Gene therapies and orphan drugs: navigating regulatory approval and reimbursement challenges
Martín Mosteirin
Marval O’Farrell Mairal, Buenos Aires
Carolina Ramirez
Marval O’Farrell Mairal, Buenos Aires
Gene therapies
A gene therapy medicine is defined as a biological advanced therapy medicine that: (1) includes an active substance containing or consisting of a recombinant nucleic acid, used in or administered to human beings for the purpose of regulating, repairing, replacing, adding or deleting a gene sequence; and (2) has a therapeutic, prophylactic or diagnostic effect that depends directly on the recombinant nucleic acid sequence it contains, or on the product of gene expression of such sequence (Article 2, ANMAT Regulation 179/2018).
Main regulatory framework applicable to gene therapies’ regulatory approval
ANMAT Regulation 179/2018 sets forth the requirements and classification to manufacture, register, authorise, and surveil advanced therapy medicines that are industrially produced, or the manufacture of which involves an industrial process. Gene therapy medicines must also comply with the regulation established for biological medicinal products, as they are included in the definition of biological medicines.
The requirements to register biological medicinal products are established in ANMAT Regulation 7075/2011. This regulation addresses medicinal products of biological origin for human use, which are industrially manufactured, or in the manufacture of which an industrial process is involved, such as:
- haemoderivatives;
- products obtained by means of recombinant DNA;
- monoclonal antibodies;
- medicines obtained from biological fluids or animal tissues; and
- other biological products.
Registering a biological product before the National Administration of Drugs, Food and Medical Devices (Administración Nacional de Medicamentos, Alimentos y Tecnología Médica or ANMAT) requires submitting a dossier that must include details of the product’s manufacturer and holder of the certificate of registration, physicochemical-pharmaceutical and biological quality information, preclinical and clinical information, and a plan for post-marketing surveillance. Further, ANMAT Regulation 3397/2012 approves the specific requirements for authorising biological drugs and/or monoclonal antibodies obtained from recombinant DNA methods. These requirements are considered complementary to the ones provided in ANMAT Regulation 7075/2011.
Reimbursement
Regulation 1200/2012 of the Superintendence of Health (Superintendencia de Servicios de Salud or SSS) created the Unique Reimbursement System (Sistema Único de Reintegros or SUR). Its main purpose is to financially support health insurance agents with the reimbursement of certain medical treatments of low incidence, high economic impact and/or long-term treatment.
SUR was recently replaced by a new Unique Reimbursement System for Disease Management (Sistema Único de Reintegro por Gestión de Enfermedades or SURGE), through SSS Regulation 731/2023, as amended and complemented by Regulation 665/2024. SURGE has the same purpose as SUR.
The reimbursement mechanism can vary according to the type of healthcare insurance provider (public or private), the particularities of the case, etc.
Orphan drugs
Medicinal specialties intended to prevent, diagnose, and/or treat rare diseases may be registered and granted ‘under special conditions’, in accordance with ANMAT Regulation 4622/2012. This regulation sets forth the regulatory framework applicable to the registration of orphan drugs.
‘Rare diseases’ are then defined as those with a prevalence in population that is equal to or less than one in 2,000 people, in relation to a national epidemiological situation (Article 2, Law 26689 for the promotion of comprehensive healthcare for persons with rare diseases). This law also states that private and public healthcare insurance providers must provide healthcare coverage to patients with these conditions and include at least those benefits the competent authority determines. In this sense, Regulation 641/2021 of the Federal Ministry of Health (MoH), as amended by MoH Regulation 307/2023, issued a list of the rare diseases, including the name of each disease and its orphan code.
Annex I of ANMAT Regulation 4622/2012 provides the characteristics of the diseases authorised ‘under special conditions’:
‘(i) Rare diseases according to the definition in article 2 of Law 26689,
(ii) Serious and life-threatening illnesses, as well as serious disabilities, which include:
- Chronic and/or debilitating diseases for which there are no effective treatments or for which only inadequate treatments are available.
- Severe illnesses or life-threatening diseases for which there are no effective or only inadequate treatments.
- The appearance during the treatment of a disease of broad resistance to treatments with the agents currently available.
- The appearance of a new disease with severe effects or which is life threatening and for which there are no effective or only inadequate treatments.’
