Regulatory Insights: Regulatory Intelligence Informs Sound Clinical Trial Strategy

Pharmaceutical product development is complex, high risk and costly, in part due to complicated regulatory requirements developers face at each stage of the process. In this post, which opens with a brief introduction by Alistair Davidson, executive director of regulatory affairs, his colleagues, Sean Schofield, senior specialist of regulatory intelligence policy and advocacy, and Ilse-Maria Nolan, senior director of regulatory affairs, highlight how regulatory intelligence can aid in formulating a successful clinical trial regulatory strategy. Our next related post will delve into the importance of regulatory intelligence to the lifecycle of marketed products.

Meeting business objectives through regulatory intelligence

The clinical trial regulatory landscape is dynamic and continually evolving, driven by local requirements, medical, scientific and technological advances, as well as industry and political influences. Regulatory intelligence forms the basis of an effective regulatory strategy and is crucial for making sound, strategic decisions to speed delivery of pharmaceutical products to market.

Even with recognition of the importance of regulatory intelligence, many small pharmaceutical and biotech companies struggle to make the necessary resource commitment. Our experience is that regulatory intelligence is an investment well worth making and can help sponsors accelerate study execution and avoid regulatory pitfalls. That’s why PPD has a team of professionals solely dedicated to gathering and interpreting regulatory intelligence and working with our regulatory affairs teams across the globe to gather and maintain this critical information. We have found that a regulatory intelligence IT tool aids regulatory intelligence management. At PPD we utilize a proprietary regulatory intelligence platform, PPD® RegView, for this purpose.

Regulatory intelligence and the life cycle of clinical trials

Let’s consider some areas where having customized regulatory intelligence can make a critical difference during the life cycle of a clinical trial.

Submission dossier

Submission dossier requirements vary across countries and jurisdictions. As an example, the U.K. regulatory authority (RA), the Medicines & Healthcare Products Regulatory Agency (MHRA) reports¹ that over half the clinical trial applications it receives require additional information, with most issues avoidable when guidance is followed. The MHRA estimates these omissions can delay final approval by up to 21 days for a Phase I application and 23 days for other phases. A thorough review of regulatory intelligence regarding local requirements can avoid such delays and improve approval timelines.

Initial submission strategy

Local RA and Ethics Committee (EC) (or Institutional Review Board)processes and assessment timelines vary across countries and jurisdictions. A sound submission strategy, based on current regulatory intelligence, is fundamental to achieve overall trial timelines. Various strategies should be considered. For example, whether to submit in parallel or sequentially to the RA/EC as permitted locally, pursuing a staggered approach to RA submissions to enable earlier approval in countries without rate-limiting dossier requirements, and utilization of centralized assessment procedures where available. Between 2013-2019, 16-23%² of all EU multinational trials underwent the voluntary harmonization procedure (VHP), which involves joint scientific assessment by member states concerned. When considering this option, its many pros and cons should be explored in detail on a per study basis.

Labeling

Depending on the trial design, labeling may be necessary for the product under investigation, comparator and/or the placebo. Sponsors must ensure adherence to local and/or regional (e.g., Annex 13 in the EU) requirements, with typical considerations being local language and warnings, investigational product (IP) information, CRO/sponsor, expiry date and lot number. In the U.S., the Code of Federal Regulations (CFR) 312.6 applies and requirements can vary across states, for certain types of IP for example. In some countries or cases, we may recommend content beyond legal requirements when key to patient safety.

Changes to ongoing studies

Sponsors must adhere to local regulatory reporting requirements when introducing changes to ongoing trials. In the EU, per Directive 2001/20/EC, amendments are considered ”substantial” if they are likely to significantly impact the safety, or physical or mental integrity of the trial participants, or the scientific value of the trial. Classification of amendments as substantial or non-substantial in the EU has implications for agency notifications. Sponsors should keep in mind that some amendments may be considered substantial by an EC but non-substantial for an RA, typically amendments relating to the patient leaflet, investigator or trial site for example.

Amendment classification in the EU differs to the U.S. Food and Drug Administration (FDA) requirements where there is no differentiation between substantial and non-substantial amendments. In the EU, U.S. and other jurisdictions there are provisions for immediate implementation of changes where patient safety may otherwise be at risk, with subsequent regulatory reporting to agencies.

End of Trial (EoT) activities

Sponsors are generally obliged to report the EoT, typically per the definition of the end of study in the protocol. Local variances exist in terms of agency notification, local EoT (i.e., EoT in an individual country) or global (i.e., the EoT in all involved countries) and submission format and timelines. Clinical study reports must also be submitted in some countries or uploaded via electronic platforms in others. Current regulatory intelligence should be consulted to comply with applicable legal and regulatory requirements.

Accelerating regulatory innovation

Globally, we are in a period of great change for clinical trials, with additional significant change expected in coming years, further necessitating proactive regulatory intelligence and monitoring of evolving landscapes:

• Various regulatory authorities continue to show pragmatic flexibility during the COVID-19 pandemic. Regulatory intelligence teams gather new information daily to enable trials to adapt and benefit from emerging flexible provisions. Some regulatory authorities, including the U.S. FDA,³ have advised that lessons learned and precedents set may lead to permanent change, accelerating developments through actions such as the move to digital trial solutions. 

• Prior to the pandemic, some regulatory authorities had already created accelerated pathways for development and approval of new drugs such as the FDA’s breakthrough therapy designation and the European Medicines Agency’s (EMA) priority medicines (PRIME) scheme. The FDA and EMA also have orphan drug designation programs. Further, the FDA has other pathways, including but not limited to priority review, accelerated approval, regenerative medicine advanced therapy designation and fast track designation. Knowing and understanding these options helps inform some critical decision-making that not only informs clinical development plans but can greatly decrease the overall product development timeline.

• The regulatory framework for clinical research in the UK is expected to change following its departure from the EU and the end of the transition period on 31 December 2020. This past June, the MHRA⁴ outlined plans for substantial change during 2020-21, recognizing its need to develop a new and effective standalone regulatory model in the U.K.

• The EMA reported⁵ progress regarding the EU Clinical Trial Regulation 536/2014 (CTR) in June, announcing a December 2021 go-live date for the clinical trial information system (CTIS.) CTR will replace Directive 2001/20/EC once applicable, resulting in major changes to trial conduct in the EU, including harmonized electronic submission and assessment processes for multi-national trials. Guidance⁶ is available to support transition of trials from Directive 2001/20/EC to CTR during a three-year transition period.

Regulatory intelligence aids in adaptation to the ‘new normal’ of clinical trial management 

In today’s “new normal,” more than ever, regulatory intelligence is fundamental to a successful regulatory strategy for clinical trial management. In reality, it has become imperative. The COVID-19 pandemic has driven rapid regulatory change, with the success of those sponsors able to act on emerging regulatory authority flexibilities across the global landscape highlighting the value of having access to the latest regulatory intelligence. As the regulatory landscape further evolves across countries globally, the upfront investment in information and interpretation of guidance from experienced regulatory affairs experts will ultimately lead to better decisions, reduced delays and more timely approvals of novel treatment options for patients.