ISPE Global Regulatory Town Hall: The Future Is Now

The panel consisted of Megan Zoschg Canniere, Chief Development Officer, Spark Therapeutics, Inc.; Hugo Hamel, Associate Director, Centre for Blood, Blood Products and Biotherapeutics, Health Canada; Yasuhiro Kishioka, PhD, Review Director, Office of Cellular and Tissue-based Products, Pharmaceuticals and Medical Devices Agency (PMDA); Anabela Marcal, European Medicines Agency (EMA) Liaison Official to the US Food and Drug Administration (US FDA); Peter Marks, Director, Center for Biologics Evaluation and Research, FDA/CBER; Andrew McKillop, Head of Pharmaceutical Sciences Small Molecule, Pfizer, Inc.; Timothy Watson, PhD, Vice President – Head of CMC Regulatory Affairs, Gilead Sciences, Inc.

The Global Regulatory Town Hall program was developed by ISPE members Ciby Abraham, PhD, Senior Director and Group Manager, Project and Product Leadership in CMC Regulatory Affairs, AstraZeneca; Connie Langer, Regulatory Intelligence Lead – Pharmaceuticals, Pfizer; and Roger Nosal, Head of Global Regulatory Strategy and Submissions, NGT BioPharma Consultants. Nosal moderated the discussion.

Question 1: How can both regulatory authorities and industry enhance mutual reliance and recognition to streamline global regulatory processes to ensure faster access to medicines globally?

Hamel indicated that there are some mechanisms already and Health Canada has started the process of making amendments to its regulations to facilitate acceptance of other agencies’ decisions, e.g. US. Heath Canada asks if a product has been approved by a stringent regulatory authority as defined by the World Health Organization (WHO) and often reads the regulator report supporting an approval and potentially accepts the conclusions of that report. Health Canada also participated in the International Coalition of Medicinal Regulatory Authorities (ICMRA) collaborative assessment pilot of post approval change (PAC) submissions as part of ICMRA’s Pharmaceutical Quality Knowledge Management System (PQKMS) program Hamel hoped that agreement of the ICH Guideline, “M4Q (R2), Common Technical Dossier on Quality Guideline” would promote reliance based on review of a single global submission.

Kishioka noted that the COVID-19 pandemic was a great example of the use of reliance giving early access to medicines. A key step towards more cooperation and reliance between regulators was to increase mutual understanding to enhance collaboration. There is a WHO good reliance practice guidance which suggests a step-by-step approach.

Nosal commented that it is not clear where leadership of further reliance activity lies. ICH was mentioned as a possibility by Theresa Mullen, PhD, Associate Director for Strategic Initiatives at the US FDA’s Center for Drug Evaluation and Research (CDER) in keynote address at the 2024 ISPE Annual Meeting & Expo on 14 October, however ICH is responsible for guidelines and what to harmonize rather than the mechanism to harmonize.

Marcal explained that in the EU there are reliance activities and mutual recognition agreements for GMP inspections. COVID-19 showed industry what could be achieved both for vaccines and some therapeutic medicines. Although there are some legal challenges to overcome, obviously reliance is the best and ultimate option. There are activities progressing such as the ICMRA PAC pilot, which has proven to be successful for regulators and industry. There are also activities such as parallel review with agencies such as Health Canada and PMDA and although informal, review reports are sometimes shared. Such parallel work does require industry to submit the same dossier at the same time to these agencies, as much as possible.

Marks shared that during the COVID-19 pandemic many regulators were doing the same thing at the same time. He asked whether it would be possible to pool resources to expedite review, without cutting corners? Working collaboratively and sharing documents could save resources. Is there an increased role for the WHO?

Nosal asked Marks if he thought progression of mutual reliance could operate under existing regulatory frameworks or whether a new framework was required?

Marks commented that some fragments of mutual reliance are happening, for example with pharmcovigilance/safety evaluation. We should build further on the oncology products-focused Project ORBIS which streamlines regulatory review across seven agencies. More work is required, however, to come together for both review and inspection.

Nosal asked the industry panelists to share their experiences with reliance.

Watson replied that Gilead Sciences participated in both the PAC and hybrid inspection ICMRA pilots. The PAC pilot was not easy and took many resources for industry and regulators, however, the outcome was what industry has been wanting for more than a decade, which is a single set of questions and simultaneous approvals. The post approval change management protocol (PACMP) used was not designed as specific to a single change but agnostic to specifics in that the criteria for a several types of change were given – “if we change this, we will meet these criteria”. The outcome was worth the effort.

McKillop stressed that industry designs a single product for global distribution and strives for a resulting single common technical dossier. However inconsistent implantation of ICH guidelines leads to complexity of realization, particularly with PACs.

Canniere stressed the need for flexibility when products are developed for a low number of patients with consequent low number of batches manufactured. It is a challenge managing multiple requests for inspections.

Question 2: What are the key challenges and opportunities of introducing AI and machine learning (ML)?

Kishioka explained that PMDA did not have much expertise in the use of these technologies. There is a business group, which consists of academics, as well as industry and regulator experts to study this new technology. Nosal asked if industry could help and Kishioka responded that yes, they are members of this group and they will work in the group to increase the level of knowledge and understanding.

Hamel commented that a risk-based approach should be taken. The revision of CTD, M4Q(R2) for submissions is scoping the extent of inclusion of AI so that M5(R2)-Q can be future-proofed. Health Canada is using AI to review adverse event reports for trends.

EMA has issued a reflection paper, which Marcel explained is at a high level and contains principles and the risk-based approach for industry guidance. There is a work plan to 2028 on the EMA web site which describes tools, steps, and timing to implement AI. The Quality Innovation Group (QIG) is the team to take examples on which companies wish to seek guidance. Examples are needed since we need to keep an open dialogue. It is too early to draft guidance.

