Early Interaction With Regulators on Innovative Technologies.
By Sarah Kendall.
Introduction
The rate of innovation in the pharmaceutical field is accelerating, with research and development spending forecasted to grow at a compound annual growth rate of 3.0% by 2024. This drive towards new and innovative technologies and medicines has been especially rampant during the recent coronavirus pandemic, with a new class of vaccine approved for use in humans for the first time. Whilst developers of novel therapeutics have pushed the boundaries of existing technology, regulators have raced to keep pace.
The role of regulators has expanded from not only safeguarding the quality and safety of products, but also to ensuring that guidelines evolve to consider the new generation of scientific technologies. For many sponsors of small molecule or biological therapeutics, existing pathways provide sufficient interaction with regulators to ensure compliance with guidelines and advice on product development concerns. However, for those cultivating new and exciting technologies that modify manufacturing pathways or generate new innovative therapeutics, additional avenues have been developed to ensure that all products have a regulatory pathway to approval, and that regulators are kept appraised of emerging technologies.
These pathways all take the form of informal, free advice that helps educate the agency on the technologies, whilst providing early regulatory advice on the developmental pathway for the sponsor.
Europe
Within Europe, many national competent authorities offer early interactions, including Germany who offer early interactions at both BfArM and the Paul Ehrlich Institute, and the Belgian Federal Agency for Medicines and Health Products (FAMHP). For more centralised advice the European Medicines Agency (EMA) has established the Innovation Task Force (ITF), whilst the Medicines and Healthcare products Regulatory Agency (MHRA) has founded the MHRA Innovation Office, as available platforms for early dialogue with creators of emerging therapies and technologies.
Both innovation platforms offer free informal advice that is quick to undertake. This distinguishes the process from other interactions such as scientific advice, which can be costly to commence and deviations from the advice given must be justified.
Whilst both offer a high quality of advice, the specialities of both offices vary slightly. The EMA ITF is known for its expertise in innovative medicines and technologies, as well as borderline products. The ITF brings together a multidisciplinary group including competencies from the areas of Quality, Safety, Efficacy, Pharmacovigilance, Scientific Advice, Orphan Drugs and good practices compliance, as well as legal and regulatory affairs. In 2019, the Agency began offering an early engagement platform for developers of therapeutic approaches for the treatment or prevention of bacterial and fungal infections to tackle antimicrobial resistance. This activity provides an entry point for Sponsors to engage with the Agency’s services for promoting innovation in medicine, technologies and methods. This enables the Agency a chance to deliver specialised expertise at an early stage and provide regulatory advice on the eligibility of medicines for the Agency’s procedures.
Particular areas of interest include pharmacogenomics and epigenetics, gene, cell and tissue engineered products as well as nanomedicines. The Agency also encourage early interactions with Sponsors intending to use new non-clinical methods and models, and new manufacturing and delivery methods.
The remit of the MHRA innovation office focuses on pragmatic advice for those who develop innovative medicines, medical devices or manufacturing processes that challenge the current regulatory framework. This includes those that utilise gene editing and nanomedicines, as well as extending to developers of innovative medical devices, and software apps. In addition to new products, the MHRA also offers the opportunity to discuss proposals for novel manufacturing processes including facility designs. The MHRA Innovation Office also offers a platform for sponsors to gain advice from the National Institute for Biological Standards and Control (NIBSC), National Institute for Health and Care Excellence (NICE) and the Clinical Practice Research Datalink (CPRD).
In addition to offering its own advice, the Innovation Office can also refer users to other more relevant services such as the Regulatory Advice Service for Regenerative Medicine.
For both processes, early interaction is advised. The application can be submitted at any stage of development; however, applicants will be referred to scientific advice if the product development is deemed to be at a suitable stage.
The Process for Application
EMA Innovation Task Force.
Applications for the EMA take the form of an initial request form, which is approximately 6 pages in length. For submission, the form should be sent to ITFsecretariat@ema.europa.eu. Upon review, the Agency will contact the sponsor via a telephone call to discuss the application and arrange a meeting. A draft briefing document should be submitted at this stage. A meeting will be confirmed post review of the draft briefing document. Prior to the meeting, a final briefing document should be submitted, this should include general background, description of technology, composition of product and all information for CMC, non-clinical and clinical development, a template for this is provided. In addition, a briefing meeting application form should be generated. These documents should be submitted via IRIS. The applicant should also generate a short presentation of the topics for discussion. The meeting will be approximately 1.5 hours in length where discussions are led by experts from the EMA’s network, working parties and committees. Meetings minutes should be generated utilising the meeting report template, which can then be submitted to the EMA for review and comments by the experts present at the meeting will be added.
MHRA Innovation Office.
In agreement with the process of the EMA Innovation Task Force meeting, the MHRA Innovation Office meeting is initiated with an application, or an email with a limit of 300 words. Appendices with additional information can be attached. Approximately 84% of respondents receive a response within 20 days, mostly in the form of a single written response. If necessary, the MHRA may request a meeting.
This occurs in a similar format to scientific advice, where applicants will be asked to submit a high-level overview and background two weeks before the meeting, as well as give a position statement and background information. Two weeks prior to the meeting a list of attendees will be requested. The meeting will be held via teleconference and will be approximately 60 to 90 minutes in length. The initial meeting with the MHRA Innovation Office is free of charge, however, as noted above, applicants may be advised to subsequently seek formal scientific advice which is subject to a fee. The meetings are attended by experts that are likely to attend any future scientific advice meetings and ultimately assess a clinical trial application or marketing authorisation application submission. The MHRA Innovation Office will not issue a formal letter or meeting minutes, however the MHRA may review the applicant’s minutes if submitted following the meetings.
