The issue of how to classify and regulate follow-on biologics is a tug of war and the stakes are high for all concerned: politicos, pharma companies and the public. One side argues for dramatic savings in both the staggering cost of and time-to-market for desperately needed biotherapeutics. The other side raises worrisome concerns over the safety and efficacy of products that could come to market without being subject to rigorous process scrutiny or clinical evaluation.
Senators Hillary Clinton (D.-N.Y.), Charles Schumer (D.-N.Y.), David Vitter (R-La.) and Susan M. Collins (R-Maine) and Representatives Henry Waxman (D-Calif.) and Jo Ann Emerson (R-Mo.) took the debate to a new level on Feb. 14 by introducing the “Access to Life-Saving Medicine Act of 2007” in their respective houses of Congress. The next day, bolstering the bill’s pro-biosimilars position, pharmacy benefits management firm Express Scripts issued a report claiming that generic biotech medicines could save U.S. health plan sponsors and patients $71 billion over 10 years.
The Senate Committee on Health, Education, Labor and Pensions further turned up the heat on Mar. 8 by holding a hearing on the subject. In addition to senators on that committee, speakers included:
- Sid Banwart, vice president of human services, Caterpillar;
- Dr. Jay Siegel, president of biotechnology R&D at Johnson &Johnson and a 20-year veteran of the U.S. Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research;
- Nicolas Rossignol, administrator of the European Commission Pharmaceuticals Unit;
- Dr. Ajaz Hussain, vice president of development at Sandoz and former deputy director of the Office of Pharmaceutical Sciences in FDA's Center for Drug Evaluation and Research.
Each speaker represented a slightly different perspective. Banwart, speaking for Caterpillar and, unofficially, thousands of other U.S. corporate human resource directors, remarked, “As you know, the escalation of health care costs is a top concern for U.S. business executives... Last year alone, [Caterpillar] spent more than $600 million in the U.S. for comprehensive medical, dental, vision and prescription benefits.”
He urged Congress to “create an appropriate regulatory route for FDA review of biogenerics” and “grant the FDA the authority to use its discretion and scientific expertise to evaluate interchangeable and comparable biogeneric products while ensuring patient safety.”
To anyone unfamiliar with the drug industry or the workings of the FDA, Banwart’s plea would likely sound quite reasonable. However, when perceived through the filter of expertise in life sciences or regulatory affairs, Banwart’s choice of words could be rather polarizing. The problem is a matter of semantics, but it is far from academic, because the specific words that end up being written into bills that become law or guidance that becomes regulation concerning follow-on biologics will affect how such products may be produced, marketed and prescribed.
For example, whereas Banwart referred to “biogeneric products,” Dr. Siegel stressed that it would be inappropriate to view follow-on biologics in the same light as generic versions of chemical drugs. “There cannot be allowance for determinations of ‘comparability’ for products that are so different in structure that they should be considered different products entirely,” he stated, adding that “a follow-on biologic product should not be considered ‘interchangeable’ with its reference product.”
Whereas one can reverse-engineer a chemical drug, most biotherapeutics are logarithmically more complex in structure and effect.
This slide demonstrates the complexity of a biologic (epoetin) versus a small molecule drug (ranitidine). Courtesy of the Biotechnology Industry Organization (BIO).
Siegel emphasized this by referring to an FDA letter written last September to the World Health Organization, to wit: “Different large protein products with similar molecular composition may behave differently in people and substitution of one for another may result in serious health outcomes, e.g., generation of a pathologic immune response.”
In his testimony, Rossignol described how the European Union (EU) has addressed all these issues. His agency set forth a framework that is both open and limiting, with broad parameters that are applicable throughout the EU, but specific details may be applied and enforced by each member state individually. The European Medicines Agency (EMEA) then issued guidance based on that framework. Rossignol explained, “…the licensing route for biosimilars is based on the principles that 1) biologics are not chemical drugs; and 2) the generic approach is, in the quasi-totality of cases today, very unlikely to be applicable to biologics: biosimilars are not ‘biogenerics’.”
Further, he said, “The EMEA guidelines make it clear that it is not expected that the quality attributes (e.g. the molecular structure) in the biosimilar and the reference product should be identical. Actually, minor structural differences are reasonably expected given the very nature of biologics and the inherent variability in the way they are produced. However, those differences should in any event be justified on scientific grounds and would be considered on a case-by-case basis, in relation to their potential impact on safety and efficacy. The underlying scientific assumption is that differences between the biosimilar and the reference product are, a priori, regarded as having a potential impact on the safety/efficacy profile of the product. They will therefore influence the type and amount of data required by the regulators in order to make a satisfactory judgment of compliance with EU standards.”