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Otto Licks and Patricia Helena Nunes Momsen, Leonardos & Cia

On December 17, 2010, the National Health Surveillance Agency (Anvisa) issued Regulation No. 55/2010, establishing the requirements for granting marketing approval to new biological products and biological products. Despite the fact that the Brazilian legislation does not use the terms ‘biosimilars’ or ‘biogenerics’, the concept of registration by reference to third parties’ data packages is fully supported by the regulation. Tis raises concerns regarding Brazil’s widespread lack of enforcement of data package exclusivity (DPE).

A request for marketing approval of biological products (not new) can be made in two different ways: individual development and development by comparability. When choosing individual development, the applicant must submit a technical report, non-clinical studies and clinical studies performed on the product. However, the scope of the non-clinical studies can be reduced and the phase I and II studies can be exempted. Phase III studies are mandatory (with exceptions) and must be comparatives of ‘non-inferiority’, ‘equivalence’ or ‘superiority’ to the new biological product. Otherwise, when using the development by comparability standard, it is necessary to submit a comparative dossier containing non-clinical and clinical studies used to demonstrate comparability between the biological product to be approved and the biological product used as a comparator.

Article 18 of the regulation provides that all therapeutic indications requested for marketing approval must be documented in the clinical studies. Article 19 allows, though, the extrapolation of data on safety and efficacy for additional therapeutic indications of biological products registered by comparability.

Tis represents a huge challenge to the Brazilian regulatory institutions. Tere is some consensus on the possibility of showing efficacy and safety for some small molecule drugs using bioequivalence tests. Te biological products present a much higher complexity. Te relationship between efficacy and safety of biological products and the results obtained from the chemical tests, bioequivalence or tests that demonstrate the pharmacodynamic effects is not sufficiently established. Regulatory authorities demand comparative clinical data capable of directly and unequivocally proving efficacy and safety of existing biological products.

A good example is low molecular weight heparins (LMWHs)— anticoagulants obtained from animal tissues. VMHs have a lot of therapeutic indications, including the treatment of deep vein thrombosis (DVT).

Tere’s a consensus on the need to perform clinical studies with patients to compare LMWHs (not new) with the drug that is considered the reference. However, there is a lot of divergence concerning the extrapolation of data

50 World Intellectual Property Review May/June 2011


obtained in these studies to cover therapeutic indications that have not already been tested, which might infringe not only data package exclusivity, but food and drug, consumer protection and several other laws.

As the indications approved to the LMWHs involve different patient groups, there’s a huge discussion of which studies would be necessary to establish the efficacy and safety of biological products (not new) for each of these patient groups. Te International Society on Trombosis and Haemostasis (ISTH) states that this should be demonstrated in comparison to the originator LMWH in clinical trials for every indication for which marketing approval is sought. Marketing approval of LMWHs proceeding in Brazil is included in the regulation. A recent review demonstrated that three LMWHs with recent marketing approvals granted by the Anvisa did not comply with the recommendations of ISTH. Two of them obtained marketing approvals only based on pharmacodynamic studies data; the third had its marketing approval granted based on a clinical study performed in patients with low risk to venous thrombosis and the number of patients was not enough to determine the non-inferiority of the tested product in relation to the comparator biological product. Despite that, the three products had their marketing approval granted on all indications in Brazil. Tis constitutes a violation of the data package exclusivity laws protecting against new biological products without any technical scientific basis.

In addition to the intellectual property infringement, there’s a clear violation of the consumer law, as the consumer is now vulnerable to products that have no unequivocal proof of efficacy and safety for all the approved therapeutic indications.

Otto Licks is a partner at Momsen, Leonardos & Cia. He can be contacted at:

Patricia Helena Nunes is an associate at Momsen, Leonardos & Cia. She can be contacted at:

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