Although the Biologics Price Competition and Innovation Act (BPCIA) became law and established a legal pathway for the approval of biosimilar protein products in March 2010, many details of the pathway was not clear till the latest release of three draft guidelines.
In February 2012, FDA finally published three biosimilar draft guidelines and asked for comments for 60 days. During this period, FDA received several comments on the guidelines and we decided to summarize some of the critical points here. For a full list of comments, you can check the below links.
Genentech generally stated that, the Q&A guideline does not address what will happen after a biosimilar has been approved and the innovator then obtains a new indication. The innovator of several monoclonal antibodies asks FDA; “Will the biosimilar be able to extrapolate/change its label to include the new reference product indication?”
The company wants FDA to clarify in a new biosimilar Q&A how they will handle extrapolation of future line extensions of the innovator product after the biosimilar product has been approved.
For using a foreign reference product, Genentech states that, as a scientific matter, the biosimilar applicant would generally be expected to provide adequate data or information to scientifically justify the relevance of the comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S.-licensed reference product.
Interchangeability is also an another point of interest of Genentech. The company states that, the answer to the question on determination of interchangeability in an original 351(k) application acknowledges that FDA is still considering the data and information needed to determine whether a biosimilar product is interchangeable with the reference product. And Genentech asks FDA to focus its efforts on guidance development for interchangeability.
Trade secrets and immunogenicity are the other major points in Genentech’s comments. The company states that, potential differences in rates and or severity of immunogenicity are important safety concerns, and should be addressed in the scientific justification for extrapolation of indications.
For trade secrets, Genentech wants to ensure that FDA takes all appropriate and legally required measures to safeguard the confidentiality of innovator applicants’ trade secrets and confidential commercial information, and to prohibit inappropriate reliance by biosimilar applicants on such material. Finaly Genentech advises FDA to take this opportunity to revise the existing regulation relating to confidentiality of data and information in BLAs (21 CFR 601.51).
Government of the Republic of Korea:
Yes, the Government of the Republic of Korea conveyed comments and inquiries expressed by the South Korean biosimilars industry regarding the announced draft guidelines.
The Korean Government states that, the first interchangeable biosimilar biological product to be approved as interchangeable for the reference product shall be granted one year of exclusivity and asks FDA ” What kind of documents needs or what kind of data needs to be submitted to get approval as interchangeable for the reference product?”
In order to clarify some major issues, the Korean Government asks FDA, “Isn’t equivalence testing required for extrapolation of indication? If extrapolation of a condition can be recognized through non-inferiority testing, what are the requirements?”
Government of Korea also asked some questions about extrapolation of conditions: “Extrapolation of a condition should address the mechanism of action in each condition of use, the PK and bio-distribution of the product, differences in expected toxicities in each condition of use, and any other factor. Even though differences in a certain issue among these factors are found in the condition, is extrapolation of the condition possible?”
As you can see, rather than giving comments to improve guidelines, Korean Government wants to get some answers from FDA on behalf of the South Korean biosimilars industry.
Watson recommends that FDA endeavor to maintain an adequate degree of flexibility in the required development approach, while providing more specificity in its final guidance, with respect to fingerpringint, rare immunogenicity events and interchangeability requirements.
Watson supports FDA’s opinion that clinical studies usually will be required as part of the biosimilarity assessment. The scope of the any required clinical studies, should be determined on a case-by case basis, with justification provided by the sponsor. If so required, these studies whould be appropriately powered to determine efficacy equivalence and confirm a non-inferior safety profile.
As part of the immunogenicity discussion, Watson declares that clinical evaluation of immunogenicity is a “key element in the demonstration of biosimilarity”, as written in the Scientific Guidance. It is Watson’s opinion, that in many cases, it would be more appropriate to perform post-market surveillance programs to monitor rare immune responses rather than to conduct a post-market study.
Surprisingly, Watson recommends FDA that, biosimilars should be assigned an identifying suffix (based on Greek letters or manufacturer abbreviation), with a common root that is identical across all biosimilars and the reference product. The non-proprietary naming of biosimilars was a debate in the EU years ago but Watson, insists on this topic and asks FDA to address this issue in the future guidelines.
There are several other comments from industry associations (e.g. BIO, PhRMA), innovator (e.g. Abbott, Novartis) and biosimilar/generic (e.g. Teva, Mylan) companies. If you want to have a look at the whole list, you can check the links below…