Bridging the perceived regulatory guideline gap for innovative medicines

Jörg Schneider | Associate Principal Consultant, Biopharma Excellence

There is a perception that regulatory guideline gaps across advanced therapeutic medicinal products (ATMPs) – or cell and gene therapies as they are referred to by the US FDA, are a serious issue. However, as I outlined in a recent presentation to the 2022 Euro Convergence meeting, these gaps are actually covered by the principles that are outlined in various guidelines. As outlined below these broad guidelines provide a good starting point for discussions with regulators.

While regulators recognize more needs to be done to streamline and simplify the process for innovators, the speed of innovation and the diverse scope of technologies being researched does require a broader approach by the regulators, at least until a technology moves further along in the development pipeline and into wider use by patients. It is at this point that more specific regulatory guidelines tend to be published.

To better understand the progress of regulations, it’s important to explore the stages and forms of innovation, which is itself dependent on what is driving that innovation.

Drivers for ATMP innovation

Much is happening across the board in ATMP R&D, made possible by three major drivers: technological progress, investment and medical need.

The first of these is the speed of technological progress in tools and platforms feeding the stream of novel potential biopharmaceutical products. Several of these breakthrough technologies have already reached the market, including CAR-T cells, gene replacement therapies, oncolytic virus therapies, and bispecific antibodies and antibody-drug conjugates (ADCs). Many others are in early stages of clinical development, including gene editing, bioprinting, extracellular vesicles/exosomes, DNA origami technology, and live biotherapeutic products

The second major driver is investment and the rapid changes in funding models. Conventional ways of fundraising will continue for the long term – venture capitalists, raising money through research organizations and from grants. But there is also a new wave of investment approaches. Crowd funding has become a bigger phenomenon, particularly for rare diseases. But perhaps the most novel approach is biohacking, which has been described as “do-it-yourself biology aimed at improving performance, health, and wellbeing through strategic interventions[i].” While biohacking is hugely varied, in the scientific community and within the more moderate branches of biohacking, there is an objective to bring solutions to people with serious disease by developing treatments faster than companies are able to.

A third major driver is, of course, medical need, which is what spurs scientists and technology experts, as well as families of those suffering from disease, to seek treatments and cures. This need has led to extraordinary innovation. As an example, Intellia Therapeutics has conducted first-in-human gene editing trials for patients with transthyretin (ATTR) amyloidosis, with recent data demonstrating a reduction in serum levels of transthyretin, or TTR, was maintained in patients for a year. This finding will be key to further research and to securing more funding.

Regulating early-stage innovation

These innovations might not have specific guidelines, but there is broad guidance. For example, the Guideline on Human Cell Based Medicinal Products from European Medicines Agency (EMA) covers everything from concept, to quality and manufacturing, to nonclinical and to clinical. At the other end of the spectrum, there are guidelines with a more limited scope specific to a product class such as the ICH’s Considerations: Oncolytic Viruses.

The FDA has produced several guidances for cell and gene therapies, including two this year. The first is Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, which is also applicable to other genetically modified lymphocyte products, such as CAR Natural Killer (NK) cells or T cell receptor (TCR) modified T cells. A second significant guidance from FDA this year is Human Gene Therapy Products Incorporating Human Genome Editing, which is a multidisciplinary guidance on gene editing approaches.

Two other very exciting areas that I have been more heavily involved with in providing cell and gene therapy consulting, and which are in early-stage development, are extracellular vesicles and bioprinting. While there are no specific guidelines for these yet, both are supported by various different guidelines as well as from leading professional societies.

In the case of exosomes and extracellular vesicles, there are two different issues and therefore regulations at play. EVs and exosomes are both biologics with the potential to be therapeutics in their own right as well as cell-derived delivery systems, and the regulatory guidelines companies would need to apply depends on what they are trying to deliver. In addition, recommendations from the International Society for Extracellular Vesicles (ISEV) provide some guidance for studies into EVs.

Bioprinting is another exciting area of research, which combines living cells and biomaterials to fabricate biomedical parts. It’s a field that has potential in drug development, replacing living subjects to support studies into a drug candidate’s efficacy; it has potential in wound healing; and ultimately it could be used for organ replacement.

Such products therefore fall under several different guidelines. They are cell therapies so cell therapy guidelines are relevant, but there is also highly sophisticated machinery involved, so guidelines for the manufacturing of devices is also relevant. Once the bio printed product has been produced it needs to be tested, not only as a cell therapy but as whole, and here ISO guidelines for the biological testing of biomaterials apply to determine how compatible the product is with the part of the body that it will be inserted into or applied.

This is another field where industry guidelines are invaluable. The American Society for Testing and Materials has published a raft of documents or guidelines for how do test these products as potential organ replacement, including how to test tensile strength, and lays out specifications and performance standards for medical and surgical materials and devices.

Early regulatory collaboration

While the regulatory processes involving ATMPs can be complex, particularly for technologies that don’t have specific guidelines, companies do need to be ready to engage with the regulatory authorities early on. The priority should be to get the development plan and data lined up and justified, then prepare to talk with the regulators.

Regulators are eager to get these novel technologies approved and to patients in need. Across the EU and the US, there are programs in place offering early scientific advice and companies should be taking advantage of these.

About the author:

Jörg Schneider is Associate Principal Consultant, Biopharma Excellence, providing biotech regulatory consulting to companies and innovators working with ATMPs.  Learn how we can help you with your regulatory agency interactions.

[i] Aimed at improving performance, health, and wellbeing through strategic interventions, February 2021,

[ii] Biohacking: The Ethical Implications of Democratizing Biotechnology, October 2021,




[vi] New Guide for Bioinks and Biomaterial Inks Used in Bioprinting Tissue-Engineered Medical Products, ASTM International,

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