¹ 

With more regulatory assessments, designations, and clinical information being made available, finding meaningful regulatory precedence on similar product types or indications becomes practically achievable. Precedence, such as orphan-drug designation status for the intended indication, will provide a useful insight into the acceptability of the indication within both regions. Further precedence on competitors’ clinical studies may be available through public domains such as the NIH National Library of Medicine.² At this stage, fundamental differences may exist and will need to be addressed for a go/no-go decision.

2. Regulatory Authority Engagement

In the context of this article is important to make a clear distinction between regulatory authority engagement and scientific advice. Engagement with regulatory authorities includes communication between the sponsor and the authority, from sending a query to the authority, to calling the authority helpline to having a nonbinding and informal briefing meeting with the EMA’s Small-to-Medium Enterprise (SME) Office,³ assuming the sponsor qualifies, or an INTERACT meeting with the FDA.⁴ 

Conversely, scientific advice is a pre-prepared (often rehearsed) meeting, with binding opinion(s) on a sponsor’s development program, centred around specific predetermined questions/answers across all areas of development (i.e., quality, safety, efficacy, and regulatory). 

The suggested approach would be to conduct independent regulatory engagements with both the EMA and FDA. First, assess the general pathway for the development program and the intended indication/therapy area. Then, explore wide-raging questions (where possible) and assess the authorities' capability to support and enable the development pathway, as the program may involve novel technology that could require additional training/education for the authority itself. Consolidating nonbinding feedback, along with regional KOLs and relevant patient advisory feedback, would also provide a useful insight into each authority’s ability to support and enable the program and, by default, enable the sponsor to assess the general capability to align the development program.

COVID-19 Precedence For Alignment Between Regulatory Authorities

In a high-level meeting on COVID-19 policies, organized by the EMA under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), international regulators discussed strategic issues and regulatory approaches to ensure a coordinated response to the pandemic. They stressed the need for alignment on pre- and post-authorization regulatory requirements to facilitate the rapid development, evaluation, and availability of medicines for the treatment and prevention of coronavirus disease.¹ 

The participants focused on regulatory considerations and challenges related to the development of medicines and vaccines for the prevention and treatment of COVID-19. They raised concerns about multiple small, rather than large, clinical trials and stressed the need for the development of priority criteria for planned trials. In addition, they called for the inclusion of vulnerable or neglected populations, such as pregnant women, children, and elderly people in COVID-19 studies. The regulators reiterated that it is crucial to align on common study protocols to ensure the results meet regulatory requirements and allow the evidence to be used to support the approval of medicines or vaccines.⁵

It is interesting to note that the ICMRA’s principle point of alignment was the COVID-19 clinical trials. The clinical trial protocol being the critical regulatory document agreed with regulatory authorities and allowed them to proceed with the planned studies. This scenario is comparable to aligning any drug development program: The focus of aligning the proposed studies, within the clinical development plan, is essential for true regulatory alignment. 

3. Scientific Advice 

In terms of the alignment approach, at the stage of seeking scientific advice, the sponsor would have completed the previous steps and be well underway (if not completed) with their non-clinical studies. In some cases, prescriptive early Phase 1 clinical studies may be completed. Early regulatory scientific advice may also be undertaken via a pre-IND meeting.⁶ Assuming the previous steps have been diligently exercised and the non-clinical and clinical data are in line with expectations, the scientific advice stage may be initiated via one of the two methods described below. 

The goal of scientific advice is to ensure sponsors perform the appropriate tests and studies so that no major objections regarding the design of the tests are likely to be raised during the evaluation of the final registration authorization application. If scientific advice within the target market/authority is not undertaken, this may result in unanticipated questions that may be insurmountable at the registration phase.

Fundamental questions at the advice stage are often centred around any planned deviations from the guidance or the prospective clinical study(s). 

Alignment on these topics may be achieved between EMA and FDA in one of two ways: 

1. Through the EMA/FDA Parallel Scientific Advice program.⁷ This is a dedicated procedure designed to provide a mechanism for EMA assessors and FDA reviewers to concurrently exchange with sponsors their views on scientific issues during the development phase of new medicinal products.
2. Staging individual scientific advice meetings. This occurs when the obligation is on the sponsor to coordinate timely scientific advice meetings between both FDA and EMA. This option requires careful planning, where advice meetings are tightly scheduled between the authorities. 

Pursuing option 1 or 2 above does not necessarily guarantee concurrence and alignment from the regulatory authorities. Certain discrepancies may be tolerated in the management of the clinical program within the protocols, such as minor differences for inclusion/exclusion criteria or emphasis on primary vs. secondary endpoints. 

4. Regulatory Accelerated Pathways 

It is common to associate programs that have novel technologies and/or target rare diseases with the accelerated regulatory approval pathways within the EMA and FDA, namely, the FDA’s Breakthrough designation⁸ and EMA’s PRIME designation.⁹ Both pathways offer (if designated/eligible) enhanced regulatory support, as they are designed for products for an unmet medical need. A sponsor that may have aligned its RS and be eligible for both pathways could incur a significant drain on resources and budget and, critically, the time frame to align and adjust (e.g., protocols) may prove too short to fulfill.

Life Cycle of a Multiregional Regulatory Strategy 

Writing and approving an RS does not stop here. Considerable effort is required to maintain the currency of the RS. Guidance can change as new requirements may impact the development pathway of your program. Similarly, the sponsor may decide to change the course of the program. Feedback from an agency, via scientific advice or results from a previous study, may require a redraft of your clinical protocol, not to mention the effects of an ever-changing competitive landscape. All facets of the RS need to be evaluated on a regular basis. The sponsor will require reliable resources in both regions to keep abreast of the necessary regulations. 

Summary 

The addition of a regulatory strategy to a development program offers value and insight on the trajectory of the program. The above approach presents a progressive stepwise method to potentially align an RS to address two regions. The dividends, to name a few, in achieving an aligned RS are rapid entry to both regions and efficiency in running a single consolidated clinical development program. However, complexity in the regulatory landscape or eventual divergence between the authorities’ opinions on a clinical trial protocol may invoke the need to amend the RS into two separate RSs. The RS should be a living document and require regular, timely updates, based on incoming clinical data generated or changes in the regulatory landscape. It also requires the sponsor to maintain a degree of flexibility in their thinking to sustain a strategic approach to the program.

References:

1. ICH Q6B Specifications: test procedures and acceptance criteria for biotechnological/biological products - Scientific guideline https://www.ema.europa.eu/en/ich-q6b-specifications-test-procedures-and-acceptance-criteria-biotechnological-biological-products-scientific-guideline 
2. NIH National Library of Medicine https://clinicaltrials.gov/ 
3. EMA SME - https://www.ema.europa.eu/en/about-us/support-smes 
4. INTERACT - https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-meeting 
5. https://icmra.info/drupal/en/covid-19 
6. Pre-IND Guidance https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-pre-ind-meetings 
7. Parallel Scientific Advice - https://www.fda.gov/drugs/news-events-human-drugs/fda-ema-parallel-scientific-advice-psa-program-03162022 
8. Breakthrough Therapy https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy 
9. EMA PRIME https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/prime-priority-medicines 

About The Author:

Pete Embley has worked in several regulatory areas, including CROs, pharma, generic, and consulting industries for over 26 years. Working as an independent consultant, Pete provides global consulting expertise for a wide range of early to late clinical programs for start-up biotech and mid-to-large pharma