It can feel like the mountain stage of the Tour de France…
A lot of effort goes into preparing for meetings with Regulators. There is also a lot we can learn at such meetings. Today we start a series of blogs detailing personal experiences and learnings, highlighting do’s and don’ts.
We had a fair number of interactions with regulators in the US, Canada, Europe, and Asia presenting and defending global projects and country specific development plans, We also have experience with Briefing Books, Guidance development and responses to queries.
Meetings with Regulators are usually stressful encounters as much is at stake, for your company and for your project. A team’s ability to interact productively and skillfully will be put to the test (and scrutinized at the post-mortem).
Companies invest considerable time and effort preparing for Agency interactions by assembling teams and coaching internal speakers and outside experts/KOLs. This all requires a lot of planning and coordination. The outcome of an End-of-Phase 2 (EoP2) meeting can have major consequences for a program if the Regulators demand an extra study or a more complex pivotal trial. These delays cost time and effort; ultimately lost time is lost money. On average, the opportunity costs of each additional year spent in development are in the range of $300 mio – $400 mio. Such extra costs may sink or derail an entire program, as the company elders may decide to invest elsewhere.
Occasionally we had Agency interactions dealing with unanticipated events. We once requested a meeting regarding a Phase 3 trial for which a change in primary endpoint was considered desirable based on newly published data. The company suggested changes that also included an added interim analysis and a new SAP. However, the Agency made it clear that any late stage changes to the originally agreed study plan would be risky and considered problematic. Reviewers would question the company’s motivation and investigate whether the true reason was an unblinded data review.
Other meetings dealt with emerging safety aspects during a trial or program. For example, several meetings were prompted by the FDA regarding quinolone safety. The topics were pediatric use, tendon and cartilage damage, effects on CNS, and, of course, QT prolongation. When increases in BP and HR were noted by a partner company studying a CNS drug, these deviations from normal were considered to be minor. Regulators were informed and agreed with the interpretation and proposed monitoring plan.
Post-approval, companies may be asked to evaluate safety signals identified in the AERS system. All of these become high-stake interactions.
Then there are the more technical meetings. Regulators sometimes ask for company input on diverse topics like the role of data modelling, the use of adaptive study design, PK/PD and its value for dose selection, or the appropriateness of certain animal tests. At times, industry or PhRMA is invited to comment on proposed changes to guidances.
There are numerous Regulatory Service companies that can help prepare for important meetings like an FDA Advisory Board session. Having dealt with several such companies, we need to be realistic about what to expect. Those that specialize in Advisory Board presentations are usually very good with the technical aspects and logistics of such meetings. They also can be good coaches on the behavioral ‘soft skills’ and how to deal with challenges. Of course, they cannot be expected to be subject matter experts; it is their operational know-how that is most useful. These AdBoard prep teams have people with fast fingers and grandmaster-level skills with Powerpoint. This allows the project team to focus on the task at hand without being encumbered by slide production and other onerous but necessary chores; this is not a minor contribution.
Of course, these presentations should never have promotional overtones. The in-house team, clinician consultants and subject matter experts are expected to stick to the data in the context of similar compounds.
Interacting with regulatory authorities across the world teaches that – beyond the specifics – certain general themes emerge. When we present our data, they will be evaluated by Agencies with the rules in their jurisdiction, ie., within the ‘regulatory framework’ of a country or region. Looking at the same data package, regulators in the US may have different views from their counterparts in Europe or Asia. The same data presented by Lilly for Xigris/drotrecogin resulted in different labeling from the FDA and EMA. We will give examples and try to explain why this is unlikely to change in the years ahead. Vive la difference!
As you know, there was a rather disjointed regulatory ‘world’ out there before ICH was implemented, to the point that truly global pharmaceutical development only became feasible after ICH implementation. From acceptance of development philosophies for certain indications to the specifics of study design, especially endpoints and statistical approaches, ICH had a monumental impact on global drug development. While local or regional approval studies may still be required, we now have a much greater level of consensus among Agencies than before ICH.
Agencies globally also exchange assessments and meeting minutes. Do not assume that a rejection by the FDA would not be known to EMA by the time you knock at their doors!
It goes without saying that interactions with Regulators are never fun. So much can go wrong, and we are not at our best sometimes when in the witness stand, Even a well-rehearsed team can be caught off-guard by a reviewer’s aggressive remark, an incompetent ‘expert’ speaking out of line, or a misunderstanding. Even today we have to deal with language barriers. Questions about obscure technical details may throw us off. The 60 minutes usually allotted to make our case can go by very slowly. Stay calm, listen and ask for clarification; engage your colleagues as needed.
In the next blogs we will deal with common mistakes that can come back to haunt you. We will also dedicate a blog to ethnic and cultural sensitivity. Stay tuned as we continue our Tour de France of regulatory insights.
ABBREVIATIONS
AERS Adverse Event Reporting System
EoP2 End-of-Phase 2 (meeting)
ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
PAC Post-approval commitment
PhRMA Pharmaceutical Research and Manufacturing Association
SAP Statistical Analysis Plan
SOC Standard of Care
