Precision medicine in paediatrics: Progress and priorities.

From Lipoproteins to Chondrocytes: A Brief Summary of the European Medicines Agency's Regulatory Guidelines for Advanced Therapy Medicinal Products

From Molecule to Patient and Ways to Get the Dose Precisely Right

Mapping the European landscape and specificity of ATMPs guidance.

Advanced therapy medicinal products (ATMPs) are a significant innovation in medicine, categorized by the European Medicines Agency into four types: gene therapy medicines, somatic cell therapy medicines, tissue-engineered medicines and combined ATMPs. They hold potential for treating various conditions, including rare diseases, degenerative diseases like Parkinson’s and Alzheimer’s and cancers. The global market for ATMPs was valued at US$9.28 billion in 2023 and is projected to reach US$22.80 billion by 2032, growing at a compound annual growth rate of 10.50%. Gene and cell therapies are advancing rapidly, with over 1,700 approved clinical trials worldwide. Notable successes include Glybera for lipoprotein lipase deficiency and Roctavian for haemophilia. Despite limited current approvals, many gene therapies are expected to gain market approval soon. Challenges include stringent regulatory requirements, safety and ethical concerns. For example, Glybera faced multiple rejections before approval due to safety issues. Current clinical studies are exploring immune-based therapies like CAR-T, cytotoxic T lymphocytes, natural killer cells and mesenchymal stromal cells. CAR-T cell therapies, such as Yescarta and Kymriah, have shown promise in treating B-cell lymphoma. However, high development and manufacturing costs limit accessibility, exemplified by Hemgenix, a gene therapy for haemophilia B priced at US$3.5 million. Increased ATMP sales have spurred investor interest in R&D, leading to advancements in technology and manufacturing processes. Despite challenges, the future is promising with more academic and commercial ATMP clinical trials. There are now 32 approved gene therapies globally. To attract industries, the focus should shift from rare to common diseases, and alternative reimbursement models could help manage high costs. A trained workforce and public involvement are crucial for the successful delivery of ATMPs.

Advanced therapy medicinal products (ATMPs), such as gene therapies that consist of or contain genetically modified organisms (GMOs) need to comply with the European Union (EU) GMO legislation, as implemented in each EU Member State, before a clinical trial can commence. Complying with GMO requirements is complex, varies significantly across EU Member States and is leading to delays to clinical trials with ATMPs. Such delays and varying implementation of the GMO legislation makes the EU less attractive as a region to conduct clinical trials with investigational gene therapies. This is detrimental to EU patients, since their timely access to these transformative potentially curative medicines is delayed. Despite recent initiatives coordinated by the European Commission (EC) to facilitate and reduce discrepancies across the EU regarding the application of the GMO requirements, it remains particularly difficult to conduct multicenter clinical trials with ATMPs containing or consisting of GMOs involving several EU Member States. The recent decision for the EC to temporarily derogate potential coronavirus disease 2019 treatments and vaccines from some provisions of the GMO requirements was made on the basis of a clear recognition of such complexities and resulting delays to clinical development. The Alliance for Regenerative Medicine, the European Federation of Pharmaceutical Industries and Associations, and the European Association for Bioindustries call upon the EC, together with national competent authorities, to exempt ATMPs containing or consisting of GMOs from the GMO legislation. Such a simplification will eliminate the delays currently reported to occur when submitting environmental risk assessments and GMO applications to the national competent authorities. An exemption from GMO requirements will make the EU a more attractive region for clinical development of gene therapies and could accelerate European patients' access to these potentially life-saving medicines. Maintaining a system for GMO assessment that is different across countries may also prevent ATMPs from realizing the full benefits of a harmonized clinical trial approval process under the Clinical Trials Regulation. The undersigned organizations to this publication urge the EC to use its right of initiative to put forward a legislative proposal to exempt ATMPs in clinical development from the EU GMO legislation, within the timeframe proposed in the 2020 EU Pharmaceutical Strategy (by 2022). Implementation of a GMO exemption scheme before the end of the transition period for the Clinical Trial Regulation (the end of 2023) is important to avoid new Clinical Trial Application submissions for ATMPs under the Clinical Trial Regulation having to conduct the whole GMO assessment process in parallel. It is considered that ATMPs pose negligible risk to the environment. Such ATMPs include the following: human somatic cells modified ex vivo; recombinant virus-based vectors, including those containing genome editing nucleic acid sequences (which may also be delivered nonvirally); and bacterial vectors. Outside of controlled storage conditions, gene therapies cannot survive for any appreciable length of time. Upon clinical administration, any recombinant gene therapy viral vector particles that do not enter host cells are diluted within the body and if excreted are in such low multiplicity to no longer be viable or considered infectious to persons, animals, or living organisms within the environment. Any nucleic acids released into the environment are rapidly degraded.

