Guest Column | January 12, 2024

Need To Improve Your Change Management? Regulators Can Help With That

A Conversation with Ben Stevens, GSK

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As drug sponsors strive to keep increasingly complex products and processes in compliance with global regulatory authorities, understanding how to successfully navigate change management protocols is critical. While products and processes evolve over the course of their lifecycle, sponsors may find limitations within their initial protocols that need to be adapted or harmonized with global regulators as they expand to new markets.

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) released the ICH Q12 guideline, “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management” in 2019 to address technical and regulatory considerations for pharmaceutical lifecycle management. ICH Q12 includes the post-approval change management protocol (PACMP) which helps guide drug developers in how to implement changes to an approved protocol during the commercial phase.

To help sponsors navigate their first PACMPs, organizations like the International Society for Pharmaceutical Engineering (ISPE) have established working groups focused on ICH Q12. ISPE’s working group has been active since 2019. Its mission is to support and facilitate adoption of ICH Q12 by regulatory agencies and the implementation of ICH Q12 principles by the industry. One such member of this ISPE working group, Ben Stevens, Director of CMC Policy and Advocacy at GSK, previously worked for the U.S. FDA where he reviewed comparability protocols, the FDA equivalent of PACMPs. After assessing protocols from both sides, his unique insights can help inexperienced sponsors conduct change management successfully.

We caught up with Ben to learn more about how the state of change management protocols has evolved, what strategies are available to minimize bottlenecks, and how enhanced protocols might be the wave of the future. The interview has been edited for clarity and length.

As modalities, technology, and processes grow more complex, how are change management practices, well, changing?

Stevens: As products and processes get more complicated, it's likely that you'll have to deal with more change management. Companies have had to address extensive post-marketing regulatory requirements as they become increasingly difficult to manage. This is exacerbated by the fact that the classifications under which you file changes globally are not aligned globally. You're not just dealing with more changes, you're also dealing with the fact that the impact, the way you register, and the amount of time it takes to review and implement, are inconsistent.

The industry relies heavily on project planning and risk management. There’s an extensive need for project planners and post-marketing teams to build in risk management around any hurdles or delays. This must be clear to the organization so that they can effectively implement changes. When a change is particularly ambiguous or high risk, we seek direct regulatory feedback. PACMPs have already gotten a lot of use in managing changes and are rapidly becoming a critical tool for extensive change management. Long-term, ICH Q12 is one of the areas that a lot of companies are moving towards implementing to manage more complex and frequent changes. ICH Q12 aims to enable more effective registration and management of “established conditions” by clarifying the scope of changes that require regulator notification and allowing for the downgrading of filing classification of some change categories with supporting justification and effective quality oversight. Though this is in the early stages of implementation, this is a big part of where lifecycle management is moving.

What are some common bottlenecks or blind spots companies should watch for when doing change management?

Stevens: It sounds a bit odd to say, but a lot of change management bottlenecks come from your initial filing. With complex products, companies frequently over register or put in too much information regarding specific aspects of the process or the product that don't impact quality. Often people will inadvertently file part numbers or inconsequential details about container closure or process components, which becomes something that has to be managed through post-marketing filings. It's not that the impact is necessarily high, but you still have an administrative requirement to make sure what you're doing is consistent with the registered information in the dossier.

Another bottleneck is the ability to deal with a harmonized global dossier, which to some extent is more of an ideal than a reality. It's almost impossible to get one global dossier. However, if an organization can strive towards having most of the information in their global filings consistent, it ensures more effective change management because you don't have the issue of having to treat each region distinctly during impact assessments. If you have registered information that's different in some regions, it can create a lot of bottlenecks in post-marketing.

Ensure that you're benefiting from meetings with regulators. Sometimes companies try to avoid extra interactions with agencies, but it can be effective to make sure that changes are pre-aligned before you start to file and implement them within your pharmaceutical quality system. If you file the changes without aligning, you may see differences in the outcomes, leading to a lack of harmonization in your global dossier.

The FDA has a different term for what ICH calls PACMP, it's "comparability protocols." Is that where the variation ends? How do change management expectations vary across regions?

Stevens: Both the U.S. and EU have used these protocols for a long time, and fundamentally, there aren't many differences between the way they treat them, or more broadly, the way it's treated under ICH Q12. The one thing that has been somewhat apparent is the fact that the FDA has been more receptive to the idea of an enhanced protocol, which is a single master protocol that is being used across multiple products.

There's still not a ton of experience with this, but the FDA seems amenable to that approach, whereas we haven't seen that receptiveness in other regions that have implemented ICH Q12. They are focused more on protocols being part of each product’s marketing application. When you think about platform technologies for mRNA or monoclonal antibodies, enhanced protocols are where things must go. Hopefully, global regulators will move towards accepting this approach.

