Legality of AI and machine learning in new generation technologies (2.0) for the manufacturing of gene therapy drugs from the perspective of the EU ATMP regulations.

The use of AI and machine learning solutions in drug manufacturing technologies with the use of machine learning and quantitative, high-throughput in vivo experiments; the EU regulations for advanced therapy medicinal products (ATMP) and the procedures for placing the most modern drugs on the world market by the European Medicines Agency.

The intensive development of medicine affects the medical regulatory law in the European Union, which should cover more and more new legal problems related to the increasingly common application of advanced solutions of artificial intelligence, machine learning, telemedicine solutions and cyber solutions to the technology of manufacturing medicinal products.

In the current legal status, however, the legality of the use of such state-of-the-art AI and machine learning technologies in pharmaceutical production should be assessed on the basis of the regulations on the assessment of their final effect, i.e. the level of admissibility of placing ready-made alternative therapy products on the market, as well as the legal aspects of commercialization of such technologies.

Paradoxically, the procedures related to the introduction to the market of the end products of new technologies, with the use of AI and machine learning, are as long and costly as they enormously accelerate the inventive process and the pharmacological production process, because it is AI and machine learning information technologies that prove useful for the purpose of accelerating and improving the production of the world’s most advanced drugs and the fight against diseases in general. The above legal problems relate primarily to EU procedures and regulations for modern, although still relatively rarely used, experimental therapies, the so-called ATMP (Advanced Therapy Medicinal Products).

ATMP products, including those created using modern AI and machine learning technologies, are specified in Article 2 paragraph 1 point a of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No. 726/2004 (Journal of Laws of the European Union of 2007 No. 324, p. 121, as amended). The definition classifies the general concept of the most complex and modern drugs in the world within advanced (including experimental) therapies into three main sectors:

– gene therapy medicinal products,

-medicinal products of somatic cell therapy,

-tissue engineered products.

Due to the common occurrence of alternative therapy products, it is also reasonable to divide them between the next two groups:

– ATMP – advanced therapy medicinal products, subject to central registration by the European Medicines Agency, therefore the marketing of such products is applicable throughout the European Union;

– ATMP-HE – (Advanced Therapy Medicinal Products – Hospital Exemption) advanced therapy medicinal products authorized under the “national” procedure by the regulatory authority of a specific European Union country. In this case, ATMP-HE is admitted to trading under hospital exceptions (exemptions). It is therefore an advanced therapy medicinal product, which, for example in the case of Polish jurisdiction within the European Union, is prepared in the territory of the Republic of Poland in a non-systematic manner in accordance with quality standards and used as part of hospital services within the meaning of Article 2 paragraph 1 point 11 of the Polish Act of April 15, 2011 on medical activities (Official Journal of Laws of 2020, items 295 and 567) in the territory of the Republic of Poland, under the sole responsibility of a physician, in order to perform an individually prescribed medicinal product for a given patient.

Regulation No. 1394/2007 is therefore a special regulation in relation to the provisions of the European Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (Journal of Laws of the EU. L. of 2001, No. 311, p. 67, as amended, hereinafter: “Directive 2001/83/EC”). The Directive after amendment, in legal matters relevant to the use of AI technology in modern medicine, expresses general principles of the harmonization of medical law in individual European Union countries, such as:

– an order to define the product in detail and its properties in relation to the modernity of the products,

– the prohibition of conflicting regulations on advanced therapies with decisions of Community countries, in particular as regards the use of human and animal embryonic cells,

– the possibility of subjecting advanced therapy products to specialized tests or establishing a product and patient route control system.

Thus, from the perspective of the Polish and European legal system, the legal problems related to the marketing and commercialization of new technologies for the development of new methods of gene therapy drug production should be analyzed primarily from the level of the above-mentioned legal acts.

They are the basic source of the rules of legalizing modern therapies on the EU market, the origin and scientific term of which, paradoxically – as shown by popular scientific press sources – were used for the first time in the 1960s. Then, a fragment of genomic DNA was introduced into human marrow cells using a calcium phosphate solution.

