Five regulatory pitfalls for cell and gene therapies in the US, EU, and China, and how to avoid them

Precaution: Design a phase-appropriate CMC roadmap

CAGT developers struggle with a core question: Why should we invest early and heavily in chemistry, manufacturing, and controls (CMC) before knowing if a product works? Under pressure from investors, strapped for cash, or using an expedited regulatory mechanism that compresses development, they must balance the time and cost of every decision. However, small CMC shortcuts and gaps can grow into outsized problems. 

For example, emerging companies often struggle to identify, qualify, and validate appropriate potency assays. These are critical for CAGTs because regulators want proof that the manufacturing process yields a product with consistent, measurable quality characteristics. And when a sponsor modifies the process during development, which is inevitable, agencies will need evidence that the commercial product is comparable to the one used in clinical trials. 

A typical scenario occurs with companies that in-license technology from an academic institution. At some point, say, a post-doctoral student developed an assay and even published the data. But assays that work for peer-reviewed journals may not necessarily comply with Current Good Manufacturing Practice (CGMP) regulations. The developer may be tempted to overlook that they cannot reproduce the assay and proceed without addressing the problem. Since every stage in the manufacturing process is inseparable from the others, such a misstep will have negative consequences.

At Parexel, we advise CAGT clients to develop phase-appropriate potency assays. Characterize a product’s critical quality attributes stepwise, progressing from a functional to a cell-based assay. There is no need to develop a biological assay that fully reflects the product’s mechanism of action for Phase 1 trials. In most cases, an assay measuring a function that gives reasonable assurance of activity, such as the protein expression of an introduced gene, is sufficient. Based on our knowledge of FDA requirements, we analyze gaps and prioritize product characterization tasks into those that need immediate attention versus those that can be addressed two years later. 

The answer to CMC challenges is not always to start earlier, spend more, and take longer. It is possible to work a little harder and a good deal smarter. Devising a CMC roadmap, complete with a timeline of regulatory expectations, is prudent. For CAGTs, there is typically less time for product characterization and manufacturing refinements than for other modalities because Phase 1 trials can readily morph into pivotal efficacy and safety trials. A CMC roadmap and a tightly organized approach can be crucial factors in determining success or failure.

Precaution: Develop a disciplined scientific and clinical rationale

Imagine you are an FDA reviewer: you have 30 days to review an investigational new drug (IND) application for a novel cell or gene therapy. You must preserve at least half that time for back-and-forth queries with the sponsor and internal agency discussions. Would you like to read a poorly written, relatively unstructured 300-page document? Faced with complex scientific issues, a tight deadline, and the need to ensure patient safety, you might be forced to place the IND on clinical hold if you cannot digest the data quickly enough.

When I reviewed CAGT IND applications at the FDA, I found that even leading companies with impeccable scientific credentials routinely submitted unwieldy IND dossiers. Recently, I worked with a client that tested its drug in six different animal models as part of its preclinical program. Why? They realized that the standard animal model used in their target indication would not provide interpretable data given their drug’s mechanism of action (MOA). They did significant extra work to overcome that model’s limitations, relying on different animal models to address particular safety and efficacy issues. However, their IND application simply included the data from all six experiments without sufficient explanation. There was no narrative about what they learned from each or why they felt compelled to do so many. Can FDA reviewers ultimately wade through this and still have time for interactions with the sponsor and their supervisors? Yes. Can they do it in 30 days? Maybe not, given their heavy workload and competing priorities. 

FDA reviewers want to read a well-organized and structured document. The logic and reasoning must be transparent. If it is, clarifications may not be necessary. Too often, sponsors will lavish time and attention on their clinical story, including the unmet patient need and treatment landscape, but treat the CMC and nonclinical sections as a compendium of data that needs no summary. In fact, these sections should tell a concise scientific and technical story. IND applications need to deliver three arguments: 1. The target validation and MOA for the product; 2. The rationale for selecting a specific disease and patient subpopulation; and 3. How the optimal starting dose for a first-in-human trial was determined and why the product’s benefit-risk profile is favorable. 

Although CBER resources are currently stretched, it’s a good idea to seek a pre-IND meeting before submitting an IND application. Nowadays, the FDA usually handles these via Written Response Only (WRO), which has reduced delays in pre-IND scheduling. Since companies may not speak directly with agency reviewers for long stretches, it is critical to prioritize your questions and frame your position succinctly. It takes time and discipline to think and write clearly, but companies can build rapport with the agency team reviewing their program by doing so.

Precaution: Know the guidelines

The EMA leads the world in cell and gene therapy approvals. The agency has licensed 17 Gene Therapy Medicinal Products (GTMPs) as of April 2023, five more than the FDA. Most were developed with extensive regulatory guidance: for example, 86 percent utilized the PRImary MEdicines (PRIME) scheme (Table 1). GTMP developers who win PRIME designation enjoy early appointment of a dedicated Rapporteur, tailored support, iterative Scientific Advice (SA), Protocol Assistance (PA), and faster review times. For companies that do not win PRIME (and those who do), the EMA has published dozens of guidelines on developing a GTMP. Sponsors would be well advised to study these guidelines thoroughly because knowing them is critical to success.

For example, the EMA established the Innovation Task Force (ITF) to help developers with innovative products, methods, and technologies. Sponsors can apply for a 90-minute ITF Briefing Meeting to discuss methodological and technical issues with subject matter experts from the EU regulatory network. They can also seek advice from the EMA’s Scientific Advice Working Party (SAWP). Yet I regularly speak with companies that do not know these programs exist.

