Since 2002, the Agência Nacional de Vigilância Sanitária (ANVISA) has accelerated its operational plan to provide guidance for pharmaceutical companies surrounding the development and approval of biologics, complex medications derived from live proteins or recombinant DNA, and biosimilars (subsequent-entry biologics), their generic counterparts. Due to the growing number of expiring patents, interest in development for these complex products in Brazil has been vastly amplified in an increasingly competitive environment.
In 2010, ANVISA released revised guidelines (RDC no. 55/2010) outlining the approval pathway for biologics and biosimilars in an effort to encourage development of these medications. The procedures stemmed from review of previously released regulatory guidelines from around the world including Cuba, the U.S., Europe, Canada, Korea, Japan, and the World Health Organization (WHO). The final direction provided by ANVISA most closely resembles the WHO biosimilar framework and the most noteworthy differences between the two are related to specific issues in Brazilian laws and the national context.1 The ANVISA guidance was a significant step in providing pharmaceutical companies with the tools needed to begin bringing affordable versions of these products to market. As ANVISA continues to revise and perfect these guiding principles, it is necessary to present additional recommendations surrounding the regulatory pathway for chemically-synthesized complex drugs, or nonbiologic complex drugs (NBCDs), as these products follow a differing manufacturing process than biologics.
Highlights of The ANVISA Guidance
The ANVISA guidelines provide an overview of the necessary procedures for bringing biologics and biosimilars to market. ANVISA requires that biosimilars be at least as efficacious and safe as the innovative product and without contaminants.2 This burden of proof is placed on the company bringing the biosimilar to market, permitting ANVISA to decide, on a case-by-case basis, whether full-scale placebo-controlled trials should be conducted to meet the requirements of efficacy and safety. This approach ensures the opportunity for pharmaceutical companies to submit biosimilar applications under an abbreviated pathway allowing more affordable versions of these drugs to come to market quickly by cost-effective means.
The ANVISA guidance outlined a two-pronged approach for submitting applications for biologics and biosimilars. The development copy for comparison path outlines an approach in which the biosimilar is compared to the reference product in terms of quality and available data, and closely resembles that of the WHO guideline. A comparative dossier containing preclinical and clinical studies is necessary to demonstrate comparability between the products. Based on the obtained results, the requirements for preclinical and clinical data can be adjusted and/or simplified. This pathway allows for extrapolation of therapeutic indications between the biosimilar and reference product.
In instances where a biosimilar cannot be compared to an innovative product, the individual development copy path can be utilized. With this method, the applicant must submit a summary of the preclinical and clinical studies performed on the biosimilar product. The scope of the preclinical studies may be reduced and Phase I/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.3 It is important to note that under the ANVISA guidelines, pharmaceutical companies are striving to demonstrate similarity between biosimilars and the reference product, rather than bioequivalence. This method is parallel to the guidance put forth by WHO.
Differences Between WHO And ANVISA Biologic And Biosimilar Guidelines
There are a number of similarities between the guidelines published by ANVISA and those from WHO. The Table provides highlights of the differences between the critical components of the WHO and ANVISA comparative guidance. As shown, the WHO regulations do not provide an individual pathway as outlined by the ANVISA guidelines. While both agencies provide for specific pharmacovigilence plans and post-marketing reports, WHO offers a more detailed approach surrounding the need for preclinical/clinical trials with an emphasis on design and statistical analyses.
In contrast, ANVISA intends to release subsequent guidelines specific to disease states/products that will provide additional details surrounding how much data will be required. In Brazil, only the copies licensed by the comparability pathway will be considered as a biosimilar and can therefore claim for extrapolation of indications.4 By considering guidelines from other global agencies, ANVISA has been able to adapt best practices into an approach that works best for Brazil.
Additional Guidance in Brazil Is Necessary
The guidance released by ANVISA allows for the agency to have flexibility in determining requirements for biologics and biosimilars on a case-by-case basis. Further guidance is anticipated surrounding specific classes of medications, such as interferons and monoclonal antibodies, to provide individualized requirements for products of a complex nature. As such, it is important for ANVISA to consider releasing direction surrounding the regulation of NBCDs. NBCDs are complex products similar to biologics, but are produced via chemical synthesis, rather than live proteins.
In a recent article published in BioProcess International, Dr. Vera Weinstein notes, “NBCDs are medicinal non-biological products where the active substance is not a homo-molecular structure, but consists of a variety of different, closely related, structures which cannot be fully characterized.”5 Oftentimes these products lack a defined mechanism of action (MOA), and pharmacokinetic (PK) or pharmacodynamics (PD) testing is not sufficient to predict clinical outcomes. Due to the inability to characterize these products, significant issues related to the immunogenicity of these medications can arise. One such example of an NBCD is Copaxone®, a treatment indicated for relapsing-remitting multiple sclerosis (RRMS). It is currently impossible to identify the active sequences or epitopes in Copaxone®, even using the most technologically sophisticated separation techniques. Furthermore, the MOA and its specific effects on the immune system for Copaxone® are still not fully elucidated.6
NBCDs such as Copaxone® were a focus for a recent meeting held in São Paulo, Brazil, “U.S. & Brazil: Navigating New Frontiers in Pharmaceutical, Medical Device & Food Law & Regulation,” which brought together regulatory and industry experts to discuss food, medical device, and pharmaceutical regulations in the U.S. and Brazil. A panel discussion highlighted the need for additional regulations surrounding NBCDs to ensure products of this nature that are brought to market have proven safety and efficacy profiles.
ANVISA has made significant progress since it began developing guidelines surrounding biologic and biosimilar products in 2002. As technology and science continue to advance, the ability to characterize these complex therapies will continue to evolve. Until then, ANVISA should continue to provide specific guidance on products such as NBCDs and monoclonal antibodies to encourage Brazilian pharmaceutical companies to bring these complex medications to market.