Summary of Session 5: Regulatory Updates 17 August 2023
Gabrielle O’Sullivan and Craig Wright,
Royal Prince Alfred Hospital, Sydney
TGA Presentation: Regulation of cell and tissue therapies, an update
Dr Glenn Smith, Director Biological Science Section, Therapeutic Goods Administration (TGA), Canberra, Australia
The TGA representative gave an overview of what is, and is not a biological, how biologicals are classed according to the level of risk to patients associated with their use, and the regulatory pathways for biologicals. The classes range from Class 1 (low risk, faecal microbiota transplant products subject to certain conditions are the only products defined as Class 1 biologicals at present) to Class 4 (high risk, e.g. gene modified cells, iPSCs, xenogeneic cell therapy), and are assigned based on the level and method of processing of the biological, its intended use, and the extent of external governance and clinical oversight for its use. The regulatory pathways for clinical trials are the Clinical Trial Notification (CTN) and Clinical Trial Approval (CTA) pathways. Human Research Ethics Committees (HRECs) review both CTNs and CTAs, whereas the TGA reviews safety data for CTAs but not CTNs as CTNs are notifications after HREC review. All Class 4 biologicals are CTAs, unless there is evidence supporting a CTN from previous clinical trials, or an approval for an equivalent indication from a comparable national regulatory authority. First-in-human trials are exempt from GMP but any trials after first-in-human require GMP. Dr Smith also provided updates on the recent Priority Pathway and the Export Only Pathway for biologicals.
OGTR Presentation: An update on the regulation of human clinical trials with GMOs
Dr Sarita Dhounchak, Assistant Director, Office of the Gene Technology Regulator (OGTR), Canberra, Australia
The OGTR representative described the different types of authorisations required in Australia to work with GMOs (Exempt, NLRD, Licence, GMO Register, Emergency Dealing Determination), the role of Institutional Biosafety Committees (IBCs) in assessing applications, the risk analysis approach taken by the OGTR in assessing licence applications, and the ways in which the risks are managed through licence conditions. An OGTR licence is required for in vivo gene therapy using viral vectors, viruses or other infectious agents. No licence is required for ex vivo gene therapy (such as gene modified cell therapy) if no viral vectors, viruses or infectious agents are present in the cells and there is no intentional release into the environment. Ex vivo gene modified cell therapy would require a licence if these exclusion criteria are not met. Samples from patients treated with viral vectors or GM-viruses under a licence are regulated if the samples contain the GMOs. Regulatory innovations were outlined such as the new broad AAV gene therapy licence by which a standard licence for AAV clinical trials can be issued by the Regulator if certain conditions are met by the licence holder. This will remove the need for case by case assessments where the conditions are met. Also the OGTR has a Practice Review Program which can help organisations assess their capacity to meet licence conditions in advance of a trial commencing.
New Zealand EPA Presentation: Current GMO and biotechnology regulation in New Zealand
Dr Tim Strabala, Principal Scientist, New Organisms, Hazardous Substances and New Organisms, Environmental Protection Authority (EPA) NZ, Wellington, New Zealand
The EPA representative described the Hazardous Substances and New Organisms Act (1996) (HSNO Act) under which all organisms that were not present in New Zealand on or before 29 July 1998 are regulated as new organisms and must be approved by the New Zealand Environmental Protection Authority (EPA) before they can be released into the environment. This includes GMOs. The available approval pathways are Importation into Containment, Development in Containment, Field Test in Containment or Release With or Without Controls. Interesting examples were given such as gene edited Auckland Island pigs (Indoor Containment), specific types of CAR T-cells in clinical trials (Medicine Release With Controls), and CARVYKTI (Medicine Release Without Controls). The EPA also has the power to determine what is and isn’t a GMO on a case-by-case basis. For example, it determined that certain mRNAs in lipid nanoparticles are not GMOs. Māori Engagement is essential to EPA decision making and the EPA has a Māori Engagement unit that can assist with this process. The New Zealand Government is consulting on changes to the HSNO Act to improve New Zealand’s ability to conduct medical research and a number of changes related to GMOs have been proposed.
