The regulatory regime
The principal piece of legislation is Law No. 16,463, the Law of Medicines, issued by Congress, which has been in force since 1964. Law No. 16,463 is further complemented by decrees issued by the Executive Power. These decrees are subject to more specific regulation by means of resolutions issued by ministries, mainly the Ministry of Health. Finally, ANMAT also establishes multiple specific regulations.
ANMAT, consisting of a decentralised controlling entity on matters related to pharmaceutical products, food and medical devices, was created in 1992, through the enactment of Decree No. 1490/92. ANMAT is dependent upon the Ministry of Health, usually through the intervention of the Secretary of Health.
The faculties granted to ANMAT in connection with the pharmaceutical industry not only relate to the approval of laboratories, storehouses and products, but also enable it to act as the controlling public office with respect to the industrialisation and commercialisation of pharmaceutical products.
As a general principle, importers, exporters, manufacturers and distributors of pharmaceutical products must be qualified by ANMAT to develop their activities within the pharmaceutical industry. This authorisation, once granted, is valid throughout the country. Nevertheless, provincial laboratories (authorised to act only at a provincial level) may also be qualified.
ANMAT also plays an important role in the approval and control of clinical trials that take place in the country.
Law No. 16,463 establishes that in order to be authorised, laboratories must manufacture their own products. Considering scientific, economic and political environments, certain laboratories have been authorised to import and commercialise pharmaceutical products without the obligation to manufacture them. There are rules by which ANMAT authorises the referral to third-party laboratories for specific stages of manufacturing. Despite these exceptions and other specific situations that exceed the general scope of this chapter, laboratories are required to have their own quality control laboratory that should be in accordance with the products commercialised by the laboratory, a storehouse and a technical director. In recent times, ANMAT has discouraged the qualification of companies only acting as sole importers and sellers of pharmaceutical products. Licensing to authorised laboratories is a common way to enter the market when the laboratory is not registered in Argentina. Another way is related to import through exceptional channels as named patients programmes.
Owing to the industry's development, ANMAT has issued certain specific regulations that apply to clinical trials, traceability of products and other matters. Additionally, some specific laws that deal with the pharmaceutical industry have been enacted, such as Law No. 26,529, which relates to the patient's rights, and Law No. 26,689, which relates to orphan diseases.i Classification
The regulatory regime is broad and covers regulations that apply to the commercialisation of all products of its incumbency.
The principal regulations that deal with pharmaceutical products are Decree No. 150/92 and Resolution No. 233/1996, which establish requirements to register pharmaceutical products and qualify as a laboratory (including manufacturer, importer and distributor laboratories); Decree No. 1299/97, which regulates the commercialisation of products; Disposition 3602/2018, No. 3287/2018 and others, which establish the good manufacturing practice (GMP) to be followed classifying all different product alternatives; and Resolution No. 627/2007, which regulates the promotion of ethical products.
Regulation No. 4890/2005 establishes regulations that deal with free-sale pharmaceutical products (over-the-counter (OTC)), medical devices including those that apply to dentistry, cosmetic products, food, dietary supplements, household cleaning products, and in vitro and self-testing diagnostic products.
As mentioned above, for pharmaceutical products to be authorised, they must be registered with ANMAT. For such registration, the following information must be provided:
- product information;
- technical information;
- label information; and
- leaflet information for patients.
In cases where the product to be registered is imported from the countries listed in a specific annex to Decree No. 150/92 (these are countries that have highly developed methods of health control), the certificate of commercialisation of the health authority of the corresponding country shall also be provided. Marketing authorisations are granted for a five-year term and can be renewed as many times as required by the holder.ii Biological products
Regulations Nos. 3397, 7075 and 7729 have been issued by ANMAT to establish specific requirements for approving biological products.
Biological products listed in Regulation No. 7075 include hemoderivatives, products obtained with recombinant DNA techniques, monoclonal antibodies and biological medicines produced from animal tissues.
To register biological products, strict requirements must be met, including providing detailed information regarding the active principle and the manufacturing process of the active principle. Requirements vary in the case of monoclonal antibodies.
The approval of biological products was, during the past year, a matter subject to claims made by laboratories – mainly those that develop innovative products. The fact that triggered such claims was that the regulations issued to approve biological products included the obligation for the authorities (mainly ANMAT) to issue specific guidelines to be complied with to obtain the approval of such products.
