Is Model Informed Drug Development Regulatory Pathway an Exception or the Norm?

Charlotte Jones-Burton MD, MS

While Model Informed Drug Development (MIDD) should be a norm for internal decisions making, it is worth asking whether the regulatory engagement via the US Food and Drug Administration’s (FDA) MIDD Pilot Program should be the norm? The MIDD program is a pilot program established by the FDA to innovate drug development. Our observations suggest that the current system is designed to ensure MIDD regulatory pathway be an exception to the norm.

This article attempts to highlight our experience utilizing the MIDD pathway. As a strategic leader in a pharmaceutical company, I’m lending my perspective on changes needed in the current MIDD pathway to have this channel effectively utilized by the industry, as well as provide a point of view on our collective responsibility as industry executives to actively support the changes to revolutionize drug development.

The FDA has a strong history of programs designed to promote innovation and collaborate with industry to speed development of innovative medical products, as well as increase the quality of drug applications through early meetings between sponsors and the FDA.¹ The recent MIDD pilot is a paired meeting program. As the name suggests, it is unlike most FDA meetings where the sponsor is granted two meetings at the beginning of the process.

The MIDD pilot program was created to facilitate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources, referred to as MIDD approaches.² A group of industry leaders recently published their experience of participating in the MIDD program and the quantitative and qualitative benefits of participation.³ Despite the published benefits and mutual recognition of MIDD in the community^4,5,6, the program remains a pilot which may constrain its effective utilization and limit its full potential.

The Clinical-regulatory team at Otsuka examined several key questions as it pertains to the MIDD program’s usefulness as a drug development avenue.

Why does the industry need a channel like MIDD Paired Meeting Program?

LA summary of 19 examples¹, as well as our own, we believe the industry needs MIDD to engage the agency in three ways:

1. Discuss complex drug development topics that need a deep scientific dialogue to uncover the science and identify the role of MIDD
2. Clarify complexity of science through two-way dialogue
3. Align on scientific information prior to regulatory negotiations

While it is possible to accomplish these in traditional pathways, there are at least two reasons for MIDD being more amenable to complex discussion. One, the conversation is focused on scientific topics and less on tactical discussions (e.g., format, timelines). Second, the paired meeting format allows discussion topic prioritization without having to obtain agreement in one meeting.

What are the constraints of MIDD for effective utilization?

In its current form, the MIDD program has the following limitations for effective utilization.

• Quarterly application process: Most FDA meetings can be requested on an as-needed basis. MIDD meetings have a quarterly application process. The agency accepts applications on a continuing basis, but the Meeting Request Grant/Deny Notifications are not sent out until 3-4 weeks after that due date. These logistics make it challenging to incorporate the MIDD route in the drug development plan to keep up the pace.
• Limited number of meetings: The agency expects to grant 2-4 meeting requests per quarter. This limitation, likely due to resource constraints, creates challenges for drug development teams who need to factor in a scenario whereas MIDD meeting will be denied and the traditional regulatory pathways (e.g., Type A/B/C meeting) will need to be utilized.

Why more programs are not utilizing MIDD?

While MIDD is seen as a useful avenue by the industry, it’s also true that, to the best of our knowledge, the agency is not overwhelmed with requests. Only 42 meeting requests from 28 sponsors have been received since 2018 with 35 meetings granted.⁷ This is surprisingly low, as one would assume the agency should be overwhelmed by industry requests. This is the main reason for this article–to initiate a call to action from the industry to:

1. Acknowledge and awareness for the MIDD pilot within decision-makers are minimal.This is understandable as any pilot regulatory from the agency would be deemed riskier on face value than the traditional pathway.
2. Correct the limitations noted above to make MIDD more attractive. The uncertainty and timelines of agency meetings versus the traditional regulatory pathway nullify the advantages of the MIDD. This is understandable from a pharma executive’s drug development program standpoint. Regulatory uncertainty and risk cannot be underestimated, and it would be impossible to leverage the MIDD pathway without the champions being also in the decision-making capacity.

Is the MIDD pathway appropriate for all drug development programs?

While MIDD regulatory interaction is not for every drug development program, a sponsor may choose to incorporate MIDD in their internal decision-making as several MIDD touchpoints do not need regulatory agreement. Our experience shows the greatest value of MIDD is when the drug development pathway needs to integrate information across different sources and utilize the totality of the evidence for regulatory decision making. Also "model informed" is a misnomer as it indicates a need for technical complexity. The truth is that the agency is more focused on "drug development" than being "model informed." The fact is, the use of simple mathematical modeling, focusing on the totality of evidence to solve complex drug development issues, leads to productive discussions with the agency.

What does the industry need to support MIDD?

As an industry we hold a responsibility to ensure that MIDD has a permanent place in regulatory interactions and is not seen as an exception. In the short term, we need to support the expansion of these meetings to open more slots and reduce the uncertainty of rejection due to capacity within a given quarter. As an industry, we need to pave unprecedented pathways to revolutionize drug development. As a call to action, we recommend the industry take the following measures:

• Communicate internally and externally: It’s very important for internal stakeholders to be aware of both the benefits and limitations of such programs, MIDD’s logistics constraints may be seen as prohibitive, therefore limit seeing its advantages compared to a traditional pathway, if viewing from simply a business standpoint. However, making use of this pathway and publishing our experience and perspectives, internally and externally, on its utility we as an industry can move the needle forward on it MIDD having a permanent place in regulatory interactions.
• Support MIDD through PDUFA negotiations: Industry members need to make MIDD utility known to the Prescription Drug User Fee Act (PDUFA) Reauthorization steering committee. Both FDA and industry stakeholders must balance several innovative proposals across stakeholders. We must make an active effort to realize that MIDD has delivered more significant value to the industry^4,5,6 than many theoretical promises on the table.
• Think hybrid for regulatory strategy: It is understood that communication to internal and external stakeholders and PDUFA negotiations requires change management. However, this should not stop the industry from pushing the boundaries of the MIDD by creating a hybrid strategy that incorporates both MIDD and traditional pathways (e.g., Type C meeting) for effective regulatory interaction. Neither should it stop the industry from gaining agreement on complex modeling issues to avoid a round of questions during regulatory review that could lead to a request for information (RFI). Overall, the industry should be working together to develop a hybrid approach that provides the best of both worlds.

In conclusion, MIDD is a powerful pathway for the industry to revolutionize drug development. While not the only one, it can help find drug development pathways that would seem impossible within through traditional ones. Utilizing this innovative pathway requires industry leaders, like myself, to be strategic, proactive, and supportive of MIDD. Only then can we decrease the time to market and pave new drug development paradigms. Both industry and the FDA have much to gain by ensuring that the science is effectively translated to pave the path of innovation to help the for patients, families, and caregivers we serve.

References

1. https://accp1.onlinelibrary.wiley.com/doi/10.1177/0091270007311111
2. https://www.fda.gov/drugs/development-resources/model-informed-drug-development-pilot-program
3. https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.2265
4. https://pubmed.ncbi.nlm.nih.gov/31502691/
5. https://pubmed.ncbi.nlm.nih.gov/29446068/
6. https://pubmed.ncbi.nlm.nih.gov/30653670/
7. https://www.youtube.com/watch?v=7mS-jY4RGls

Charlotte Jones-Burton MD, MS, Otsuka Pharmaceuticals Development and Commercialization