Guest Column | November 9, 2023

What Regenerative Medicine Manufacturers Have Been Waiting For

By Mark A. Tobolowsky and Richard A. Lewis, Hyman, Phelps & McNamara

Multi ethic laboratory scientists-GettyImages-1251894006

On Oct. 20 FDA announced the availability of the final guidance authored by CBER titled “Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies.” It finalized a draft guidance published in 2022. Although fairly short and light on substance, it has the potential to reshape the industry in ways that are sorely needed.

In short, voluntary consensus standards (VCS) are intended to be exactly what the name conveys – standards that are adopted by consensus and are not mandatory (not legal or regulatory requirements). These standards would be developed outside the federal government, leveraging the expertise of the private sector. This program is modeled after a similar program in place for medical devices, the formal standards and conformity assessment program (S-CAP). In the device world, the benefits of voluntary consensus standards are two-fold:

  • Sponsors are able to refer to standards for protocol design, generating a potentially massive time saving in development.
  • If a sponsor provides a study report that conforms to a consensus standard, FDA does not need to spend time reviewing the details of the protocol and can focus reviewer resources on the results and their meaning for an application.

The hope with this new program is that it can similarly benefit the development and review of regenerative medicine therapies. It is not especially novel even within CBER, as previous publications had encouraged the use of standards in product development. However, in creating a standards recognition program (the “standards recognition program for regenerative medicine therapies”, or “SRP-RMT”), this guidance has the potential to get regenerative medicine to a place where it has struggled to reach: standardization.

We have heard clients and other stakeholders repeatedly express frustration with the absence of standards in regenerative medicine. We are also aware that FDA spends a tremendous amount of time and resources answering the same questions for sponsors. For example, CBER’s Office of Therapeutic Products (and its predecessor the Office of Tissues and Advanced Therapies) has held six town hall meetings in the past 13 months (by our count) on the following topics: gene therapy CMC, cell therapy CMC, clinical development of gene therapy products for rare diseases, gene therapy CMC (again), cell therapy CMC (again), and nonclinical assessment of cell and gene therapy products. These meetings have a question-and-answer format to provide clarity to sponsors about the particular topics at hand. The town hall meetings are initial steps toward both standardization and efficiency that the new program seeks to advance.

FDA needs assurances regarding the safety, purity, and potency of regenerative medicine products to approve them. Because this is a relatively new field that has exploded in recent years in terms of the diversity of medical products, there are a lot of unanswered questions as to how this can be demonstrated. A considerable roadblock in the development of RMT products is a lack of regulatory predictability. Voluntary consensus standards will not design the measuring tools, but they will help companies validate these tools and define acceptable results. While on the surface this may not seem like major advance for the field, this could be a game changer for the gene therapy space. While the diseases and conditions being investigated are very diverse, the treatments, delivery systems, and measuring tools have a high degree of overlap across this entire sector. The implementation of voluntary consensus standards to methodologies that assess potency or safety could yield a profound acceleration in new treatments.

The absence of standards was a focal point of the Cellular, Tissue and Gene Therapies Advisory Committee meeting in September 2021, which was convened to discuss the toxicity risks of AAV vector-based gene therapy products. The minutes from that meeting reflect the discussion on that topic well in a wide variety of areas:

Regarding the merits and limitations of animal studies to characterize risks and recommendations on specific preclinical study design elements: “Current scientific gaps/limitations, emerging technologies for integration analysis, and the value of developing and standardizing methods were discussed.”

  • Regarding the risk of oncogenesis: “Monitoring for signs of hepatocellular carcinogenicity could be done by adopting standard approaches.”
  • Regarding screening for risk of liver injury: “Total and/or neutralizing antibody titers are screened in many clinical studies, but how such testing is performed, the cut-offs, and the acceptance criteria are all variables that may need standardization.”
  • Regarding the risk of hepatotoxicity with high doses: “An arbitrary upper limit of the total vector genome dose or total capsid dose is not recommended, as it is hard to standardize vector measurements across studies or to determine if there is an appropriate upper limit. … Assays for empty capsids need better standardization.”
  • Regarding the risk of thrombotic microangiopathy with high doses: “One challenge for recommendation of an upper limit on vector dose per subject is the lack of reference standards, limiting the comparison of critical quality attributes across sponsors and/or products.”

