Biologic products developed over the past three decades and approved by the Food and Drug Administration (FDA) now provide important therapeutic options for a variety of serious clinical conditions.
As recognized by a recent article in the New England Journal of Medicine (NEJM), “therapeutic biologics such as genetically engineered recombinant proteins and monoclonal antibodies represent a large portion of newly approved therapies for conditions such as chronic inflammatory diseases and cancer.” Moreover, the article asserted that, “Biologic enzyme-replacement therapies provide clinical benefits in previously untreatable genetic disorders.”
The article noted that, “although typically more structurally complex than the small-molecule drugs more prevalent in today’s market, biologics vary in complexity from cellular therapies to small, highly purified proteins.”
Consequently, according to a recent article from BioCentury, Janet Woodcock, Director of the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research, told BioCentury This Week that the agency has completed work on biosimilars guidance documents and expects them to be released “promptly.”
In an interview with BioCenutry, Woodcock described approval criteria for biosimilars, which will be based first on evaluation of analytical similarity to an innovator, with that evaluation driving FDA’s requirements for clinical data. She said that using this approach, creating an “interchangeable biosimilar is feasible.”
Separately, FDA and industry stakeholders have come to “tentative agreement” on a biosimilars user fee program, according to meeting minutes. The agreement calls for biosimilars user fees to equal PDUFA fees; however, FDA would begin collecting biosimilars fees when an IND is filed as compared to when an NDA or BLA is filed in the case of PDUFA fees.
FDA agreed to an industry request for special protocol assessments for biosimilars. The agency also committed to spending at least $20 million in non-user fee funds on biosimilars reviews every fiscal year prior to collecting user fees.
Background
To improve access, Congress passed the Biologics Price Competition and Innovation (BPCI) Act of 2009, authorizing the FDA to oversee an “abbreviated pathway” for approval of biologics that are “biosimilar” to already-approved products.
Specifically, “under the BPCI Act, biosimilars will also have the opportunity to meet a higher standard of similarity to a reference product — “interchangeability,” reflecting an FDA assessment that pharmacists can make substitutions between biologics without the prescriber’s intervention.”
Additionally, “a biologic will be considered interchangeable with a reference product if the developer demonstrates that it can be expected to produce the same clinical result in any given patient and that the risk associated with alternating or switching between the two products is not greater than that involved in continuing to use the reference product.”
Since 1984, U.S. laws regulating nonbiologic products have allowed an abbreviated approval pathway, permitting the rapid approval of thousands of less expensive generic drugs based on comparisons to reference drugs and dramatically increasing medicines’ affordability.
In 2009, almost 75% of small-molecule prescriptions dispensed in the United States were for generics, and the approval of a generic drug resulted in average savings of 77% of the product’s cost within 1 year. Although cost reductions for biosimilars probably won’t be as large, the Federal Trade Commission predicts that their availability will significantly reduce biologics’ cost and increase their accessibility
Discussion
As industry and FDA seem to be on the verge of issuing long-awaiting guidelines for the development of generic versions of complex biotechnology medicines, “the FDA still plans to release the guidance by the end of the year.”
However, Janet Woodcock indicated it could come “as early as the next few weeks, maybe even days,” Janice Soreth, deputy director of the agency’s Europe office in London, said on Friday. Soreth made her comments during a biosimilars panel at Windhover’s Pharmaceutical Strategic Alliances Conference, held in New York.
An article from Reuters noted that, “Europe is ahead of the United States on this front, having already approved cheaper copies of some biotech medicines.”
Drugmakers, investors and others are eager to gain more insight for the approval process for cheaper versions of biotech drugs, known as “biosimilars” — a potentially multibillion-dollar market.
Soreth said the article in NEJM, “was an indicator of what the guidance might look like.” Agency officials said in the article that approval for biosimilars “will require a new paradigm of sponsor-FDA interactions,” involving analysis of much more data than traditional generics.
Unlike conventional, easy to replicate, chemical-based drug compounds, biotech drugs are derived from living organisms, such as proteins, and often produced using recombinant DNA technologies.
Agreement on a pathway for producing cheaper versions of biotech drugs — which treat diseases such as cancer, rheumatoid arthritis and multiple sclerosis — has been far more difficult than for traditional pills and capsules because their complex manufacturing process does not lend itself to production of exact copies.
Making biotech copies is also expected to be more costly, as manufacturers must conduct extra clinical trials to show the new version is as good as the old one. Additionally, the NEJM article noted that, “to help ensure that any additional animal and human testing is appropriately targeted and that biosimilar development plans are optimally streamlined, studies assessing biosimilarity must be carefully tailored to address residual uncertainty.”
The NEJM article asserted that, “the FDA evaluation of biosimilarity must consider the product’s complexity, its formulation, its stability, and the usefulness of biochemical and functional characterizations and incorporate these factors into a risk-based approach.” Moreover, the article maintained that, “evaluating biosimilarity with a risk-based approach is scientifically appropriate and familiar to the FDA, whose decisions are commonly based on reducing residual uncertainty to an acceptable level in any given clinical setting.”
Additionally, the NEJM article noted that, “Immunogenicity remains a critical factor when assessing biosimilarity, and the FDA will evaluate immunogenicity in a risk-based manner. For example, aggregation of proteins may be associated with higher risks of immunogenicity, and the risks related to an immune response are greater with products that stimulate immunity to nonredundant self-proteins, such as erythropoietin.”
The article also asserted that, “The FDA process for biosimilars must include product-specific safety monitoring.”
Conclusion
Soreth said the FDA has received about two dozen meeting requests for proposed biosimilar products, involving potential versions of nine or 10 brand biotech drugs, or “reference” products.
Consequently, “the potential players in the burgeoning market include traditional generic drugmakers, such as Novartis’ Sandoz division, as well as large pharmaceutical companies like Pfizer and Merck — all of whom participated in the panel on Friday.” Other companies such as Biogen Idec and Amgen Inc , have also expressed an interest in manufacturing biosimilars at some point.
As the market develops for biosimilars, Reuters noted that, “it remains unclear to what extent it will mimic the market for pills — in which generics of widely sold drugs are substituted for brands at pharmacies and are sold at 90 percent discounts.”
For example, the article noted that, “the biosimilar process, at least initially, may not allow such direct substitutions or involve such hefty discounts. Indeed, panelists on Friday agreed the discounts thus far have been about 20 percent to 40 percent.”
“Michael Kamarck, president of Merck BioVentures, said the European experience with biosimilars has demonstrated the products will demand marketing and other support similar to that required for brand products.” Kamarack noted that, “doctors and patients may demand more evidence for these products, beyond just FDA approval, before using them.”
However, “Jim Roach, chief medical officer of Momenta Pharmaceuticals Inc , said the pressure brought by health insurers and other healthcare payers to lower drug costs may ultimately prompt increased use of biosimilars, should they win approval.”
Roach maintained that, “to the extent you can convince regulators that your product is highly similar and perhaps indistinguishable and potentially interchangeable, I think the products will be taken up quite well.”