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Both biosimilar and generic drugs have an abbreviated approval process; however, the clinical trial requirements differ enormously.
Both biosimilar and generic drugs have an abbreviated approval process; however, the clinical trial requirements differ enormously.For generics, very limited clinical trials (often only Phase I pharmacokinetic studies) are required and the company usually only needs to submit tests demonstrating that the generic is bioequivalent to the original drug. Provided laboratory analysis confirms that the two drugs are identical, the generic’s safety and efficacy can be assumed based on the data for the original product. Consequently, a generic that is demonstrated to be bioequivalent is considered clinically interchangeable with the corresponding innovator product.
For biosimilars, it’s not quite so simple because biological-based products are much more sensitive to manufacturing changes than traditional small molecule drugs. As such, extensive clinical trials, including Phase I and Phase III studies, are required to facilitate approval of a biosimilar. Thorough consideration will need to be given to the trial design, target population and endpoint criteria for establishing equivalence, and the trial must also be sensitive enough to detect any clinically meaningful differences. In fact, the size of the trial may even need to be larger than that for the reference product in order to prove therapeutic equivalence with adequate confidence. One benefit of the rigorous development of a biosimilar, however, is that in some geographical regions it is possible to extrapolate the findings to other related indications that have not yet been trialled.
Under current EU guidelines, certain proteins, such as blood factors, are considered too complex or heterogenous to qualify for a biosimilar pathway. In part, these exclusions are based on the limitations of current analytical methodology to accurately determine, quantify and control the variation in post‑translational modifications seen in these types of biological products. Consequently, for complex biosimilars like monoclonal antibodies, some additional trial data may be required regarding the extent and impact of any physicochemical and biological differences, the existence of measurable sensitive endpoints, the clinical relevance of these endpoints to the claimed therapeutic indication and the magnitude of the therapeutic response compared with placebo.
It is impossible for the manufacturer of a comparator product to use the exact same processes as the innovator — manufacturing processes are proprietary and are not available in the public domain, either in public assessment reports or product monographs. Consequently, the comparator product manufacturer will be unable to reproduce a product exactly. Factors such as the expression system, media components, equipment and raw materials suppliers may all be different and, in the case of sensitive biologics, could impact the final product. This is recognised by regulators and as such, there is no requirement or expectation for the manufacturing processes to be identical. Furthermore, an original expression system will remain the property of the innovator unless a cross-licensing deal is struck.
There are wide ranges quoted in the literature for the estimated costs of developing small molecule generics, biosimilars and biological products, but the Pharmaceutical Research and Manufacturers of America (PhRMA) estimate it costs in the region of $1.2 billion to develop a new biologic compared with approximately $375 million and $1.5–4 million for a biosimilar and small molecule generic, respectively.1 In terms of development timelines, a biosimilar is generally shorter than a novel biologic as there is no need for a Phase II programme and Phase I and Phase III can often be truncated.
In some instances, the cost of developing and marketing a biosimilar has deterred companies from entering the biosimilars market. However, once approved the manufacturer can apply modern production cost saving technology which can cut the cost of manufacturing by 70%. Costs will probably be further reduced in the future.
In most cases, companies will ultimately target the EU market for product launch because of the more established pathway for biosimilar development. Launching a biosimilar product in the US can be more difficult because the legal framework for biosimilar medicines has only just been developed.
Biosimilars are expected to be sold at a lower price than the reference product, but the actual price differential will be dictated by the development costs, which can be high. However, even a small reduction could offer enormous benefits to healthcare payers. According to the European Generic Medicines Association, a price reduction of only 20% on six off‑patent or soon‑to‑be off‑patent biopharmaceuticals could save the EU more than €1.6 billion.1
C.J. Kelly and F.A. Mir, BMJ 2009;339:b3276.European Generic Medicines Association, Biosimilar Medicines (2007). www.egagenerics.com