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States

With the increase in drug development studies for rare diseases, gene therapies have recently come to the fore more frequently. In addition to orphan drugs used in the treatment of rare diseases, advanced therapy medicinal products have been developed. Advanced therapy medicinal products are a fast-growing field. Although it is not a treatment method used only in the field of rare diseases, it is also used in the fields of oncology and cardiovascular diseases, musculoskeletal diseases. Regenerative medicine can be promising in cases where advanced therapy medicinal products are difficult and clinically uncertain. There are various cell therapies related to regenerative medicine and cell-based therapies are one of them. Gene therapies, cell-based therapies, advanced therapy medicinal products and regenerative medicine products have high producer price and high production cost. Because all these treatments have limited clinical evidence and high costs, they are difficult to evaluate in terms of health technology assessment (HTA), and special considerations are needed for evaluation. As a solution, costs should be limited and clinical developments should be provided in cooperation with the society. SAVE (equivalent to young life saved) is recommended to evaluate the lifetime health profiles of curative treatments such as gene therapies. In order to reduce the budgetary burden of gene therapies, outcome-directed entry agreements with income-based payments are recommended. Compulsory use of gene therapies and non-reimbursement of these drugs can lead to catastrophic health expenditures. Various payment methods are offered to avoid catastrophic health expenditures. Income-based payment and outcome-based payment are some of these methods. It is also advocated that high prices should be accepted by the society, since gene therapies to be applied in the treatment of rare diseases will be applied to a small population. Both the support of the society to accept the high price of gene therapies, the support of the producer and the support of the payer are important in the development of gene therapies and their supply to the market.

PHP80 - HOW CLASSIFICATION OF CELL AND GENE THERAPIES AS DRUGS, DEVICES OR PROCEDURES COULD HAVE SIGNIFICANT IMPLICATIONS FOR THEIR PRICING AND REIMBURSEMENT AND COMMERCIAL SUCCESS

Background Advanced therapy medicinal products (ATMPs) are new medical products based on genes (gene therapy), cells (cell therapy) and tissues (tissue engineering). Mycoplasmas are among the world’s smallest bacteria capable of independent reproduction. They belong to the class of Mollicutes, have a very slow and parasitic growth and can cause human infections. Mycoplasma contaminations of ATMPs can arise from unsterile source material of different human origin, starting materials or the complex manufacturing process. The traditional growth-based detection method requires a cultivation time of at least 28 days before a contamination can be ruled out with certainty [1]. But shelf lives of final ATMPs are often extremely short compared to classical drugs (24 48 h, sometimes only a few hours). That is why the official culture method or indicator cell method are not suitable. Furthermore ATMP sample amounts are usually limited and of great “value”. Nucleic Acid Amplification Techniques (NAT) allow reducing time to result to just hours and only small sample amount are necessary to generate highly sensitive results. A Mycoplasma Real-time PCR kit was designed especially for the detection of Mollicutes (Mycoplasma, Acholeplasma, Spiroplasma) contamination in ATMPs and cell cultures by using the cells itself, cell culture supernatant or a defined mixture as test material. An acceptable sample volume in respect of the expensive, unique and limited sample is processed for Mycoplasma detection. In this studies the robustness of the kit was demonstrated by testing 20 randomly selected Advanced Therapy Medicinal Products from samples submitted by customers for Mycoplasma detection. These tests were done as part of the kit validation. All selected ATMPs were tested negative for Mycoplasma and could therefore be used as spiking matrices for the intended studies. These 20 different products were spiked with 10 CFU/ml of Mycoplasma fermentans. Each spiked ATMP matrix was then subjected to a DNA isolation process and tested by Real-time PCR. All 20 randomly selected ATMPs out of 20 in total were tested positive in duplicate and fulfilled the acceptance criterion. These results confirmed the suitability and the robustness of the designed Mycoplasma Real-time PCR kit for ATMP testing.

