PharmaLex in Bulgaria

ATMPs constitute a novel class of innovative therapies, also known as living drugs used for personalized medicinal approaches. These second generation of biological products can offer unique possibilities to not only treat a disease where limited, or no alternative treatment options exist but to target the disease at its root cause and to fully eradicate it. They have already shown outstanding results in previously untreatable conditions such as cancer indications including treatment in patients with B-cell ALL and Melanoma and patients with vision loss due to inherited retinal dystrophy.

ATMPs provide life-changing benefits to patients and their families!

The umbrella term ATMPs is comprised of 4 distinctive classes of advanced products in EU, in comparison in the US, the sub-classification covers two significant groups of products: gene therapies and cellular therapies.

1. Somatic cell therapy medicinal products (SCTMP) – substantially manipulated cells that treat prevent or diagnose a disease.
2. Tissue-engineered products (TEP)- substantially manipulated tissues to regenerate, repair or replace human tissues.
3. Gene therapy medicinal products (GTMP)– recombinant nucleic acid that regulates, replaces, repairs, adds or deletes a genetic sequence.
4. Combined (cATMP)- a medical device that includes a cell or tissue component

ATMPs are very novel and complex therapeutics. They require substantial upfront investment costs from manufacturers, use of sophisticated and expensive manufacturing technologies, strict regulatory demands should be met and of course, require a significant time investment. Moreover, since these innovative therapies target rare diseases, it is very challenging to conduct clinical trials and to enrol enough patients, thus to gather reliable results and to prove both clinical safety and efficacy. Another major obstacle is its commercialization and high cost per therapy. The significantly higher value of R/D leads to the increased price per product and subsequently rise affordability concerns of these breakthrough therapies for health care systems and patients. For example, the CAR-T cell therapy -Zolgensma recently got approval from the FDA for the treatment of Spinal Muscular Atrophy at the unprecedented price of 2.1million per treatment and become the most expensive product worldwide. There is an increased need for more adaptive pricing methods such as pay for performance, conditional reimbursement, annuity-based payments, and special funds to provide these life-changing therapies to patients with high unmet medical needs.

As of January 2020, 14 ATMPs have granted marketing authorization in Europe: seven gene therapies, three cell therapies and four tissue-engineered products. However, due to commercial reasons, the marketing authorization of the first four was withdrawn. In comparison, in the US, ten cellular and gene therapy products have been granted biological licence applications. Advanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The pipeline of ATMPs is rapidly evolving with lots of promising drug candidates already in late-stage clinical studies. Based on the most current information, there are more than 1,000 clinical trials of ATMPs ongoing worldwide, and over two-thirds are in mid or late-stage development (Phase II or III). The future is very bright for this novel class of biologics, and it is expected that by the end of 2020 we will see many more ATMPs on the global market.

The regulatory framework for gene and cell therapy medicinal products and tissue-engineered products was established in the European Union with Regulation 1394/2007. ATMPs are subject to a centralized authorization procedure, involving a single scientific evaluation of the quality, safety and efficacy of the product. The European Medicines Agency (EMA) together with three of EMA’s scientific committees involved in the evaluation:

1. Committee on Advanced Therapies (CAT),
2. Committee for Medicinal Products for Human Use (CHMP)
3. Pharmacovigilance Risk Assessment Committee (PRAC);

is responsible for the scientific evaluation of the marketing authorization applications of these novel therapies.

Due to the diversity and complexity of ATMPs, a tailored approach for regulating these products is necessary. Specific expertise not only in the traditional pharmaceutical field but also in other areas as biotechnology, tissue engineering and medical devices is required for the assessment of ATMPs.

As provided for in the ATMP Regulation (EC) No 1394/2007, the scientific evaluation of Marketing Authorisation Applications (MAAs) for ATMPs is primarily performed by the Committee for Advanced Therapies (CAT). The CAT prepares a draft opinion on the quality, safety and efficacy of each ATMPs subjected to marketing authorization application which is sent for final approval to the Committee for Medicinal Products for Human Use (CHMP). The CHMP recommendation is then forwarded to the European Commission, which adopts a decision binding in all Member States.

The CAT also gives recommendations on the classification of advanced therapy medicines, provides scientific advice and expertise on innovative medicine and therapies, participates in certifying quality and non-clinical data for small and medium-sized enterprises developing ATMPs, develops guidelines, contributes to cross-committee projects, works on simplification of procedures and requirements for ATMPs.

As we have already discussed, one of the significant limitations associated with ATMPs is the inability to produce comprehensive and reliable results from clinical studies due to the fact that these products target very rare conditions and to enrol enough patients is sometimes quite difficult or even not possible. Taking into account the significance of these advanced products, there is a high need to provide a short cut to meet the high unmet medical needs and to offer these life-changing products to patients. For this reason, optimized regulatory strategies and expedited pathways are implemented for early access of these products on the market.

1. 1. Hospital Exemption Procedure (HE) was introduced in the EU as a potential alternative for the centralized marketing authorization application. EMA allowed the use of unauthorized custom-made advanced products in hospitals under special circumstances for a specific patient. Every Member State (MS) can adopt a local procedure (specifically tailored legislative) to comply with the criteria (rules) for granting HE set in REGULATION (EC) No 1394/2007. HE procedure is a highly valuable source to obtain real-world data from patients and to produce comprehensive safety and efficacy information supporting future marketing authorization applications.

2.PRIME Scheme (Priority Innovative Medicines Eligibility scheme) – This scheme was launched from EMA to enhance the support and to improve the development process of innovative medicines that target high unmet medical needs. This voluntary scheme is based on enhanced interaction and early dialogue with developers of promising drugs to optimize development plans and to speed up the evaluation of these medicines to reach patients at a faster rate. MAHs of innovative products can benefit from early dialogue (scientific advice) with regulators (national regulatory agencies) to optimize the development plan.

3. 3. Conditional Marketing Authorization – (CMA) marketing authorization is granted based upon completion of Phase II studies to provide innovative medicines to patients with high unmet medical needs. CMA is likely to be converted to standard Marketing Authorization when the MAH provides comprehensive safety and efficacy data at later stages to prove the positive benefit-risk balance of the innovative product.
4. 4. Marketing Authorization under exceptional circumstances is specifically tailored for those extreme situations when a disease is rare and/or a clinical endpoint is difficult to be measured. One significant difference between CMA and MA under exceptional circumstances is that the second one is unlikely to be converted at later stages to a standard MA.

PharmaLex can offer consultancy services for the development of ATMPs.

We can provide broad expertise in every stage from the initial research phases guiding through the preclinical and clinical development and supporting the MAHs with marketing authorization applications and providing strategic partnerships and negotiation with national regulatory authorities for market launch and future reimbursement procedures.

These are some of the key areas where PharmaLex provides expert solutions to our clients:

1. Preparation of Investigational Medicinal Products dossiers (IMPDs), developing and writing of paediatric investigation plans (PIPs).
2. Consulting on appropriate development strategies (e.g. biodistribution, tumorigenicity, orphan designation), CMC gap analysis.
3. Planning, submission and management of regulatory procedures for dossiers for marketing authorization via centralized procedures in EU and Biological Licence authorization in US
4. Preparation of dossiers for PRIME scheme, Hospital exemption, conditional marketing approval submissions, compassionate use for patients and early access programs
5. Health Technology Assessment; Preparation of core value dossiers and preparation of reimbursement applications to regulatory authorities