Self-reliant developers can help
over-stretched regulators expedite reviews

By Amy McKee, M.D., Chief Medical Officer & Global Head, Oncology Center of Excellence

7 min

Self-reliant developers can help over-stretched regulators expedite reviews

New cell and gene therapy (CAGT) applications are inundating regulatory agencies worldwide, making it harder for companies to receive timely regulatory advice. Amy McKee, former FDA Oncology Center of Excellence Deputy Director and now Parexel’s Chief Medical Officer and Global Head of Oncology, offers three strategies to mitigate regulatory bottlenecks.

With more than 3,000 CAGT assets in the global pipeline at the end of 2022,¹ it is unsurprising that regulators are struggling to review the deluge of applications, some involving next-generation gene editing technologies. At the FDA, senior staff have departed the Office of Tissue Products (OTP), stretching resources further. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER), recently said that OTP is hiring aggressively to increase agency interactions with sponsors during the 30-day investigational new drug (IND) review period and potentially reduce clinical holds on gene therapies.² 

The agency could also use some help from drug developers. At Parexel, we advise clients to be more self-reliant and use data to inform their development path so that they can better defend their decisions. Here are three ways Amy Mckee recommends developers can do that:

Do more CMC preparatory work

Often CAGT companies wait for the FDA’s advice to make sure their assays and specifications for evaluating a drug substance and product are adequate. In my experience, developers can do more internal preparatory work, building a data-driven argument for why the chosen parameters are stage-appropriate and relevant to their product. Studying precedents from already-approved products can help. 

The scientific rationale for chemistry, manufacturing, and controls (CMC) decision-making—always important—becomes especially critical if you propose something novel to the agency. Sometimes there are no existing data or FDA opinions. In that case, companies may need to provide more evidence than they need to support their analytical methods and process steps.

Failure to compile robust internal data on a potency assay or comparability between manufacturing processes (or sites) can lead to costly delays, even during the biologics license application (BLA) filing stage. It is best to get an external opinion on the quality of your science and rationale—not just from regulatory consultants but objective scientific experts. Companies can become so immersed in their science that they neglect to challenge their CMC roadmap.

Mitigate that risk by providing a solid justification for every step of the validation or manufacturing process before presenting it to regulators in an IND. If there are six steps before the final one, justify all six, not just the last. 

Recently, I worked with a client developing a next-generation cell therapy with no precedent at the FDA. They had not optimized their manufacturing process and were not yet delivering the monotherapy doses specified in the protocol. Meanwhile, data emerged suggesting that combination therapy might produce a greater benefit to patients. They wanted to start a trial testing the new regimen immediately, but the cell therapy’s manufacturing process had not yet been optimized or reproduced. Each component of a combination regimen must be reliably manufactured and delivered before you can test them together. Nail down the basics before you leap ahead. 

I advise clients to make conservative stage-gate decisions in the context of a complete understanding of how the therapeutic landscape might change.

Amy McKee, M.D.

Scrutinize your clinical development plan

In the current environment, companies need to think critically about their overall clinical development plan and not assume that, because they are developing a novel CAGT, short-term efficacy data from a limited number of patients will suffice. Just because a product represents a scientific or technological breakthrough does not mean it delivers long-term results. 

I advise clients to make conservative stage-gate decisions in the context of a complete understanding of how the therapeutic landscape might change. Unless a product demonstrates unprecedented—and reasonably durable—efficacy, clinical development may require more time and money than a company anticipates. 

For example, in chronic conditions that are not life-threatening, the FDA has made clear it wants more follow-up data. And we are seeing this even with oncology products. We recently had a client who was surprised that the FDA pushed them for longer-term efficacy than the three-month mark, which served as the primary endpoint in their hematologic cancer trial. The agency wanted to know what happened to patients one year out: they wanted evidence that benefits persisted beyond three months. 

The first CAGTs approved in oncology produced results that changed the short-term narrative for heavily pretreated patients. But regulators are increasingly scrutinizing how the patient risk-benefit profile changes over time. And that profile is entirely different for conditions that are not immediately life-threatening, such as beta-thalassemia or sickle cell disease. In these cases, existing disease management involves procedures—such as repeated transfusions—that significantly decrease patients’ quality of life. In contrast, cell or gene therapy might eliminate the need for such procedures. The goal is to make life longer and better lived; it’s not to achieve short-term clinical outcomes.

Companies must think critically about whether the patient needs they are addressing would be better met by demonstrating the durability of the effect, as with many CAGTs, there will be no retreatment.

Think like a regulator, then make prudent tradeoffs 

Many emerging companies must make critical development decisions with limited resources. Two concerns are top of mind: how long will it take, and how much will it cost? Some seek to do the minimum required at each step. But when regulators do not have the bandwidth to provide frequent and timely advice, companies need to ensure that short-term decisions do not create long-term gaps or problems. What appears to be an economical option may result in costly rework.

One way to manage risk is to assume a regulator’s mindset and consider what a company should be doing. The answer is not necessarily to spend more time and money on everything. Instead, anticipate which questions regulators will ask and identify the data you need to answer them. This iterative process guides how you build your data package. In our work with clients, we rely on our team of former regulators to mock role-play meetings and reviews and help companies refine their arguments. We have found that meticulous preparation reduces delays and maximizes the benefits of ever more valuable FDA interactions. 

Regulators are scientists, and to convince them that you have made the right choices, you must show them how you made vital decisions step-by-step. To justify testing a CAGT in the clinic, you must offer a hypothesis that is understandable and supported by evidence. Too often, when I worked as a regulator, I saw companies try to dazzle reviewers with science and neglect the more mundane work required to support their proposition. Remember: the FDA and other agencies already have much experience regulating CAGTs and are not starry-eyed about novel technologies. They want all the traditional boxes checked and to hear compelling arguments.

Sometimes, a company may need to take a leap of logic in a critical manufacturing step. Word to the wise: do not try to skim over those leaps, hoping nobody will notice. Regulatory agencies may be willing to take that leap if you have acknowledged the potential flaws and examined alternatives. They are less likely to agree if they discover the leap themselves. 

When regulators do not have the bandwidth to provide frequent and timely advice, companies need to ensure that short-term decisions do not create long-term gaps or problems.

Amy McKee, MD

Contributing Expert

  1. Shields, A. et al. (2023) White Paper High Points and stumbling blocks in cell and gene therapy ..., Health Advances. Available at: (Accessed: April 1, 2023). Health Advances operates as an independent strategy consulting unit of Parexel International.
  2. Sutter, S. (2023) US FDA cell/gene therapy office 'aggressively recruiting' amid reorg, senior staff departures, Pink Sheet. Available at: (Accessed: April 1, 2023).