These guidelines were listed during the last quarter of 2018. They appeared on ANMAT's website on 12 October, but were not published with any detail as to when they would have to come into force. In addition, these guidelines have not been identified with any regulation number.
The guidelines refer to biological products establishing the need to file a guide, the requirements to register biological products related to the plants, a location of the plants, a report of the clinical aspects, etc. They also refer to vaccines, radiopharmaceutical products, medicines for advanced therapies, blood banks and related products.
Unfortunately such guidelines are only listed and not described. It is not clear if the purpose of complying with them is for internal purposes only, if they would contribute to a final report or how the information compiled would be kept.iii Non-clinical studies
No specific legislation refers to the welfare of animals in clinical trials carried out in Argentina. However, there are several references to how these kinds of trials should take place in Regulation No. 6677/2010 issued by ANMAT and related to the performance of clinical trials. Several articles written on this topic relate to bioethical concerns about clinical trials and, moreover, it has been stated that, if possible, this kind of trial should be replaced according to the circumstances of the matter under investigation.iv Clinical trials
Requirements to perform clinical trials are regulated by Resolution No. 1480/2011 issued by the Ministry of Health, complemented by Regulation No. 6677/2010 issued by ANMAT – the regulatory authority in charge of authorisation and control of any clinical trials to be performed. Additionally, ANMAT has created the National Registry in Health Investigations. Last year Regulation 4009/17 issued by ANMAT established the requirements needed to perform Phase 1 trials.
A clinical trial is an area that has shown a constant increase in activity in the past few years. Investments in research and development in the private sector and pharmaceutical industry reached 22 per cent of the total investments of this sector, according to the most recent information.
ANMAT must grant prior authorisation for any clinical trial. The sponsor, which must be a locally domiciled company or a foreign company's representative in Argentina, must request authorisation from ANMAT. Information about the sponsor is required, not only for legal purposes, but also for financial purposes to substantiate that it will be able to afford any eventual damages. In addition, a guarantee may be required.
Information related to the clinical trial is also required, such as:
- the name of the study;
- the phases of the trial;
- the product involved;
- the number of subject participants;
- consent forms that are required from subjects participating in the trial;
- information about the principal investigator; and
- information about the site.
The informed consent of the participating subject is required and the wording of the form should prove that the subject clearly understood the implications of participating in the trial. It is the principal investigator's duty to obtain and keep the consent forms. Certain requirements apply to subjects who are vulnerable owing to educational disadvantage. The informed consent form must be approved by ANMAT, the ethics committee appointed in connection with the trial and the Data Protection Registry.v Named-patient and compassionate use procedures
Regarding orphan drugs, closely related to the named-patient situation, ANMAT issued Resolution No. 840/1995 regarding compassionate use of drugs. This resolution regulates the mechanism for the import of products that are not commercialised in the country and in the instance that a patient requires a specific treatment duly prescribed by his or her physician. The import of such drugs has to be requested in each case by the patient or a civil association. Patients must file a declaration by the manufacturer of the drug, the prescription of such drug by the physician and the informed consent of the patient to be treated with such drug. The total amount of drugs to be imported shall be for a treatment that does not exceed 60 days. If the treatment is longer, a new and different request shall be made in each case.
According to Resolutions Nos. 942 and 426 of 2001, the import of these drugs is exempted from the payment of custom taxes and fees.
ANMAT specifically clarifies that its only intervention in this process is to issue a document that will provide the customs authority with evidence that the Board of Health endorses the request of the patient. The Board of Health also clarifies that it does not have competence with respect to aspects such as the authorisation for the acquisition of drugs by social security entities, or the provision of the drugs or the acts that need to be carried out to acquire the drug abroad.
Resolution No. 2324/97, also from ANMAT, specifically authorises non-profit civil associations that are legal entities to import drugs for compassionate use to sell to their members on a cost-price basis, and establishes that, to carry out that import, they must request authorisation from ANMAT (as described in Section II.iii). It is important to underline that in many cases, non-profit civil associations have made these requests.
Law No. 26,689 could be defined more as a list of intentions and 'to dos' rather than a specific regulation on the matter. In practice these cases assume the presence of the patient before ANMAT and compliance with specific steps to obtain the import of the necessary drugs, which is usually granted. Specific organisations, such as associations of patients or foundations, usually help to support the psychological state of the patient and family during the procedure.vi Pre-market clearance
No pharmaceutical product or medical device can be commercialised without having the approval of the Board of Health, with the exception of products included in clinical trials duly authorised.
