In an effort to address lingering confusion, the World Health Organization (WHO) has released a draft Q&A document addressing a number of issues surrounding the development of biosimilars. At the top of its list are the requirements for and duration of clinical trials.
“Very little is known about the safety and efficacy of these individual products,” the WHO says in the new Q&A document. “Consequently, these products need to be reassessed by national regulatory authorities (NRAs),” including the U.S. Food and Drug Administration (FDA).
The WHO addresses several specific clinical trial-related questions, including:
How can similar biotherapeutic products (SBPs) be approved for indications for which no clinical studies have been conducted?
“The aim of the biosimilar comparability studies is to demonstrate a high similarity between the SBP and reference biotherapeutic product (RBP). If this is achieved, it can be expected that the function of the products is also similar. Additional studies are needed if the therapeutic indication that was investigated in the clinical comparability study is not representative of other requested therapeutic indications in terms of safety and efficacy.”
Is there always a need to conduct a clinical study for an SBP?
As noted in WHO’s Guidelines on evaluation of similar biotherapeutic products (SBPs), the demonstration of comparability of an SBP to its RBP in terms of quality is a prerequisite for the reduction of the nonclinical and clinical data set required for licensure. Thus, the WHO guidelines mention the reduction, but not the complete omission, of clinical data. The complexity of biotherapeutic products varies enormously. Some pre-licensing clinical data are always required for an SBP, but the clinical development can be abbreviated, as outlined by the WHO guidelines for SBPs.
How should inexperienced NRAs deal with differing regulatory decisions of major experienced NRAs?
In general, the major experienced regulatory bodies have reached similar conclusions and decisions on SBPs. However, national legislations may introduce some differences in the regulatory approach. For instance, legislation in the U.S. provides additional approval criteria for interchangeable SBPs, whereas European legislation prohibits the European Medicines Agency (EMA) from taking a position on interchangeability. The same is true in Canada, where interchangeability decisions are in the hands of the provincial health authorities. Consequently, it is important to understand the background to regulatory decisions.
Differences in judgement/interpretation of scientific data exist across regulatory agencies. In such cases, in order to understand the reasons for the different interpretations, it is helpful to read publicly available assessment reports of regulatory agencies that have reached different conclusions. In addition, it may be useful to review post-marketing data on safety and efficacy from the NRA that made the positive decision.
The WHO plans to update the Q&A document regularly to reflect new developments, but it will not address issues such as interchangeability, switching, substitution, naming, or shortages. The public comment deadline is September 20. The WHO’s Expert Committee on Biological Standardization is set to review the draft at a late October meeting.
Author: Michael Causey