Gene therapy is currently mainly used to treat hereditary diseases. It is an extremely effective method because it removes not only the symptoms, but also the source of the disease. It consists in the therapeutic use of both genes and shorter, non-coding, DNA or RNA sequences. The repair of a genetic defect is achieved by introducing the correct form of a mutated gene into the cell in order to obtain its expression, or by modifying the activity of individual genes. In the latter case, additional copies of those genes that are not functioning efficiently are introduced into the cell to enhance their function. It is also possible to inhibit the activity of overexpressing genes, also with the use of non-coding DNA or RNA sequences.

The issue of gene therapy is regulated in detail in Annex I to the European Directive 2001/83/EC. It defines a gene therapy product as obtained by a set of production processes with the aim to transfer for either in vivo or ex vivo execution of a prophylactic, diagnostic or therapeutic gene (i.e., a nucleic acid fragment) into human / animal cells and its subsequent expression in vivo.

Therefore, the introduction of a gene therapy product to the market in a Member State, regardless of the type of modern production technologies (also with the use of AI and machine learning), requires compliance with standardized rules:

1) both the general ones specified in Directive 2001/83/EC,

2) as well as specific ones from Regulation No. 1394/2007,

3) as well as to complete all regulations specified in the legislation of a given state and to obtain a permit from an appropriate national body – this requirement is stipulated in Art. 6 (1) of Directive 2001/83/EC.

An entity running a business in a Member State is therefore obliged to submit an application for a permit for implementation to the relevant national authority. Along with the application there must be attached, inter alia, such documents as: detailed description of the product and its properties, reason for introducing the product to the market, attachments to the clinical trials carried out on the product, description of the potential risk generated by the product or a certificate of employment of qualified personnel in the course of product production – these and other requirements are specified in detail in Article 8 of Directive 2001/83/EC.

Attention should also be paid to the requirement to conduct tests on gene therapy products in accordance with the principles set out in Directive 2001/20/EC on clinical trials. This document defines an “investigational medicinal product” as a pharmaceutical form of active drug substance or placebo, tested or used as a reference product in a clinical trial; the definition covers products already registered but used or prepared (in pharmaceutical form or packaging) differently from the registered form, or used in a description not covered by the registration, or used to obtain additional information on an already registered form.

Therefore, if the product meets the legal requirements, and the introducer demonstrates all the conditions set out in the Directive, his application should be accepted by the Member State within a period not exceeding 210 days from the date of submission of the application. Theoretically, public authorities (in the case of Polish jurisdiction, this would be the President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products) notify the entity of the decision and then issue a decision to admit the product to the public. After obtaining the decision, the entity is obliged to inform the relevant state authorities about the data concerning the current turnover of the product. This does not mean, however, that from that moment its further actions are unlimited – it is obliged to inform the authorities about current matters related to its activity, such as, for example, bans and restrictions imposed on it.

The above-mentioned general EU regulations overlap with specific legal mechanisms for the introduction and commercialization of advanced therapy medicinal products, as specified in Regulation No. 1394/2007. As a rule, in order to obtain an authorization to place an advanced therapy product on the market throughout the European Union, a scientific opinion of the product is required by the Committee for Medicinal Products for Human Use of the European Medicines Agency and additionally by the Committee for Advanced Therapies of the European Medicines Agency. When consensus is reached on the evaluation, the draft of such scientific opinion on a new advanced therapy medicinal product shall be sent to the chairman of the Committee for Medicinal Products for Human Use for approval. After obtaining the authorization, the entity is required to create a patient and product monitoring system; hospitals also have this obligation when they use advanced therapy products.

In this context, it is worth translating these EU general regulations into the practice of a particular European Union country, for example into a detailed implementation basis regulated in the Polish Pharmaceutical Law. In this case, the definition of “advanced therapy medicinal product” specifies such a product by referring to the above-mentioned European Directive and, additionally, defining such a medicinal product as a product prepared in the territory of the Republic of Poland in a non-systematic manner in accordance with quality standards and applied in the territory of the Republic of Poland under the sole responsibility of a doctor in order to make an individually prescribed medicinal product for a given patient (Article 2 point 33b of the Polish Pharmaceutical Law). Therefore, only products that have been authorized by the Council of the EU and the relevant national authority – the President of the Office of Medicinal Products, Medical Devices and Biocidal Products – may be placed on the domestic market. Only those advanced therapy medicinal products that belong to the group of hospital products are exempted from this obligation. The conditions for the approval of the product into the market by the President of the Office are provided for in Art. 8 of the Polish Pharmaceutical Law and subsequent provisions. After verifying the correctness of the application, the President, as a rule, prepares a report evaluating the medicinal product, and then publishes it, together with the justification and a summary, on the website of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products and on the website of the Public Information Bulletin of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products and Polish Health Ministry. If the President finds no deficiencies, he issues decisions on the authorization of the product to be marketed. Pursuant to the EU regulations, the procedure for admitting the product to the market should be completed within 210 days from the date of submitting the entity’s application.

