Interchangeability of Biosimilars in Brazil

In Brazil, biological products are regulated by the Brazilian Health Regulatory Agency – ANVISA pursuant to Resolution RDC No. 55/2010, and are defined as product containing a molecule with known biological activity, which has passed through all manufacturing steps. A molecule not yet approved in Brazil is called “new biological product”, while a molecule already registered in Brazil is called “biological product”. Brazilian regulation has not embraced the expression 'biosimilars', like United States and Europe.
 
Approval of new biological products requires a complete technical and scientific registration dossier. Biological products, in turn, have two approval pathways; individual development or comparability.
 
In the individual development pathway, the applicant must provide ANVISA with a complete technical and scientific registration dossier including clinical and non-clinical data and immunogenicity studies.
 
Except for blood products, vaccines and biological products with oncological indication, in the registration process by the individual development pathway, the phase III clinical studies shall attest the non-inferiority, equivalence or superiority of the biological product in relation to the new biological product. Also, the safety and efficacy data presented to ANVISA cannot extrapolate to other therapeutic indications not approved for the new biological product.
 
In the comparability pathway, the biological product is approved upon comparison of its efficacy and safety attributes with a comparator product already approved by ANVISA, and requires comparative pre-clinical and clinical studies to evidence the biosimilarity between the comparator and the biological product products.
 
The extrapolation of safety and efficacy data for other therapeutic indications of the biological products recorded by comparative development pathway, however, is allowed, and the conditions must be established in specific guides issued by ANVISA.
 
In either pathway, ANVISA does not require any specific showings required for an interchangeability determination.
 
Recently, ANVISA, through Technical Opinion 003/2017/GBIO/GGMED/ANVISA, stated that the interchangeability is not a requirement for registering a biological product but a medical practice that should be analysed considering the patient’s clinical scenario.
 
For ANVISA, biosimilars and comparators interchanging must be decided by the prescribing physician and the Ministry of Health. Once the comparator biological product is replaced by the biosimilar, medical assessment and oversight are essential to find what product best fits based on the patient’s response.
 
Accordingly, ANVISA has already advised that, upon registration of a biosimilar, it will not classify or determine what the interchangeable biological product is for the relevant product given such classification may involve assessment of data other than those required by legislation. Nor does the agency believe necessary to issue a specific regulation to govern this matter.
 
In 2015, ANVISA started to publish in its website a document called Drug Approval Public Opinion, which describes the technical and scientific arguments used by the Agency in reviewing the dossier for registration of drugs approved thereby. In case of biological products, such document does not provide information about the studies that could be used to evaluate the interchangeability of biossimilars and the comparator.
 
ANVISA, however, believes prudent to include such information in its public opinion, and also in the label of the product since, it may assist the interchangeability exercise. However, no specific regulation has been issued by the Agency in this regard up to this moment.
 
ANVISA defends that the patient’s assessment and oversight by the prescribing physician is the most relevant factor in case of substitution or interchangeability between biosimilars and their comparators, mainly for purposes of pharmacovigilance and post-market oversight. In addition, multiple alternation between biosimilars and the comparator product must be avoided not to impair traceability and oversight of the product use.
 
The subject has been gaining ground, including in the national political environment.
 
The Social Affairs Committee of the Senate, in order to gather information on the possibility of changing the comparator by the biossimilar to guarantee their safe and effective use, at more affordable costs to patients, launched a Public Hearing on 15 August 2017 to discuss the matter.
 
The medical class then expressed their discomfort with ANVISA’s stand and is pushing for a regulation. The main argument is that biosimilar product substitution requires additional clinical evidence and such decision cannot be left in physicians’ hands.
 
The government, in turn, worried about the cost-effectiveness ratio, at said public hearing, and stated that increasing access to biosimilars with proof of interchangeability and possibility of automatic substitution would also increase access and consequently bring benefits to the population and to the Brazilian health industry.
 
Brazil is working in an effort to reach a consensus in relation to the interchangeability, and, in the present moment, for ANVISA, the prescribing physician, responsible for the patient’s assessment and oversight, is the most relevant factor in case of interchangeability between biosimilars and their comparators.