The Need for Increased Clarity and Transparency in the Regulatory Pathway for Gene Medicines in the European Union

In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs). We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation. Prior to its introduction in 2008, 4.5% of the products submitted for orphan designation met these criteria. This percentage went up to 15% after 2008. We analyzed several parameters associated with active ATMP ODDs focusing on sponsor type and EU-Member State origin, therapeutic area targeted, and ATMP classification [i.e., somatic cell therapy medicinal product, tissue-engineered product (TEP), or gene therapy medicinal product (GTMP)] and the use of regulatory services linked to incentives such as the use of protocol assistance (PA) and other Committees [Committee for Advanced Therapies (CAT) and the Pediatric Committee]. The aim here was to gain insight on the use of different services. The UK submits the largest number of ATMPs for ODD representing ~30% of the total to date. Few submissions have been received from central and Eastern European Member States as well as some of the larger Member States such as Germany (3.6%). ATMPs ODDs were primarily GTMPs (48.7%) and SCTMPs (43.3%). TEPs only represented 8% of all submissions for this medicinal class. This is different from non-ODDs ATMPs where GTMPs make only 20% of ATMPs. A total of 11.7% of ATMP ODDs had received formal CAT classification. A total of 29.8% of all orphan drug (OD) ATMPs requested PA. A total of 71.8% did not have an agreed pediatric investigation plan (PIP). Four products (Glybera one PA; Zalmoxis two; Holoclar one; Strimvelis three) have received a marketing authorization (MAA) and a 10-year market exclusivity. Strimvelis also completed their PIP, which was compliant and received the additional 2-year extension to their 10-year market exclusivity. One OD ATMP (Cerepro) received a negative opinion for MAA. The use of services linked to incentives offered by different legislations for ATMP ODDs is low, indicating a need for increasing awareness.

The EHA Research Roadmap: Hematopoietic Stem Cell Gene Therapy.

BackgroundParents of children living with chronic but manageable conditions hope for improved therapies or cures, including Advanced Therapy Medicinal Products (ATMPs). Multiple pediatric clinical trials for ATMPs are underway, but the risk profile of ATMPs for chronic conditions is largely unknown and likely different than for terminal pediatric illnesses. Applying Protection Motivation Theory modified to the context of pediatric ATMP clinical trial enrollment, our study analyses information needs of parents of children living with chronic manageable conditions: Type 1 Diabetes (T1D) or Inherited Retinal Diseases (IRD).MethodsWe conducted semi-structured interviews with 15 parents of children living with T1D and 14 parents of children living with an IRD about: a) family background and the diagnostic experience; b) awareness of gene and stem cell therapy research and clinical trials for T1D and IRD; c) information sources on trials and responses to that information; d) attitudes to trial participation, including internationally; e) understanding of trial purpose and process; and f) any experiences with trial participation. We then discussed a pediatric ATMP clinical trial information sheet, which we developed with experts. We applied directed qualitative content analysis, based on PMT, to examine the information preferences of parents in deciding whether to enrol their children in stem cell or gene therapy clinical trials.ResultsParents balanced trial risks against their child’s ability to cope with the chronic condition. The better the child’s ability to cope with vision impairment or insulin management, the less likely parents were to assume trial risks. Conversely, if the child struggled with his/her vision loss, parents were more likely to be interested in trial participation, but only if the risks were low and likelihood for potential benefit was high.ConclusionsFear of adverse events as part of threat appraisal was the predominant consideration for parents in considering whether to enroll their child living with a manageable, chronic condition in a pediatric clinical trial of an ATMP. This consideration outweighed potential benefits and severity of their child’s condition. Parents called for available safety data and fulsome communication processes that would enable them to make informed decisions about clinical trial enrolment on behalf of their children.

PHP59 - MOVING FROM THE REGULATOR TO THE PAYER AND PRESCRIBER - HOW PHARMA CAN WORK BETTER TO EFFECTIVELY MANAGE EMERGING CHALLENGES TO THE COMMERCIAL SUCCESS OF INNOVATIVE NEW THERAPIES

Advanced Therapy Medicinal Products (ATMPs) comprise novel cell, tissue and gene therapies and offer the potential of durable remissions for diseases where there is a high unmet clinical need. Once considered a niche area of academic research, ATMPs now represent one of the fastest-growing areas of clinical development. The field has seen a rapid expansion of academic and commercial entities successfully translating ATMP research into the clinic. This is reflected in projection that the global gene and cell therapy market will be worth US $11.96 billion by 2025. However, these treatments are complex to deliver and frequently do not fit naturally into established healthcare systems. In the United Kingdom (UK) there has been a long-standing interest in ATMP research and, in order to meet the ambition to act as an international hub of activity for delivery of ATMPs, a collaborative network of Advanced Therapy Treatment Centres (ATTCs) has been established. This review explores the challenges of delivery in the clinical setting, focussing on one form of ATMP, Adoptive Cell Therapy (ACT). We describe the strategy being implemented in the UK to optimise the roll-out of these exciting new therapies.