WHO Biosimilar Guidance Is Based on Weak Science

The European Medicines Agency (EMA) became the first regulatory agency to issue biosimilar guidance in 2005; the FDA and the World Health Organization (WHO) followed in 2009. Most of the developed country guidelines draw from the FDA and EMA guidance, while the rest of the world relies on the WHO guidance to assure the safety and efficacy of biosimilars. A comparison of the global guidelines shows that the WHO guidance that has impacted the largest patient population is replete with scientific misconceptions, leading to lack of trust in the safety and efficacy of biosimilars developed under this guidance.

This brief review points out a few questionable elements of the WHO guidance and the dire need for it to be aligned with acceptable scientific grounds.

First, the WHO suggests that before a biosimilar product can be approved, reference products should have been marketed for a “suitable duration” of time in “a jurisdiction with a well-established regulatory framework and principals.” This creates doubts about the safety of an approved product. The guidance does not indicate how long this waiting period should be. However, there should be no doubt about the safety and efficacy of a product if a credible regulatory agency approves it. The WHO also fails to identify the jurisdiction of the approving agency. The standard should be the first approved biological product based on a complete dossier.

Second, the WHO recommends that regulators use their prior knowledge, based on the evaluation of the manufacturing process of similar products, to judge the safety and efficacy of new biosimilar products. Besides the ethical considerations, such comparisons are scientifically flawed, because it is not possible to draw a parallel between products manufactured using different processes.

Third, the weakest area of the WHO guidance is in the most critical part of the evaluation of biosimilars: their analytical similarity. The WHO allows the use of production lots from different manufacturing sites to establish analytical and biological similarity with the reference product, an allowance that violates the basic principles of similarity testing, even if each of the manufacturing sources is good-manufacturing-process compliant. No other regulatory agency allows this practice.

On a more specific scientific consideration, the WHO states that “It may not be possible to set a definite number of lots to be analyzed in the comprehensive comparability exercise.” Nothing is farther from the truth. The number of lots tested is well-defined in the standard equivalence testing models, where at least 6 to 10 lots must be analyzed to establish an acceptable statistical basis. The WHO considers that statistical models are not yet ready to apply to analytical similarity assessment, contrary to the well-established utility of statistical modeling by all developed agencies.

In another significant scientific mistake, the WHO considers comparative stress testing of the biosimilar and the reference product unnecessary. However, this is one of the most sensitive methods to test structural similarity, and all developed country agencies require it. The WHO states that these studies only help establish appropriate conditions for shipping and storage. The fact is that the biosimilar must have the same storage condition as the reference product, and there is no need to justify a new storage condition. The shipping stress testing is conducted under a different protocol based on the prevalent practices of shipping.

Fourth, one of the most divisive suggestions by the WHO is that toxicology studies in monkeys should be avoided. This has led to the approval of a large number of biosimilars across the globe based on valueless testing in rats, which do not have receptors to show toxicity to monoclonal antibodies. The WHO suggestion to study pharmacodynamics and immunogenicity in animal species does not take into account that certain animals do not replicate human responses.

The WHO’s animal testing protocols based on multiples of human dose are also flawed because this dosing is not in the linear toxicity range to detect any difference between a biosimilar and a reference product.

Finally, the WHO suggests using a noninferiority testing model for clinical efficacy, allowing acceptance of higher efficacy, without realizing that higher efficacy may also lead to higher adverse events. The correct protocol for efficacy testing is the equivalence model. Further, the WHO does not recommend evaluation of the most frequent adverse effect of local reactions at the injection site that are caused by the agent’s formulation and not by the active molecules. Because biosimilars are allowed to have a different formulation composition, evaluation of local reactions is pivotal in assuring the safety of the products.

The WHO guidance is widely adopted in many countries that have added their own arbitrary and unjustified changes. For example, in China, India, and Russia, local clinical trials are required, but not a suitable a statistical protocol. Iran, Peru, Nigeria, and Venezuela have removed all clinical testing requirements. And none of the Indian biosimilar antibodies were tested for safety in monkeys, the only suitable model, because of religious constraints.

I strongly urge the WHO to revise its guidelines, bringing it into compliance with the current scientific and logical thinking to assure the safety and efficacy of biosimilars used by the majority of the world population. Not doing so will continue to risk the lives of patients.