And here we stand today, on the brink of potentially transformational change to the industries affected – in theory. The new guidance notes that “[i]ncreased development and use of standards has the potential to contribute to regulatory predictability and facilitate the overall development of safe and effective [regenerative medicine therapy] products.” The guidance describes the following as potentially being suitable for the VCS recognition program:

  • Common rules, conditions, guidelines, or characteristics for products or related processes and production methods.
  • Definition of terms; classification of components; delineation of procedures; specification of dimensions, materials, performance, designs, or operations; measurement of quality or quantity in describing materials, processes, products, systems, services, or practices; test methods and sampling procedures; formats for information and communication exchange; or descriptions of fit and measurements of size or strength.
  • Terminology, symbols, packaging, marking or labeling requirements as they apply to a product, process or production method.

The guidance describes elements that would be required of VCS bodies for recognition of standards they adopt: openness (with meaningful opportunities to participate), balance (broad range of stakeholders), due process, an appeals process, and consensus. Consensus does not require unanimity, but a general agreement. The standards would, as stated previously, be voluntary, unless mandated by statute or regulation, and they cannot conflict with existing law or regulation.

Existing published VCS may be identified internally by FDA or externally by stakeholders. CBER would receive a candidate VCS from FDA staff or external stakeholders (the guidance includes a specific email address for this purpose), determine within 180 days, as resources permit, whether to recognize it in whole or in part, and then list recognized standards on its website along with summaries for future use.

As previously stated, the novelty of this guidance and the SRP-RMT program is not the use of standards, but rather the publication of standards publicly acknowledged by FDA to be generally appropriate. CBER may still request additional information when deemed appropriate, but the stated hope is that increased use of VCS can facilitate product development by reducing the need to develop unique methods for individual products and that they will typically reduce the amount of necessary documentation “and may reduce FDA review time.”

Only time will tell how successful this program will be, but there is certainly the potential for order to come to the field of regenerative medicine, where there is currently a frustrating amount of variability and uncertainty. Perhaps even more encouraging is the fact that FDA is deferring to the expertise of the private sector. The agency is turning to the players who struggle intimately with this variability and uncertainty in their efforts to meet FDA’s standards and get regenerative medicine therapies to patients. By collaborating with the private sector, the hope is that FDA can leverage the expertise that such close familiarity engenders and can provide sponsors with some level of clarity and consistency for their development programs. Not only does this provide an opportunity for sponsors and other stakeholders to shape FDA policy and to provide leadership on crucial unanswered development questions, we can only hope it will deliver answers (or at least options) for sponsors dealing with these challenges where there are currently few certainties.

A version of this article was published first on Hyman, Phelps & McNamara’s FDA Law Blog. It is republished here with permission.

About the Authors:

Mark Tobolowsky is an associate at Hyman, Phelps & McNamara, where he focuses on drug development counseling and helps developers find creative solutions to unexpected challenges. Previously, he worked for more than 10 years the FDA legal and regulatory field where he gained developed a passion and experience with regenerative therapy development. He earned his J.D. from Washington University in St. Louis School of Law.

Richard Lewis is a senior regulatory device and biologics expert at Hyman, Phelps & McNamara. He started his career in the FDA’s Center for Devices and Radiological Health in the division of chemistry and toxicology. Later, he moved to CBER’s Office of Compliance and Biologics Quality where he worked on manufacturing reviews and pre-license inspections. While at CBER, he was the principal advisor for all device submissions in Manufacturing and Review Branch 2.