The approval of pharmaceutical products by ANMAT should be required by a laboratory duly qualified as such before the Argentine authorities. Laboratories that are not qualified are not allowed to register pharmaceutical products. Nevertheless, it is possible for such laboratories to appoint a local laboratory (either a local subsidiary of a foreign laboratory or a national laboratory) as its representative to obtain the marketing authorisation issued by ANMAT in the name of the local laboratory acting on behalf of the foreign laboratory that is not qualified in the country.
General aspects of the procedures have been described in Section II.i; however, it is important to highlight that products registered in highly sanitary developed countries can be locally registered through a fast-track procedure that implies local recognition of the foreign marketing authorisation. Once a product is registered, similar products may be registered through a fast-track procedure to be carried out before ANMAT.vii Regulatory incentives
There are no regulatory incentives that would grant an extension of the patent term in cases in which a specific product has been subject to a patent application.
Nevertheless, a law that deals with confidentiality issues was enacted on 18 December 1966 (Law No. 24,766). This law establishes that during the process to authorise a new product, the confidentiality of the file related to that process should not be made public. Nevertheless, the same law establishes that if a patent has been granted for a product, it is possible to perform trials with it, but commercialisation should be kept on standby until the patent expires.
In contrast, Law No. 25,649 (enacted on 18 September 2002), favours the use of generic drugs and obliges doctors to prescribe pharmaceutical products using the name of the active principle of products. Law No. 25,649, however, does not prohibit use of the trademark in the packaging of the product, nor does it prohibit prescribing the use of the commercial name. The concrete application of the Law has not been clearly effective to date.viii Post-approval controls
Post-approval controls are managed by ANMAT, principally by means of reports made by parties on infringements to current regulations. Nevertheless, ANMAT is authorised to carry out inspections and to review products already authorised for commercialisation. Technical directors, being jointly and severally liable with the laboratory for any damage that a product may cause, are also keen to review batches of products during the manufacturing process and once finalised.
Additionally, laboratories usually carry out pharmacovigilance of their products, and agreements specifically related to such issues are commonly executed between laboratories that license their products to third parties.
In connection with this aspect of the business, the Ministry of Health issued Resolution No. 435 in April 2011, concerning traceability of pharmaceutical products that follow a specific product from its manufacture or importing stage, to the time it is exhibited for sale.
In connection with the control of products currently on the market, although not specifically pharmaceutical products, ANMAT prohibited the use of cloflucarban, fluorosalan, hexylresorcinol, triclosan and other antibacterial substances to be used in personal hygiene products.ix Manufacturing control
Regulation No. 2819/2004, issued by ANMAT and including GMP, is the main rule that regulates the manufacture of pharmaceutical products. This Regulation was drafted in line with the Recommendations on Good Manufacturing Practices and Control issued in 2003, by the World Health Assembly and reports of the Pharmaceutical Inspection Corporation Scheme (PE 009–1) and International Conference on Harmonisation – Guide of GMP (Q7A).
For the purpose of verifying the compliance of GMP, ANMAT is empowered to supervise the manufacturing laboratory as well as the sites in which commercial companies and importers develop their business. ANMAT may carry out technical inspections that cover the functioning conditions and quality control used in such places. Additionally, the manufacturing sites should also be approved by the municipality in which they are located and specific approvals on certain aspects, such as disposal of residues and other environmental issues, also apply. Some of these approvals are incorporated at a municipal level.x Advertising and promotion
Section 19 of Law No. 16,463 prohibits any form of public announcement of products that require an authorised prescribed delivery. The Supreme Court of Justice has supported this rule in several judgments by stating that the mere release of prescription medicines to the public without professional control may endanger public health.
The Ministry of Health Resolution No. 627/2007 regulates permissible practices for the promotion of pharmaceutical products requiring a medical prescription. Importantly, the resolution forbids pharmaceutical companies from, directly or indirectly, granting, offering or promising healthcare professionals (HCPs) any kind of incentive, such as bonuses or financial perks.