FACT Presentation: The role of voluntary accreditation in cellular therapy: an update from FACT
Prof Phyllis Warkentin, Chief Medical Officer, Foundation for the Accreditation of Cellular Therapy (FACT), Professor of Pathology /Microbiology and Pediatrics University of Nebraska Medical Center Omaha, NE, USA
The FACT representative outlined the role of FACT in accrediting cell therapy services around the world using a peer-based audit review system. FACT has a main goal of being among the primary global accreditation bodies for cell therapy. FACT and JACIE have aligned to ensure harmonised standards and improved patient safety across borders and streamlined accreditation processes. It was noted there has been a large increase in the number of cell therapy programs being FACT accredited since 2016 and this includes over 10 Australian sites. A major aim is to provide confidence in FACT accredited centres for multiple third-party commercial providers of cell therapy products (e.g. CAR T cell manufacturers) to reduce the burden of multiple audit and on-site inspections by many different organisations as occurs now. The value of peer-to-peer inspections for learning and teaching was discussed, as well as a new FACT Audit and Inspection assessment service that is being developed.
Summary of Session 6: ‘Ask the Regulator’ Session, 17 August 2023
By Kasey Kime,
Co-Chair of the ‘Ask the Regulator’ session
Director of Regulatory Affairs - Cell and Gene Therapy, Thermo Fisher Scientific
In this session the conference delegates were provided with three scenarios for discussion as outlined below.
In scenario 1 we discussed the complexities with the clinical trial pathways for high-risk biologicals (Class 4) manufactured locally versus overseas with open US FDA INDs. The general advice from TGA is that in the particular instance outlined in the scenario it is the Sponsor’s and HRECs decision on what clinical trial pathway to take. It is also the Sponsor’s responsibility to assess the quality of the CDMO to generate the comparability evidence for any manufacturing changes and to update their US IND with comparability data and new manufacturer’s details. The TGA reiterated that all Class 4 biologicals (including CAR T) are required to file a CTA unless certain exemptions are met which enables them to file a CTN. If a sponsor was to tech transfer their CAR T manufacturing to Australia under an existing US FDA IND, assuming the sponsor is assured of comparability, the clinical trial described in the scenario presented could still meet the CTA exemption clause enabling them to perform the trial under the CTN pathway. However, when making decisions on the correct clinical trial pathway for Class 4 biologicals, it is recommended to engage with the TGA to ensure the CTA exemptions are being properly met. It is also important to consider that if a product is a GMO, it may also require an authorization from the OGTR.
In scenario 2 we discussed how different delivery methods for an mRNA based gene therapy impact the GMO-status of the investigational medicinal product. Both OGTR and EPA NZ agreed that a mRNA encoding a Cas9 and a guide RNA in a LNP type of gene therapy did not meet the definition of a GMO. However, if the delivery method was changed to a viral vector delivery it would meet the definition of a GMO by the OGTR. The NZ EPA does not recognise certain non-replicative viral vectors as organisms so the product would not be a GMO in NZ. However, EPA was uncertain what GMO classification the product would be if the delivery method changed to an exosome or red blood cell. In this case they would recommend a formal classification. Both regulators encouraged industry to get in touch if they are unclear about the GMO classification status of their products.
The TGA further acknowledged that the definition of a biological in Australia is limited to human cells and tissues which excludes in-vivo gene therapies. However, internationally (in US and EU) the definition of an Advanced Therapy includes both cellular and gene therapies. The TGA could not comment if the definition of a biological will change soon and gene therapies continue to be regulated as prescription medicines in Australia. The TGA also mentioned the Clinical Trial Handbook and CTA draft guidance is under review but there is no timeline for when it will be published.
In this scenario we discussed whether FACT accreditation should be mandatory as opposed to voluntary and the pros and cons of this. It was also discussed if FACT was mandatory would the cost be too high for developing countries and would this restrict access to these medicines. The FACT representative indicated that voluntary can never mean mandatory and it was unlikely to ever become mandatory.
It was also discussed if FACT audits should be unannounced to offer a more “real” indication of quality practices at the site. The FACT representative stated that while unannounced audits had been discussed they were unlikely to move to this model because it is important that key people are present during accreditation inspections.