Main regulatory framework applicable to orphan drugs’ regulatory approval
The competent authority will approve a product registration and establish the validity term of the marketing authorisation certificate on a case-by-case basis, taking into account – among others – the specific features of the drug, the complexity of the disease to be treated, and the information presented on the stages of its development (Article 3 of ANMAT Regulation 4622/2012). In practice, orphan drugs’ MA are usually granted for one or two years.
Labels, leaflets, and all the information made available for professionals must include the following legend: AUTORIZADO BAJO CONDICIONES ESPECIALES (authorised under special conditions), with the same size and enhancement as the brand name and the Argentine Common Denomination (DCA) or the International Nonproprietary Name (DCI), in accordance with Article 4 of ANMAT Regulation 4622/2012.
Annex II of ANMAT Regulation 4622/2012 establishes the following requirements and documentation for registering a product ‘under special conditions’:
- Information on early stages of research: preclinical and Phase I, Phase II of clinical pharmacology studies, and the results of the clinical trials.
- Submission of credible and reliable evidence showing that the product that will be submitted to registration has been categorised as an orphan drug or as a drug that is intended for the diagnosis, prevention and treatment of a rare or serious disease for which no effective and safe treatment is currently available.
- Monitoring plan for determining drug efficacy, effectiveness and Page 1-25 (Rel. 20)
safety to evaluate the benefit and risk of the treatment. The holder of the product registration must submit periodic reports, at least annually (or according to the frequency to be determined in each case), to inform the results of the monitoring plan. - A drug administration guide addressed to healthcare professionals, patients, and patient’s caregivers.
- Depending on the characteristics of the product, the health authority may also require an intensive sanitary surveillance.
- The health authority may require any other complementary information and/or documentation necessary for evaluating the application.
In every case, it will be necessary to obtain the written informed consent of the patient or their legal representative regarding the benefits and risks of the treatment.
Orphan drugs are subject to the mandatory traceability system established by MoH Regulation 435/2011 (as amended and complemented by ANMAT Regulation 10564/2016, among others).
Reimbursement of orphan drugs
Orphan drugs can be reimbursed by public and/or private healthcare insurance providers if they are included in the mandatory medical plan (PMO). On the other hand, Decree 794/2015 states that patients with rare diseases will have at least PMO treatment coverage (Article 6, Annex I). However, it does not determine the extent of the additional treatment coverage of medicines/treatment beyond the scope of the PMO. According to Law 26689, healthcare insurance providers and all agents providing medical assistance services to their affiliates, regardless of their legal status, must provide healthcare coverage to people with rare diseases, including – at least – the services the application authority determines. In practice, when the PMO does not cover orphan drugs, patients often resort to judicial legal action to secure access to treatments (amparos de salud – health claims). This health claims aim to force healthcare providers or insurers to cover these high-cost treatments, using arguments based on the patient’s right to the protection of their health and the need to receive treatment for rare diseases. (This is reinforced by Article 42 of the Argentine Constitution, which sets forth the rights of consumers and users, including their fundamental right to accessing health services of adequate quality. Thus, the Constitution underscores the state’s duty to safeguard public health).
In this sense, several case laws have consistently ruled out that the coverage of the PMO is a ‘ceiling’ or a limit for the obligations of healthcare providers. Instead, it has considered that the PMO should be deemed as a minimum threshold, so it cannot derive in an affectation of the constitutional right to life and health. It is not appropriate to dwell on the consideration of purely economic reasons since the right to health is guaranteed by the Argentine Constitution (Article 42) and by international treaties.
Case law on orphan drugs
In Argentina since 2011, and after Law 26689 on Rare Diseases was passed and ANMAT Regulation 4622/2012 was issued, there has been a more regulated scenario for orphan drugs. There are certain leading cases involving health claims that patients filed against their public or private healthcare insurance providers claiming treatment coverage to cover high-cost drugs, including orphan drugs. Decree 468/2023 was issued considering the complexity and recurrent nature of these claims, to create the Technical Assistance Committee for Judicial Proceeding (CATPROS).
CATPROS is an advisory and permanent agency tasked with providing technical assistance to federal and local courts on court proceedings in which a party requests treatment for rare diseases or special pathologies using innovative drugs or procedures, or medical technologies, within the scope of Law 26689. The purpose of CATPROS is to assesses the effectiveness of medicines and treatments for preventing, diagnosing and treating rare diseases, when such medicines are requested through court claims. The agency was created because such drugs or technologies are often approved ‘under special conditions’ at early stages of their development. Thus, the need to continue assessing their effectiveness, safety and quality. CATPROS’s assistance is optional for the intervening courts, and its reports are non-binding.