Andrew Merron, Biosimilars Advisory Service Director at BioTrends Research Group
On 9th February 2012, the FDA finally published draft guidance addressing the over-arching requirements for biosimilar medicines to gain approval in the United States. The publication has been met with considerable relief throughout the biosimilar industry after much anticipation and speculation, although provides only general guidance and little detailed information. Back in September 2011, the FDA hinted that their guidance for biosimilar medicines could be just a matter of days or weeks away. However, with no formal guidance published, the industry grew impatient. The only other publically available information from the FDA concerning biosimilar requirements were published in August in a New England Journal of Medicine article.
At the start of 2012, many biosimilar manufacturers were hoping for some clear guidance from the FDA on biosimilar product development, and the wait has been extensive compared with their European colleagues. The European Medicines Agency (EMA) first published over-arching guidelines on biosimilar medicines in 2005, more than six years before the FDA, and there are currently 14 biosimilars approved for use in Europe by the EMA. Despite the frustration over the lack of any guidance from the FDA, Hospira is the first company to initiate a pivotal Phase III trial for a biosimilar in the US even prior to the availability of FDA guidelines. The first patient was enrolled onto the clinical trial in January this year.
It is now nearly two years since the necessary legislation was signed into law allowing for biosimilars to enter the US market. On the 23rd March 2010, President Obama passed the Patient Protection and Affordable Care Act (PPACA); this act amended the Public Health Service Act (PHS Act) through the creation of the abbreviated pathway (also known as the 351(k) route) -allowing biosimilar approval. The 351(k) pathway is provided as part of the Biologics Price Competition and Innovation Act (BPCI Act) within the PHS.
The guidance that the FDA has issued comprises three documents: scientific guidance, quality guidance, and commonly asked questions and answers for the industry. Currently, the guidance is still in a draft version, and the FDA will welcome any public input prior to finalizing these documents. In addition, there is no product-specific guidance for individual classes of biologics. Nevertheless, we expect that eventually the FDA will issue product-specific guidance for demonstrating biosimilarity.
Overall, there are no major surprises in the draft guidelines compared to what we had expected. Essentially, the FDA is drawing on similar themes already presented by the EMA’s over-arching biosimilar guidance documents. The FDA clearly presents three over-arching themes:
A stepwise, risk-based approach to biosimilar product development including strong recommendation for early consultation with biosimilar sponsors
Justifications are required from biosimilar sponsors for their pre-clinical and clinical development strategies; also, explanations are sought for any differences seen between the biosimilar and the reference product
A ‘totality-of-the-evidence’ approach to approving biosimilars in the US on a case-by-case basis
The stepwise approach to demonstrating biosimilarity is critically important to streamline clinical trial design through later stages of evaluation. The scientific guidelines propose assessment of biosimilarity through three main steps:
1. Firstly, analytical studies are required. This rigorous structural and functional comparability exercise is important in order to smoothly proceed to the following steps. State-of-the-art techniques should be employed to assess the biosimilar and reference product.
2. Secondly, because subtle changes in functionality between a biosimilar and the reference product may not be detected in analytical studies, the biosimilar sponsor is required to perform further studies. Therefore, animal studies (including the assessment of toxicity) may be required.
3. Thirdly, a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics and pharmacodynamics) are required to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed. Because product-specific guidance is not yet available, discussion of specific end points are not included in the current draft guidelines. However, the clinical safety and effectiveness studies should select clinically relevant end points which can detect meaningful differences.
Indication Extrapolation Possible but Interchangeability is Challenging
Importantly, as we expected, the FDA is allowing for indication extrapolation for biosimilars as long as the extrapolation is founded on scientific justification. Indication extrapolation may be allowed assuming the biosimilar sponsor has considered potential differences in each indication with respect to the mechanism of action, pharmacokinetics, biodistribution, and toxicities. Despite the FDA allowing a biosimilar to undergo indication extrapolation, our research has suggested that physicians are unwilling to automatically accept and prescribe a biosimilar without specific clinical data in that indication. This suggests that clinical trials will be required in most indications in order to gain access to all indications for which the reference product is approved.
The draft FDA guidelines also consider interchangeable biosimilars. An interchangeable biosimilar must demonstrate a higher standard of interchangeability over a non-interchangeable biosimilar product. This greater standard includes demonstrating that the biosimilar produces the same clinical result as the reference product in any given patient and the risk of switching between the biosimilar and the reference product (in terms of safety or diminished efficacy) is not greater than using the reference product alone. The questions and answers document highlights that this will be a difficult barrier to overcome; although an interchangeable product may be considered eligible for automatic substitution at the pharmacy level.
The quality guidelines also released on the 9th February for biosimilar products focused on physiochemical considerations for demonstrating biosimilarity, including the expression system, manufacturing process, immunochemical properties, impurities, stabilities, and reference standards.
New Era of US Biosimilars is Imminent
The guidance is welcomed by industry and we now anticipate the confirmation of the guidelines after any public comments and expect product-specific documents to then be considered. Based on the growing number of biosimilar players, and the impending patent expiries for major blockbuster biologics, the future of the biosimilar industry can really start to gain momentum despite a somewhat sluggish start over the past five years in Europe. Once biosimilar versions of the commercially compelling products are developed, and biosimilars finally enter the US, growth in sales of biosimilar products will be significant from 2015 through 2020.
Despite the high burden, development of biosimilars represents a significant cost-saving opportunity for State-sponsored healthcare systems. In an age of increased austerity, lower cost biosimilars have the opportunity of saving in excess of $10 billion across the seven major pharmaceutical markets in 2020 - a highly attractive proposition. The publication of the draft guidelines by the FDA last week (while there is still much more we are waiting for) represents a major milestone in bringing these lower-cost products to market in the US.
The Biosimilars Advisory Service Director, Dr. Andrew Merron, will be hosting an analyst call describing the implications of these recently published guidelines on the 27th February. Learn more