From an industry perspective, Watson stressed that science should drive industry, and we should not make uninformed decisions. McKillop reflected that it was early days: the breadth of possibilities is evolving and it is better if industry and regulators go on the journey together.

In response to a question from the audience, “How do we get people together to progress AI/ML?” panelists suggested that agreement of terminology is essential to progress so that all parties are talking about the same topic and avoid divergence while promoting convergence. Hamel suggested that eventually ICH could be asked to produce a framework.

A further question from the audience asked, “What are the legal issues surrounding use of AI in a pharmaceutical regulated environment and of sharing information between agencies and sponsors?” Marks explained that in the US they were not sure yet. Does US FDA need new tools to inspect AI applications which have evaluated lots of data? US FDA does not want to receive the data given large storage volumes, privacy, and aging concerns. There could be different privacy laws between different regions evaluating information or data. For the EU, Marcal agreed with Marks’ views and had nothing further to add.

Moving to the broader topic of innovation and the background from a recent ISPE survey, Nosal commented that return on investment (ROI) was a key driver for industry to progress innovations. Of relevance responses to the next question, better knowledge of risks allows better estimation of ROI with greater chances of success.

Question 3: In what ways can innovation and information sharing between industry, regulators, and stakeholders be improved to foster better collaboration and transparency?

Vision and bravery are required by industry, commented McKillop, with ISPE being an excellent forum to bring stakeholders together for discussion and information sharing. Watson supported this by saying that more collaboration to discuss examples and principles was needed and ISPE should be used.

In the more specific field of gene therapy, Canniere noted that bravery is also required. There are intellectual property (IP) concerns, however, companies coming together to discuss and promote new innovations must be a benefit. As an example in the clinical area, several companies, each with limited experience, solved a safety issue by collaborating where a bigger picture was evident. Watson agreed that collaboration using, for example an ISPE-organized meeting, is a way to progress new technology, especially technology applicable to more than one product, so called “platform technology”. In the EU there is not a definition for “platform” technology and Marcal explained it is similar to, but may be different from prior knowledge, which has been used often by sponsors in submissions. EMA is having a listen and learning session in November devoted to platform technology where there will be case studies and discussion, which may lead to some regulatory proposals.

Kishioka recognized that US FDA had issued a draft platform technology designation guidance; however, PMDA in Japan considered it too early to issue guidance. Progressing new technology is very important and supported by PMDA, so it is included in a 2024 to 2028 plan, according to Kishioka. This plan will consider consultation services for innovation, support early communication to develop information sharing and knowledge and generally support industry to move forward.

Hamel agreed with Kishioka and pointed out that there was a difference between platform technology (use of prior knowledge) and innovation (new technology). Platform technology is use of prior knowledge using the same process and in Canada, reviewers of monoclonal antibody submissions, for example, are encouraged to streamline their review if a sponsor has a lot of experience and is using the same process.

Marks also referred to the US FDA draft guidance on platform technology designation, which may be less than perfect. US FDA is open to discussions for any cell and gene therapy product being developed, even though currently the guidance requires an approved product. In the cell and gene therapy field, sponsors could come to CBER to discuss development of multiple products with the same underpinning technology. It is possible one or more products could be approved subsequently. Early discussion helps both CBER and sponsors and facilitates development.

Nosal pointed out that alignment between regulators is a key industry concern.

Without guidances, McKillop stated that we have “rules of the road” for developing and manufacturing products and the principles of these could be broadly followed – control strategy, validation, GMPs.

Question 4: How can global regulators and industry work together to give access of medicines to patients globally and minimize supply chain disruptions?

In the cell and gene therapy world, transparency is a necessary pre-condition. Canniere suggested the ideal is for holding conversations with multiple agencies together so that everybody can hear others’ perspectives with the goal of arriving at a single set of harmonized expectations. Currently, however, Canniere’s company tends to hold meetings with multiple agencies individually in parallel since joint meetings are challenging in many ways. Canniere recognized that there were ongoing initiatives and pilots; however, these requirements are even more important in the cell and gene therapy fields where there are low numbers of patients and batches manufactured. It may not be practical to power a clinical study for two different end points or to conduct two separate clinical studies. It is better if different regulators’ perspectives are understood so that they can be coalesced and recognized. Canniere stressed that transparency is the way forward.

Kishioka agreed that collaboration and joint meetings are a very good way forward. Marks agreed that collaboration is very important and the way forward. The COVID-19 pandemic taught industry and regulators about interdependency with supply of materials such as active pharmaceutical ingredients (APIs), reagents and rubber closures being problematic. The ICMRA pilots are the way forward. Hamel confirmed that cluster meetings between regulators are extremely important and allow sharing of expertise. He noted the oncology ORBIS example is very useful as a work sharing exercise with other agencies and leads to shorter review times, maybe as much as 40 percent. Marcal agreed that cluster working was beneficial as in the ORBIS program allowing parallel reviews. There are also many other interactions between, for example, Health Canada, US FDA, and PMDA. It is always possible to request expert advice from EMA QIG.

Nosal closed the session by thanking all participants individually. He also commented that what attendees heard was that ISPE has a role to progress policymaking in reliance and recognition by fostering discussion, education and learning with technical aspects of drug development, manufacturing, and generally with innovation.

Disclaimer
 This is an informal summary of a discussion panel held on 16 October 2024 at the 2024 ISPE Annual Meeting & Expo in Orlando, Florida, USA. It has not been vetted by any of the individuals mentioned in this article, nor should it be considered the official positions of the health authorities or companies mentioned.