Marketing authorization

The Argentine drug manufacturing, importing, exporting and marketing regime is regulated by Law No. 16 463 of 1964, Presidential Decree No. 150 of 1992, and Law No. 24 766 of 1996. ANMAT grants marketing authorization.

The marketing authorization regime for drugs manufactured in Argentina allows for two different scenarios: (i) whether the authorization concerns a drug not previously authorized in Argentina or in a country with a high level of health surveillance;²⁷ and (ii) whether the drug under consideration has received prior authorization in Argentina or in a country with a high level of health surveillance. ANMAT provides a specific process to obtain permission to market for each of these scenarios.

In the first scenario the drug in question has not received previous authorization in Argentina or in a country with a high level of health surveillance. In this case, ANMAT requires clinical trials that demonstrate the drug’s safety and efficacy.

In the second scenario, the drug is similar to a reference drug that has been previously authorized in Argentina or in a country with a high level of health surveillance. In this case, the applicant can invoke pharmaceutical similarity and ANMAT will grant an exemption from the clinical trial requirement.²⁸ Decree No. 150/92 states that the process to obtain marketing authorization by pharmaceutical similarity will take no more than 120 days, and ANMAT

26 ANMAT was created by Decree No. 1490/92 in August 1992. ANMAT is a decentralized agency of the Federal Government that depends, both technically and scientifically, on the Secretariat of Policies, Regulation, and Institutes and the Ministry of Health.

27 Decree No. 150/92, Annex 1. The following countries are considered countries with high levels of health surveillance: Austria, Belgium, Canada, Denmark, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Sweden, Switzerland, the United Kingdom, and the United States.

28 Law No. 24 766, Article 5; Decree 150/92, Article 3 (without limitation, those who solicit approval of a drug invoking pharmaceutical similarity must present certain information regarding the product (e.g. name, formula, drug form, pharmacological classification, and whether it is an over-the-counter or a prescription drug), technical information (e.g.

methods of control, shelf-life, method of manufacturing in line with GMP, information on bioequivalence or bioavailability of the product in relation to similar products), and information on labelling and packaging.

has typically complied with this time limit. Marketing authorization for an approved drug or a drug imported from a country with a high level of health surveillance is granted automatically.

The Argentine regime does not grant exclusive rights to the undisclosed results of the clinical trials presented to ANMAT or the regulatory authority of another country (hereinafter, “pharmaceutical test data”) by the applicant. The Argentine regime protects pharmaceutical test data presented to ANMAT only against unfair competition.²⁹ According to Article 4 of Law No. 24 766, approval by similarity (i.e. the submission of evidence of marketing in Argentina or a country with a high level of health surveillance) does not imply ANMAT’s use of the pharmaceutical test data presented to obtain marketing authorization for the reference product, regardless of whether the pharmaceutical test data were presented in Argentina or another country.³⁰

Another noteworthy aspect of the authorization process for drugs by similarity relates to bioequivalence trials. Even though comparative dissolution tests are generally required for solid pharmaceutical formulations – between the product for which approval is sought and a reference drug – ANMAT does not require bioequivalence tests in vivo for all drugs.

ANMAT Regulations No. 3185/1999 and 2814/2002 establish a process for bioequivalence trials, based on a two-variable model, which considers health risk on the one hand, and those drugs that require bioequivalence trials in Canada, Germany and the United States on the other hand (ANMAT, 2006a).

The application of this model results in the categorization of APIs that require in vivo bioequivalence tests and a timetable for their gradual completion (ANMAT, 2006b).

Thus, drugs are classified into three categories: (i) drugs that do not require bioequivalence tests; (ii) drugs that require in vitro bioequivalence tests; and (iii) drugs that require in vitro and in vivo bioequivalence tests. Additionally, ANMAT Regulation No. 3311/2001 has mandated in vivo bioequivalence tests for antiretroviral drugs (ARVs) used in the treatment of infections caused by HIV.

ANMAT requires bioequivalence tests for 22 high-risk APIs.³¹ Furthermore, ANMAT requires bioequivalence tests for the 27 APIs or API combinations used in the treatment of HIV;³² 63 high-risk drugs and 110 ARVs have met the

29 Law 24 766, Article 11.

30 Law 24 766, Article 8, § 8.

31 The following drugs require bioequivalence tests: carbamazepine, lithium carbonate, ciclosporin, digoxin, divalproex sodium, ethosuximide, phenytoin, phenytoin sodium, isotretinoin, levodopa-benserazide, levodopa-carbidopa, oxcarbazepine, pyridostigmine, theophylline, magnesium valproate, verapamil, warfarin, everolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus and tacrolimus (ANMAT, 2011a).

32 The ARVs in question are abacavir, amprenavir, atazanavir, darunavir, didanosine, efavirenz, emtracitabine, stavudine, etravirine, fosamprenavir, indinavir, lamivudine, lamivudine/

zidovudine, abacavir/lamivudine/zidovudine, lamivudine/abacavir, maraviroc, nelfinavir, nevirapine, nevirapine/lamivudine/zidovudine, raltegravir, ritonavir, ritonavir/lopinavir, saquinavir, tipranavir, tenofovir disoproxil and zalcitabine (ANMAT, 2011b).

standard of this regulatory requirement. This requirement has also resulted in the suspension of marketing authorizations for 20 high-risk drugs and 118 ARVs that did not comply with or pass the bioequivalence tests.³³

The practice of approving drugs by similarity and the requirement that bioequivalency tests be conducted only on high-risk drugs and ARVs has contributed to the preservation of a competitive pharmaceutical market in Argentina and favours new entrants and high levels of competition in the generic drug market. For example, in 2006, ANMAT granted 1610 marketing authorizations, of which approximately 89% were products approved by similarity; 10% were drugs imported from countries with high levels of health surveillance; and only 1% were drugs that underwent clinical trials to ensure their safety and efficacy.³⁴

Multinational pharmaceutical companies and the United States Government have questioned the legal validity of the Argentine system of granting marketing authorization for drugs by similarity in both domestic and international fora. They have claimed that the Argentine system of similarity should be eliminated or modified. Their objections are based on concerns regarding the rights to pharmaceutical test data.

