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Scientific Research to Support the
Regulation of a
presentation by Many issues are raised with the introduction of generic protein pharmaceuticals, called "Biosimilars" in the US, "Follow-on Biologicals" (FOB's) in Europe, and "Subsequent Entry Biologicals" (SEB's) in Canada. (see the Biogenerics2008 website). There is an expectation, because the parent drug has already undergone clinical testing and approval, that this would reduce the price of introducing an SEB. But biologicals are inherently heterogeneous in both their structure and their efficacy.
Health Canada Health Canada can be thought of as the "Canadian FDA", but it has a significantly broader commission in the responsibility for the health and safety the population, regulating foods and consumer goods as well as drugs. It is also a provider of medical services like medicare, as well as stewarding the relevant industries and funding research. The Biologics and Genetic Therapies Division (BGTD) is about 400 people, mostly in evaluation. 65 staff in the Centre for Biologics Research (CBR), which is distinct from the Centre for Biologics Evaluation, perform research in support of regulation. The CBR has a dual mandate: in stewardship, to anticipate threats to health and provide scientific advice; and in regulation, to develop new analytical methods, including some postmarket analysis. The CBR's role is not do evaluation itself, but to advise the evaluators. Regulatory Research Regulatory research bears some distinctions from traditional basic, applied or academic research. Regulatory research is at the crossroads between basic and applied research - deriving specific methods from broad knowledge, like applied research, but providing methods capable of radiating broad, generalizable knowledge useful to the regulators, applicants, or public. In contrast to academic research, which primarily seeks to invent new methods and sell them to the community, regulatory research is just as likely to adapt an old method as to invent a new. Experiments are designed to show precisely what it can and cannot do, and to provide this information objectively, without exaggeration. Analytical Techniques for Evaluation of Subsequent Entry Biologics The goal of analysis is to assure the SEB will function comparably
as a drug, using predictive, physico-chemical, and clinical methods, but
remembering that biologicals are inherently heterogeneous. Beyond
confirming the primary sequence of the intended product, it is
necessary to confirm correct folding, and characterize heterogeneity
in posttranslational modifications (glycosylation, phosphorylation)
and degradation (deamidation, oxidation). Particularly important
is the degree of aggregation. Ideally (although not
feasible) one would like to know the stability and potency of all
related products. Analysis is both tempered and complicated by
the facts that (i) one is establishing comparability, not equivalence,
and (ii) one is comparing the formulated drug product, not the
isolated drug substance. Regulatory analysis typically includes
The physical and chemical methods include:
Although some impurities have adverse effects, many degradants are likely to occur in the body, even of the endogenous product the drug is based on. Even when impurities are benign, however, variation in the impurities present is an important indicator of whether the manufacturer has an adequate degree of process control. If you know what you are looking for, a good chemist can devise a targeted method to detect it. An outstanding question is whether and how high-content analysis could be used to screen materials when you don't know what you're looking for, like oversulfated chondroitin in heparin, or melamine in milk. Twenty years ago, when the original products were licensed, the regulatory agencies gave little information on how they came to their decision. If they had, the re-licensors might well argue, for example, that if SDS-PAGE was good enough for the original product, it should be sufficient now. The feeling of the regulators today, however, is that the "latest technology" should be required. Biophysical Methods for Higher Order Structure NMR fingerprinting. The "fingerprint" region of a proton-nitrogen 2D NMR spectrum (HSQC) provides an information-rich assessment of the protein conformation at each amino acid. These spectra can be acquired in a few hours or overnight. Superimposing plots of an analyte and a reference material provides compelling evidence for or against similarity.
Outstanding Research Issues Quantification: how much of an impurity is present? Quantitative methods are often labor-intensive. Posttranslational modifications: Need to determine the degree of heterogeneity, more than specifically what the modifications are. Can partial misfolding be detected? CD and FTIR are bulk methods. Can they detect 3% misfolding? 0.3%? Can NMR? This is being tested by generating mutant proteins with subtle or dramatic conformational differences, which can be mixed with the parent protein at various levels to determine the LOD of the different methods, for different degrees of misfolding. Can One "de-formulate"? How similar is "similar enough" ? Quality by Design
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