Gene therapies and orphan drugs: regulatory regime and reimbursement challenges

Fernando Martinez Zuviria

Allende & Brea, Buenos Aires

fmartinez@allende.com

Lucrecia Re

Allende & Brea, Buenos Aires

lre@allende.com

Delfina Buffetti

Allende & Brea, Buenos Aires

dbuffetti@allende.com

The Argentine regulatory framework for gene therapies and orphan drugs

Gene therapies

Advanced therapies such as gene therapy, somatic cell therapy and tissue engineering are an emerging field of biomedical sciences which provide new opportunities for the treatment of human diseases or body dysfunctions.

On 18 September 2018, the National Administration of Medicines, Food, and Medical Technology (Administración Nacional de Medicamentos, Alimentos y Tecnología or ANMAT) issued Disposition No. 179/2018, which regulates advanced therapies. This Disposition defines gene therapy medicines as biological medicines that include an active principle which contains, or consists 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. Gene therapies do not include vaccines against infectious diseases.

ANMAT also issued the regulations providing for the specific requirements for the production, marketing authorisation, surveillance and traceability of advanced therapy medicinal products.

In this regard, in 2021, ANMAT approved the commercialisation of the first gene therapy drug in Argentina for the treatment of patients with Type I Spinal Muscular Atrophy, commercially known as Zolgensma.[1]

In addition, the National Ministry of Health (MoH), which oversees the execution of programmes and projects aimed at improving quality and achieving equity in the country’s health systems, created the National Programme for Monitoring of Protected Health Technologies by means of Resolution No. 1380/2020, issued on 19 August 2020. The programme’s purpose is to ensure the appropriate use of health technologies. In particular, it defines ‘protected health technologies’ as those intended for the treatment of low prevalence diseases and those which, due to their elevated prices, have a great impact on the national budget.

Orphan drugs

Orphan drugs are pharmaceutical products specially developed for the prevention, diagnosis or treatment of rare diseases. These diseases have an increasing impact on public health and demand for healthcare resources, as they require multidisciplinary approaches that encompass healthcare, social care, social support, and educational measures.

On 7 August 2018, ANMAT issued Disposition No. 4622/2012, which sets forth the requirements for registering orphan drugs aimed at the prevention, diagnosis, and/or treatment of rare diseases, including:

• Chronic and debilitating conditions, or severe or life-threatening conditions for which no effective treatment is available or for which existing treatments are inadequate in Argentina.
• Conditions involving extended resistance (refractoriness) to currently available treatments during the management of a disease.
• Newly emerging diseases with severe effects or life-threatening risks for which no effective treatments are available or for which existing treatments are inadequate in Argentina.

The Disposition provides for a standardised and scientifically supported operating procedure for processing registration applications for these drugs. These medicines will be authorised and labelled as authorised ‘under special conditions’.

The Disposition also creates a special committee that will oversee the orphan drugs registration applications. It is important to highlight that the approval of the drug and the determination of the validity period for the corresponding certificate will be evaluated on a case-by-case basis. This assessment will consider several factors, including the specific characteristics of the drug, the complexity of the disease it aims to treat, and the details provided regarding its development stages.

Despite the ANMAT creating this new special regulatory framework for the registration of orphan drugs, the number of registered drugs remains very limited due to their high costs.

Notwithstanding the above, in 2019, ANMAT approved the commercialisation of the orphan drug Spinraza (Nusinersen) for the treatment of patients under two years old diagnosed with Type I, II, and III(A) Spinal Muscular Atrophy. To ensure equitable access to this drug, the MoH, through Resolution No. 1453/2019, established a set of criteria that patients must meet to receive the drug free of charge.

Reimbursement challenges

The Argentine Constitution guarantees access to healthcare as a fundamental right for all individuals. As a result, both nationals and foreigners, regardless of residency or citizenship status, are entitled to access the country’s public healthcare system.

Public healthcare facilities must cover the benefits included in: (1) the national nomenclature of medical benefits, which includes the Programa Médico Obligatorio (Compulsory Medical Plan or PMO); and (2) other specific laws (as described below).

The PMO is a set of mandatory health services that social security, comprised of union-run health insurance entities (Obras Sociales or OS), and private health insurance, through private insurance agencies (prepaid medicine entities), must guarantee. The PMO includes a large list of health benefits, such as maternity and child plans, prevention of cancers, odontology, hospitalisation, mental health, reproductive health, kinesiological and phonoaudiological practices, drugs, palliative care, haemodialysis and ambulatory peritoneal, HIV/AIDS and addictions, among others.

In addition, Law No 26,689 on ‘Comprehensive healthcare for people with Rare Diseases’ mandates that public healthcare, social security and private health insurance must provide comprehensive healthcare coverage for patients with rare diseases.

Despite this extensive list, in practice patients face difficulties when trying to secure financial coverage or payment for medical treatments, procedures or medications. In fact, notwithstanding the PMO and the specific laws such as Law No 26,689, the most advanced practices are rarely covered by the public healthcare, social security or private health insurance.

In these cases, patients are entitled to file a fast-track judicial action known as amparo de salud, by which the court may issue an interim injunction to provide the patient with the services, medications or treatment until the trial concludes. For instance, in September 2023, a court ordered a provincial health insurance agency to cover 100 per cent of an orphan drug that was not included in the insurer’s standard benefits.[2]

Likewise, it is worth noting that, with respect to a specific high-cost special medicine to treat a rare disease (Type I spinal muscular atrophy):

1. Federal courts ruled that the national state is obligated to cover 80 per cent of the cost of this medicine, citing the state’s explicit international commitments to promote and facilitate access to healthcare services. These commitments prevent the state from disregarding the financial burden associated with these therapies’[3] and
2. the MoH included this medicine as a ‘protected health technology’ and purchased 12 kits from Novartis at a total cost of US$18m, under an innovative shared-risk arrangement.

In this respect, the MoH’s press release states that:

‘[t]he shared risk arrangement implies that payments will be made as long as the results in patients align with what is expected based on available scientific evidence. Through the Ministry of Health, Argentina becomes the first country in the region to make such a public purchase under this criteria, ensuring the sustainability of the system and equity in access through efficient investment.’[4]

The National Commission for Patients with Spinal Muscular Atrophy is responsible for selecting the patients who will benefit from this therapy, in accordance with the guidelines set forth in MoH Resolution No. 1234/2023.

Finally, it is important to highlight that in 2024, Argentina hosted the 16th Annual Meeting of the International Collaboration on Rare Diseases and Orphan Drugs (ICORD). This academic event brought together not only scientists but also government officials, patients, healthcare industry representatives and all stakeholders involved in advancing scientific progress to address rare diseases. During the meeting, it was noted that many patients in Argentina are forced to travel abroad for treatment, as these therapies are not always available locally, and when they are, they are very expensive. This issue is primarily due to the lack of local production, which significantly drives up costs.[5]

Conclusion

Although Argentina has made significant progress in regulating gene therapies and orphan drugs and has pioneered innovative initiatives, such as a public-private shared-risk model, significant access challenges remain – particularly regarding the high costs and limited local availability of treatments.