In the international forum, the United States Government initiated two separate consultations under the Understanding on Rules and Procedures Governing the Settlement of Disputes (Dispute Settlement Understanding;

DSU) at the World Trade Organization (WTO) in 1999 and 2000.³⁵ In bringing its consultations, the United States alleged that Decree No. 150/92 and Law No. 24 766 were inconsistent with Article 39.3³⁶ of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement).³⁷

On 22 June 2002, after nine rounds of negotiations, the United States and Argentina notified the WTO’s Dispute Settlement Body that the two countries had reached a mutually agreed upon solution (WTO, 2002). The agreement stated that the disagreement over the meaning and applicability of Article 39.3 of the TRIPS Agreement would be resolved under the rules of DSU.

Additionally it was agreed that both parties would continue the consultation process and jointly assess the progress of legislative reforms to the Argentine Patent Law; and, in light of this assessment, that the United States could decide to continue consultations or request the establishment of a dispute

33 Source: ANMAT.

34 Source: ANMAT.

35 WT/DS171/1. Geneva, World Trade Organization, 5 May 1999, and WT/DS196/1. Geneva, World Trade Organization, 6 June 2000.

36 Article 39.3: “Members, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use. In addition, Members shall protect such data against disclosure, except where necessary to protect the public, or unless steps are taken to ensure that the data are protected against unfair commercial use.”

37 The consultations also included other allegations of inconsistency between the TRIPS Agreement and the Argentine Patent Law No. 24 481.

settlement panel related to an alleged violation of Article 39.3 of the TRIPS Agreement (WTO, 2002).

Additionally, Argentina and the United States agreed “that should the Dispute Settlement Body adopt recommendations and rulings clarifying the content of the rights related to undisclosed test data submitted for marketing approval according to Article 39.3 of the TRIPS Agreement, and should Argentinean law be found to be inconsistent with Article 39.3 as clarified by the above-mentioned recommendations and rulings, Argentina agrees to submit to the National Congress within one year an amendment to Argentinean law, as necessary, to put its legislation in conformity with its obligations under Article 39.3 as clarified in such recommendations and rulings” (WTO, 2002). The United States has not requested to reopen the consultations or to establish a dispute settlement panel since the agreement reached in 2002.

In the domestic forum, multiple multinational pharmaceutical companies have challenged the constitutionality of the Argentine regime and its compatibility with the TRIPS Agreement. In 2005, alleging that the Argentine system is inconsistent with the TRIPS Agreement, G.D. Searle & Company, Novartis Pharma S.A., Schering-Plough Corporation and MSP Singapore (a joint venture between Schering-Plough Corporation and Merck & Co.) initiated 13 lawsuits challenging the constitutionality of Decree No. 150/92 and Law No. 24 766 in Argentine courts.³⁸

Before the courts’ hearings on the merits of the cases, the plaintiffs requested preliminary injunctions to suspend the marketing authorizations for several drugs. The Argentine Federal Appellate Court refused this request, stating that there was no likelihood of success on the merits. Of the 13 cases initiated in 2005, the Court of Appeals issued a final judgment rejecting the claim in 1 case; ³⁹ the other 12 cases remain open on the merits.

In sum, there were two challenges brought against the validity of the Argentine system of drug marketing authorization, both alleging that Decree No. 150/92 and Law No. 24 766 are incompatible with Article 39.3 of the TRIPS Agreement.

The first, brought by the United States in the WTO Dispute Settlement Body, was resolved through a mutually agreed upon solution between the two countries. The second, brought by several multinational pharmaceutical companies in the Argentine courts, has yet to be resolved, although the courts have dismissed requests for provisional measures.

38 In accordance with Article 75, Clause 22 of the Argentine Constitution and the holdings of the Corte Suprema de Justicia de la Nación (National Supreme Court of Justice) in the Unilever, Karl Thomae and Pfizer cases, the provisions of the TRIPS Agreement are superior to domestic laws and legislation; therefore, TRIPS’ norms are operative and can be directly applied by a judge. National Supreme Court of Justice, cases Unilever c/ Instituto Nacional de la Propiedad Industrial s/ denegatoria de patente, decided on 24 October 2000; Dr Karl Thomae Gesellschaft mit beschränkter Haftung c/ Instituto Nacional de la Propiedad Industrial y otro s/ denegatoria de patente, decided on 13 February 2001; and Pfizer Inc.

c/ Instituto Nacional de la Propiedad Industrial s/ denegatoria de patente, decided on 21 May 2002.

39 See Novartis Pharma AG v. Monte Verde SA, Buenos Aires Civil and Commercial Federal Court of Appeals, Panel 3, 1 February 2011, published in Revista Jurídica La Ley, 16 March 2011, p. 8.

Novartis did not appeal to the Federal Supreme Court, and so the judgment is res judicata.