The EU Regulatory Environment
Camargo is known for its expertise in the 505(b)(2) pathway. But, in a global pharmaceutical business, many clients are looking to develop drugs for both the US and EU markets. We’ve written before about the EU process that is similar to the U.S. 505(b)(2) process. Now, we will be sharing a series on our drug development experience in the EU.
In this initial discussion, intended to be the first in a series of postings related to the EU regulatory environment, we will be looking at an overview of the scientific advice (SA) procedures available within the European Union (EU) and how such procedures, when sequenced correctly, can provide significant benefit to Sponsors during the course of development of a therapeutic medicinal product and subsequent strategies utilized in developing a Marketing Authorization Application (MAA) for a product.
Two key terms that will be used throughout this discussion include: National SA and Central SA. Both National SA and Central SA are mechanisms for critical feedback during product development, but are not themselves integral components of the MAA review process for product approval.
What is National SA?
National SA is a mechanism whereby a Sponsor seeks guidance regarding the scientific and regulatory aspects of product development from the national Competent Authority within one or more particular member states within the EU. For example, one may seek National SA with the Netherlands via the Medicines Evaluation Board (MEB) or with the United Kingdom via the Medicines and Healthcare Products Regulatory Agency (MHRA) in order to gain member state perspectives on program development as well as considered scientific feedback, clinical advice, CMC (chemistry manufacturing and controls) and/or other aspects related to the development of a medicinal product. In many respects, the National SA process is akin to that experienced by Sponsors interacting with the US Food and Drug Administration (FDA) in the context of a Pre-IND (Investigational New Drug) application meeting; the interaction being intended to provide the Sponsor with credible and meaningful feedback from the agency concerning scientific and regulatory considerations for a product under development.
What is Central SA?
Central SA is a wholly distinct process for seeking SA which consolidates the opinions of various member states into one unified response to Sponsor questions. This approach enables the Sponsor to submit questions which are applicable to the EU from a consolidated or “centralized” perspective. Unlike National SA procedures, the Central SA procedure will involve submission of questions to the Scientific Advice Working Party (SAWP) which is a working party under the auspices of the CHMP (Committee for Medicinal Products for Human Use) within the EU. In this sea of acronyms, the CHMP is the entity responsible for conducting an initial assessment of medicines for which marketing is being sought within the European Community. As is the case for National SA procedures, a wide range of topics are acceptable for discussion. Additionally, at the time a Sponsor submits a letter of intent to seek SA via the centralized procedure, they may request a pre-submission face-to-face meeting in order to ensure that the actual central SA request is appropriately structured, that questions are posed in an appropriate manner, and that regulatory considerations may be addressed. The preceding is important given that the Centralized SA procedure is focused on quality, nonclinical and clinical scientific considerations and is not the venue to address regulatory issues pertinent to an intended submission.
What Distinguishes National SA and Central SA?
A key consideration that distinguishes National SA and Central SA procedures is that the Central SA procedure is generally a “no discussion” meeting; in that Sponsor questions are addressed in writing by the SAWP, within the context of the briefing package submitted, in support of questions and clarifications being sought. However, as in all things, there is a possibility that the SAWP determines that questions posed by the Sponsor may be considered controversial or of sufficient broader interest or of sufficient complexity that discussion with the SAWP is warranted. In this latter case, which may more commonly relate to protocol assistance being sought via the Central procedure, a discussion meeting is held with the SAWP prior to finalization of written responses to the Sponsor. It is of note, therefore, that there are two outcome pathways for SA from the Central Procedure approach: 1) A written response only from the CHMP (following adoption of final comments of the SAWP) which involves a validation phase (45 days prior to start of evaluation phase at submission [Day 0]) and subsequent evaluation/response phase (40 days), or 2) A written response (inclusive of validation phase) with SAWP discussion (approximately Day 60) with final adopted comments from the CHMP provided on approximately Day 70 of the procedure. Note that aside from interactions in the context of a pre-submission meeting (or those associated with a requested discussion with the SAWP), the Central SA procedure is wholly written; with presentation of content and questions being keys to cogent feedback from the Agency.
Unlike the Central SA procedure, SA sought at the National level follows a very different pathway which is akin to FDA interactions mentioned previously. A Sponsor requests a meeting with the appropriate regulatory authority for a member state in the EU. Upon receipt of a confirmation of a meeting being granted (or at the time of submission of such a request as determined by the particular National authority being consulted) a comprehensive briefing packet is submitted for consideration by the National Authority. The Sponsor (or their designees) will meet in a face to face setting with the representative members (i.e. the individuals with applicable expertise to assist the Sponsor on the basis of the briefing package and questions submitted and the likely areas of expertise required) and engage in constructive back and forth discourse. Meeting minutes are taken by the Sponsor and normally provided as a courtesy to the National Authority who will not necessarily comment on Sponsor minutes; however, the National Authority will normally provide written feedback to the questions and matters of discussion raised, within approximately 30 days of a meeting. This timing will vary as a function of agency or agencies from which SA is sought. Unlike the single approach reflected by Central SA, the National SA advice allows multiple National agency inputs which can be a tremendous asset to a Sponsor who then utilizes such discrete program feedback to submit a consolidated and focused set of questions for consideration under the Central SA procedure.
And perhaps most importantly, seeking National SA enables person-person interactions and the ability to generate interest with respect to the Sponsors development candidate and disease/disease area. These interactions are critical in terms of how a Sponsor gauges interest in a program/disease indication and provides a mechanism for carefully considered input of National authority member feedback into the broader context of scientific advice. Basically, the relationships established are on par with the importance of the advice received. Finally, there are National level variations in procedures, requirements and costs for seeking National SA which need to be considered as well as variations in particular areas of expertise which may influence which particular National authority (or authorities) are approached for scientific advice.
Future blogs will delve into more specific aspects of both National and Central SA procedures, the legal basis for seeking advice, etc. While a potentially fascinating excursion, for most Sponsors this can be a daunting set of processes to consider. Camargo can provide assistance throughout the process, whether it be at the National or Central levels in the EU, or in corollary activities with the FDA in the US; our experience is hands on and hard-won and is not based on a “quick read” of a guidance document. Indeterminate factors, such as the impact of “Brexit” are not considered likely to impact elements described herein for the foreseeable future. To learn more, contact us.
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Author: Marc Wiles, PhD, Camargo Vice President of Scientific and Regulatory Affairs