The promotion of medicinal products can only be addressed to practitioners authorised to prescribe or deliver medicines. The promotion should provide sufficient information, both technical and scientific, to allow practitioners to learn about therapeutic properties of the product. Promotion should be accompanied by informational material supporting the specification data of the approved product. Information should include the generic name and trade name of the pharmaceutical product and its quantitative and qualitative composition, form, counter-indications, adverse effects, warnings and doses. The only possibility of mentioning non-approved medicinal products is in the frame of specific congresses addressed to medical practitioners, and even in this case products should be identified by their active principle denomination, not being allowed to use the commercial brand.
Only the holder of a marketing authorisation may promote a product. While the holder of a marketing authorisation may entrust promotion to a third party, it maintains responsibility for all promotional communications and materials. The holder of the marketing authorisation must ensure that its agents or visiting practitioners receive the necessary guidance and comply with the requirements of Resolution No. 627/2007.
The aforementioned regime for promotion does not apply to OTC products or medical devices. Subject to control, advertising of OTC products is permitted. The advertising of OTC products should act as an incentive to use the products. The inclusion of a disclaimer recommending a consultation with a physician is mandatory.xi Distributors and wholesalers
The work of distributors and wholesalers is also under the supervision of ANMAT. Two clear distinctive functions are differentiated: one is the physical storage and distribution of the products, and the other relates to the collection of purchase orders and invoicing of the products. Storage facilities are subject to the approval and control of ANMAT.
The latter are companies that represent several laboratories and, acting on their behalf, invoice the products to be sold to wholesalers or pharmacies. These companies later render accounts and are compensated through a commission.xii Classification of products
The classification of products is outlined in Section II.i. All products (both ethical and OTC) are considered to be pharmaceutical products and should be sold only in pharmacies.
Some years ago, it was possible to find OTC products sold outside pharmacies (e.g., kiosks); however, settled jurisprudence has established that OTC products should only be sold in pharmacies and kept behind the counter.
Products for hospital use are usually sold through bids and can be delivered without following the usual commercialisation chain directly to hospitals, both private and public, and without needing to comply with all packaging and labelling requirements that need to be followed for the sale of these products through pharmacies.
In cases in which products are delivered as free samples, the products must include the generic name and brand name in accordance with Article 6 of Law No. 25.649, which requires both names to be of the same size and be given the same emphasis. Samples should also state: 'Free sample – sale forbidden'.xiii Imports and exports
Imports of pharmaceutical products are only authorised after following the regular procedures before the customs authorities, and a prior authorisation granted by ANMAT. These procedures usually include a visit and clearance of the plant in which the product to be imported is manufactured. The only entity authorised to import a pharmaceutical product is the laboratory that holds the marketing authority granted by ANMAT. The import is subject to clearance before going to marketing by means of a control held by the technical director of the laboratory intervening in the import of the product. The import of products to be used in clinical trials, which are not authorised for marketing, is subject to prior authorisation by the health authorities.
The export of products is authorised in cases in which the marketing authorisation, or a specific document, states that the product is available to be exported.
The donation of pharmaceutical products and medical devices from abroad is also subject to the control of ANMAT, as well as the customs authorities, and is subject to specific regulations. For example, products to be donated should be individually described and are subject to control; simply providing a general description of the products is not adequate.xiv Controlled substances
Psychotropics are subject to a strict, specific regulation that is continuously updated, with strict control carried out by ANMAT. Manufacture, import and use of psychotropics in products is subject to specific procedures and requirements, such as keeping an inventory, which helps to control which psychotropics and precursor chemicals are used in the manufacture of legitimate products.
In addition to measures strictly related to the pharmaceutical industry, a specific public entity – the Planning Secretariat for the Prevention of Drug Addiction and the Fight against Drug Trafficking – has been created to control and take action against the illegal use of such products. Laboratories are also obliged to register before the entity and to comply with its regulations.xv Enforcement
ANMAT is authorised to carry out inspections on working plants and raise any kind of observations it may deem appropriate. In these cases, ANMAT issues a deed that includes all objections and then serves notice to the company to file its defence. After reviewing any evidence that might have been provided, ANMAT issues a resolution. Eventual penalties are a call for attention, fines, closure of the facility and the suspension or even annulment of the authorisation to function.
Depending on the case, the imposition of penalties can also include a penalty for the technical director of the laboratory.
The decision issued by ANMAT is subject to appeal before the federal courts.