USA
As within Europe, the FDA offers several processes for early interaction to ensure sponsors are appropriately supported with novel technologies or therapeutics. The Center for Biologics Evaluation and Research (CBER) offers the INTERACT meeting, or CBER Advanced Technologies Team (CATT), whilst the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality provides meetings with the Emerging Technology Team (ETT). Developers of new products should direct their queries to the relevant division, with CDER primarily responsible for naturally occurring substances purified from mineral or plant sources, as well as from non-human animal or solid human tissue sources excluding blood products and vaccines. CDER also maintains oversight of antibiotics, chemically synthesised molecules, and hormone products. In contrast, CBER are responsible for vaccines, human blood or human blood derived products and immunoglobulin products. Furthermore, they also review products composed of intact cells or microorganisms as well as protein, carbohydrate or peptide products produced by cell culture except those that are regulated by CDER.
CBER
INTERACT
The INTERACT meeting offers sponsors of biological products the chance for a preliminary consultation for innovative products at an early stage of development. These meetings are suggested for products prior to pre-IND stage of development, however, differ from European meetings in that applicants must have a specific IMP or biological product derivation strategy to discuss, preventing those with conceptual ideas from applying.
Sponsors can obtain initial, non-binding advice from the FDA regarding chemistry, manufacturing and controls, non-clinical, and/or clinical aspects of the development program. However, these cannot be in the format of planned studies or concerning the format of a planned IND. For these topics, sponsors will be advised to undertake a pre-IND meeting.
To apply, an initial request should be submitted including a summary of the product and disease intended to treat, as well as information on current data from CMC, non-clinical and clinical plans and future plans, and any questions the sponsor wishes to address. The FDA timelines outline an initial response will be provided within 21 days. The FDA can provide written responses only or can schedule a meeting to occur by day 90 in the process.
No meeting minutes are taken by the Agency, and whilst meeting minutes can be submitted post meeting, they will not be formally agreed by the Agency. This process allows for early interaction with the Agency to determine the correct regulatory pathway and discover potential pitfalls in their development.
Figure 1 Suggested timelines for an INTERACT meeting.
CATT
Whilst INTERACT meetings focus mainly on new biological investigational medicinal products (IMPs); the CATT meeting exists to promote dialogue and education among CBER staff and innovators of advanced manufacturing technologies. The meeting provides an Innovative mechanism to discuss implementation of technologies in development of CBER regulated products. Requests should focus on novel technologies that will impact manufacturing processes and product development, as well as regulatory implications. This includes manufacturing for products which the center has limited experience.
To apply for a CATT meeting, an initial request should be submitted that encompasses a brief description of the technology/product class, an explanation of why the technology is novel and unique, as well as the impact of the technology in terms of manufacturing, characterisation, safety or efficacy. A summary of the manufacturing or development plan, and any questions for regulatory/technical/other challenges for implementation, should also be included. This information should not exceed 2 pages, including any tables or figures, and should be submitted to Industry.Biologics@fda.hhs.gov directly. It is at the discretion of the Agency to grant meetings with the applicant. These meetings allow for a more conceptual discussion, with no specific product development necessary.
CDER
ETT
The FDA recognises the pharmaceutical industry are concerned that the use of innovative approaches to enhance manufacturing, may in turn produce new technical and regulatory challenges, and delays. To prevent setbacks in the approval of the technologies, the Emerging Technology Team (ETT) was established by CDER’s Office of Pharmaceutical Quality to enable the adoption of innovative approaches to pharmaceutical product design and manufacturing.
The program allows industry representatives to meet with the ETT to identify new potential technical and regulatory issues prior to filing a regulatory submission. It also enables the Agency to have advanced warning, and time to consider how these technologies can be evaluated within the current regulatory framework.
By joining the program, participants gain the opportunity for pre-submission face to face interactions with the ETT members to answer technical and regulatory questions. Furthermore, participants will also gain feedback in advance of a regulatory submission. To qualify for the program the proposed technology must fit two criteria:
The proposed technology has the potential to improve product safety, identity, strength, quality and purity, and
The new technology includes one or more elements subject to quality assessment for which the Agency has limited review or inspection experience.
This is open to representatives planning to submit an IND, original or supplemental NDA, ANDA or BLA, or application associated DMF as part of this CDER program. To apply, companies should submit a written request to participate in the program and proposal (not to exceed five pages). Requests and proposals should be submitted electronically to CDER-ETT@fda.hhs.gov. Applicants should refer to the Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization guide when applying.
Summary
The emergence of new and exciting innovative technologies that can improve manufacture, or produce novel therapeutics is progressing at an ever-increasing rate. Driven by renewed interest in the sector during the Coronavirus pandemic, creators of these technologies are increasingly looking to the regulatory agencies for advice on suitable regulatory pathways and pitfalls that may occur during development.
Both the European Agencies and the FDA have enabled early interaction through a variety of meetings to ensure they are kept appraised of the technology, and that existing regulatory guidelines can be applied to the development of these products. In addition, it allows the regulatory agencies to consider if new guidelines may be necessary for evolving technologies. The European Innovation meetings allow for conceptual discussions, that ensure innovators receive early, free, informal advice, whilst allowing for the Agencies to keep pace, with both IMP and manufacturing methods entering the same process for advice. The FDA has subdivided the process, with new model therapeutics receiving advice through the INTERACT meeting, replacing a pre-pre-IND meeting, to ensure development will enable successful future IND submission. Whilst new technologies for manufacture can be assessed through either CATT or ETT discussions. These meetings have driven new consortia formation, and the generation of new guidelines for groups of products including gene therapies.