The above legal problems are manifested in an example of the implementation of modern technology for the pharmaceutical production of gene therapy with the use of AI and machine learning by one of the American biotechnology companies, which, according to recent press releases, has just concluded license agreements for the use of its state-of-the-art technology for one of the pharmaceutical giants, implementation of new advanced therapy medicinal product.

One of the gene therapies in use today is vector therapy. It has found wide application in the fight against diseases of the heart muscle. It is based on the use of adenovirus-related (AAV) virus vectors, which exhibit tissue tropism, no secretion of pathogens and a long expression time. Vector studies conducted as part of the Generation of novel cardiotropic AAV-based serotypes to evade human humoral immunity were carried out to identify new serotypes based on AAV 6 and 9 (maintaining heart tropism) that would be resistant to the body’s humoral immunity. Researchers used site-directed mutagenesis to attenuate antibody-induced neutralization with single mutations in specific amino acids. They then tested and mutated the AAV vector for its resistance to AAV serotypes 6 and 9. The results of the mice injected with the modified AAV vector showed its highest degree of neutralization reduction in serum containing anti-AAV antibodies. It follows that the use of mutant AAV vectors in treatment is a hope for patients who have so far been excluded from standard clinical trials due to humoral immunity.

Viral vector therapies are innovative and appear to be of interest and commercialization to companies around the world. An example in this regard is the dynamically developing American start-up, Dyno Therapeutics, described in the WSJ, which is currently developing an innovative technique for creating new AAV virus capsids in order to use them in this type of therapy. The effectiveness of the treatment with the use of the AAV vector contributed to the business idea, as well as its rare occurrence in nature and not adapted to use in some tissues of the human body. In response, Dyno Therapeutics decided to start producing new capsids using artificial intelligence and machine learning techniques in order to find the properties of the capsid that would be best suited to the gene therapy used. The process consists in creating millions of capsids, and then condensing them into the so-called Capsid Map. Then, using computer calculations, from among millions of capsids, the ones with the most desirable properties in therapy are selected.

Dyno Therapeutics describes its product as a platform that uses artificial intelligence to effectively optimize AAV capsids and eliminate naturally occurring limitations in them in order to develop capsids that can be used in a variety of gene therapies. Capsid Map allows you to build a capacious and detailed map that in the blink of an eye allows you to find the desired units from a huge number of newly formed capsids.

To carry out the above operation, highly developed artificial intelligence and machine learning are necessary – so it should not be surprising that the world’s largest medical concerns decide to purchase a Capsid Map product licence in order to use it to modify viruses and apply them in individual medical segments.

In September 2020, Dyno Therapeutics signed a contract with Roche and Spark Therapeutics as research partner. The aim of the cooperation is to produce by Dyno capsids to be used in the future in the treatment of diseases of the central nervous system and the liver. The cooperation will combine the basis of innovative, artificial intelligence developed by Dyno with modern possibilities of gene therapy provided by Roche, which will be responsible for conducting preclinical and clinical research and commercialization of product candidates using the new gene therapy.

When transferring the above transaction and commercialization of technology into EU and Polish law, the legality of this type of technology should be viewed from the perspective of the previously quoted regulations governing the commercialization and marketing of gene therapies specified in the Pharmaceutical Law, European Directive 2001/83/EC and Regulation No. 1394/2007. Therefore, the legality of technological progress depends to a large extent on the legality of the documentation prepared for the effects of such a technology in the form of specific therapy products (i.e. from the perspective of a medicinal product), and not on the admission to the market of the technology as such, for the use of which the pharmaceutical manufacturer, as is apparent from the cited example of Dyno Therapeutics, is granted a licence by a biotechnology company to use such technology for ATMP’s own production.