Companies must have a working knowledge of all the relevant guidelines before meeting with regulators. One sure route to a clinical hold is to not prepare adequately before attending a meeting with agency reviewers. For example, the EMA has developed a clinical development checklist for advanced therapy medical products (ATMPs) such as GTMPs. Companies must be familiar with the checklist before they seek advice. To date, fifteen of the 17 GTMPs approved by the EMA are orphan medicines. Since single-arm open-label clinical trials are common in rare diseases, many companies gather real-world evidence (RWE) to compile more comprehensive data. But designing a retrospective RWE study is pointless if the methodology is flawed. Guess what? The agency recently published a guideline on how to design more rigorous registry-based studies.

EMA data show that communicating effectively with regulators is vital to success: companies that seek SA on trial designs have higher success rates, shorter development times, and fewer objections during the assessment process. Developing GTMPs is complex and involves unexpected obstacles. Getting advice from seasoned assessors who have seen what other sponsors encountered can be critical. But companies cannot dash off a request for an SA meeting every six months. That would be expensive and time-consuming, and the SAWP does not have the resources. Instead, companies must devise a clear strategy that includes planned agency interactions at strategic time points and then prepare diligently. You may not need more than one or two agency meetings to find an efficient path you can pursue to the end.

Precaution: Navigate the dual-track system strategically

China has emerged as a leader in cell and gene therapy (CAGT) clinical trials, with 953 studies initiated as of March 2021.³ However, most of these are early-stage studies. Despite a high level of R&D in China, the National Medical Products Administration (NMPA) has approved just a handful of cell and gene therapies to date (Table 2). Many smaller biotech companies do not realize that two independent pathways govern clinical trials of CAGTs in China. One is administered by the National Health Commission (NHC) and enables investigator-initiated trials (IITs) at universities and academic research hospitals. The IIT application requirements may vary across hospitals, and commercializing drugs is not the aim of this pathway. The other regulatory route is designed to support approval and is under the jurisdiction of the NMPA. 

Some companies have personal relationships with Chinese principal investigators (PIs) or academics and prefer to run early-stage trials under the IIT system. They may not realize that the Center for Drug Evaluation (CDE) will likely challenge the manufacturing work with respect to controls and criteria used to produce the investigational medical product (IMP). This can cause significant delays. Although official NMPA documents suggest that IIT data can be acceptable, it rarely is in practice because of concerns about data integrity and IMP quality and consistency. For anything but a single-center pilot study, we advise companies to conduct studies under a Clinical Trials Application (CTA) with the NMPA.

The NMPA offers a pre-CTA meeting, and it especially encourages these for CAGT applications. Up until a few years ago, it could take one or two years to schedule one. Now, regulators must respond within a prespecified period—from 30 to 75 working days, depending on the meeting type. Requests for additional information can extend that timeline considerably. In our experience, it typically takes 60 working days to get a written response and, possibly, a face-to-face for a type II meeting request. 

Since 2015, a slew of reforms has improved the Chinese regulatory landscape for foreign companies. In May 2021, China was reelected to a three-year term on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) management committee, further aligning it with international regulatory standards. With a large population of treatment-naïve cancer patients, lower study costs, and faster recruitment times, China remains a strategic priority for many pharmaceutical companies. But developers can stumble because of cultural and linguistic factors and unfamiliarity with the system: learning how it all works is essential for success.

[FPO: INSERT TABLE HERE]

Precaution: Categorize FDA comments into ‘hold’ and ‘non-hold’ issues

The FDA provides two types of feedback when it reviews an investigational new drug (IND) application: general questions, expectations, and comments on the overall development program and specific “potential clinical hold” and “non-hold” comments on proposed clinical trial protocols. Many companies may panic during the IND review process because they do not know which comments are genuine clinical hold issues to address immediately, which are essential but non-hold issues to address during development, and which are nice-to-haves. 

For example, a boilerplate agency comment is, “We recommend that you conduct randomized, double-blind, placebo-controlled clinical trials from the first-in-human trial forward.” A CAGT company recently asked us whether the agency would put them on hold because they did not believe a placebo control was ethical or feasible for the initial trial in their target patient population. That is an example of a non-hold comment for a cell or gene therapy: most Phase 1 trials of these modalities are single-arm and open-label. However, the comment may be more significant for pivotal efficacy trials: the agency may not impose a clinical hold, but they might argue that you have not collected enough rigorous evidence to approve the Biologics License Application (BLA). It takes experience and historical perspective to rank FDA comments into hold and non-hold categories and determine how and when to address them strategically and effectively. 

Many CAGT companies wonder if they can “get away with” studying just one dose in Phase 1 if they do not have the manufacturing capacity to produce multiple doses. While that is not necessarily a hold issue, the FDA is calling for more dose optimization efforts from sponsors, especially in cancer indications. Project Optimus, a new initiative of the FDA’s Oncology Center of Excellence (OCE), seeks to improve how companies choose which product dose and schedule to test in trials. Companies that don’t generate adequate data to justify their Phase 2 dosing strategy could face significant delays, including clinical holds. One solution is to combine adaptive designs for data-rich early dosing studies with pharmacodynamic modeling and simulations. 

The pre-IND meeting and, for biologics, the Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) meeting are valuable opportunities for CAGT companies to vet plans for the Phase 1 trial design and dose optimization. When I worked at the FDA, we offered that advice in pre-IND sessions, but we also provided “big picture” comments on their overall development program. In their eagerness to meet tight budgets and hit short-term milestones, sponsors may not listen as carefully to more strategic advice. At Parexel, we advise clients to be alert to all agency comments, prioritize them, and act accordingly.