The other thing to consider is that PACMPs are just starting to get implemented under ICH Q12 in ICH regions. In addition to the U.S. and EU, Canada, Japan, Brazil, and China have technically implemented PACMPs. We’re starting to see some differences in the way those regions treat PACMPs. For example, China’s NMPA requires a consultation prior to submission of a PACMP, which isn’t a requirement in the U.S. or the EU. NMPA is in the early days of implementation, so they’re trying to be proactive about agreeing to these within a pre-submission discussion. We’re going to see a lot of differences emerge in the coming years.

If my company’s preparing for a significant CMC change, and I’ve never done a PACMP or CP before, where do I start?  

Stevens: The guidance is a pretty good place to go first: ICH Q12, the FDA's comparability protocol guidance, and the EMA’s Q&A on PACMP. On the ICH website within the ICH Q12 area, there is an extensive amount of training material provided by the working group that set out the original guidance. PACMPs are treated extensively within that training material. There are a couple of good literature references that give some general indication of how PACMPs work, and how they function within the broader ICH Q12 framework. [Editor’s note: check out our further reading section].

Benchmarking is a good way to go. If you've never done a PACMP before, having direct input from folks who've lived it is helpful. For facility changes, there is a lot of experience with PACMP registration, and there are oftentimes good avenues for doing initial benchmarking via online forums. Conferences can also help with PACMP benchmarking. It may also be worth reviewing some of the recent output from the International Coalition of Medicines Regulatory Authorities (ICMRA) regarding their PACMP pilot. The idea behind this pilot is to create a joint PACMP assessment process across several global regulators to provide a single, harmonized protocol. This pilot is just the beginning, as we’re also seeing growing recognition from health authorities that joint assessment and mutual reliance are critical tools in the regulatory process (e.g., see the Medicines and Healthcare products Regulatory Agency’s [MHRA’s] recent International Recognition Procedure which has just gone live).

Let's take it a step further. My company just got its first PACMP or CP approved. What pitfalls should I watch for as we start implementation?

Stevens: It’s important to keep an eye on the ability to adhere to the initially registered protocol. If you don't have a lot of experience registering within the organization, you can commit to too much within the registered protocol. Down the line, technical folks executing the work may report that they're not going to be able to meet some of the agreed elements. There may be some panic if there isn't pre-alignment on how to handle that situation. It can lead to delays in communicating with the regulators.

In a lot of ways, PACMPs are about trust. You're agreeing to something and making the commitment to follow through on it. The worst-case scenario is folks taking the risk and not communicating deviations to regulators. That can create a lot of problems. Even if you can work through it when you're submitting the results of the studies and the change to that protocol and get past it, it doesn't leave a good impression with the regulators. This can impact you long-term as a company when you're trying to establish trust.

Ensure that you have a strong agreement internally on the strategy you're going to use if there happens to be a deviation. When you initially design the protocol, be sure to not commit to things that you can't deliver on. When you file the information to make the change, regulators like to see the original protocol submitted with that data to ensure that you're meeting the requirements of the pre-agreed protocol.

Finally, it is critical to ensure your organization continues to work within the scope of any PACMP that is not registered for a one-time change. As the organization changes and you start to work with new CMOs or subject matter experts, there needs to be continuous awareness that these protocols are in place and locked into a registered dossier.

Further Reading:

  1. Case Study: Facilitating Efficient Life-Cycle Management via ICH Q12
  2. A Path Forward to Optimize Post-approval Change Management and Facilitate Continuous Supply of Medicines and Vaccines of High Quality Worldwide
  3. ICH Q12: A Transformational Product Life-Cycle Management Guideline
  4. A Vision for ICH Q12: Current Experience, Future Perspectives
  5. ISPE Team Assists Health Canada with Training on ICH Q12 Implementation
  6. Related: ISPE Comments on FDA ICH Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management

About the Expert:

Ben Stevens is a director of CMC policy and advocacy at GSK and has nearly 15 years of drug discovery and regulatory experience. Before GSK, Ben was a director of regulatory affairs CMC at Alnylam where he led the clinical regulatory CMC development of vutrisiran prefilled syringe in over 30 countries and the initial U.S. NDA and EU MAA submissions. Before Ben joined Alnylam, he was a principal consultant at PAREXEL and an acting branch chief in the Office of New Drug Products at the FDA. Ben represents GSK in numerous external trade and association working groups, where he has led and supported policy positions and interactions with global regulators. He received a Ph.D. in chemistry from the University of Pittsburgh, an M.P.H. from the Johns Hopkins Bloomberg School of Public Health, and is a co-author of more than 30 publications and patents.