Info Service on Health Issues (Oct19/04)
We the undersigned thank the Expert Committee on Biological Standardization (ECBS) for their willingness to start a discussion that will hopefully lead to the review and update of 2009 Guidelines on the Evaluation of Similar Biotherapeutic Products (SBPs), in line with WHA67.21 Resolution.
We acknowledge the work of the ECBS after the adoption of WHA 67.21 Resolution regarding the issuance of the supplementary guidelines and documents on SBPs namely:
These documents still reinforce the SBP Guideline approach requiring phase III clinical trials for the approval of SBPs. A huge amount of evidence has been produced since 2009 highlighting the scientific improvements on the characterization of proteins. The technology has matured, the consensus around best practices has increased and the methods used for the production of different biopharmaceuticals have become highly comparable. Besides, the hardware and ingredients used in the production are similar and sourced from the same limited number of suppliers. Hence, any remaining uncertainties about safety and efficacy are marginal and can be evaluated throughout PK/PD studies, which will provide sufficient clinical evidence. PK/PD studies should be the only clinical assays required for the marketing authorization of SBPs. This should be clearly stated in all WHO SBP Guidelines.
The 2009 SBP Guidelines are based on some of the below mentioned assumptions have become scientifically obsolete:
1. Relatively large and complex proteins, such as biotherapeutics, are difficult to characterize.
2. Because of the former assumption, clinical studies are always required to support safety and efficacy, as the clinical performance of biotherapeutic is highly influenced by the manufacturing process.
3. SBPs are manufactured and controlled according to their development, and the manufacturer of an SBP normally does not have access to all the necessary manufacturing information on the originator product.
4. Even minor differences in the manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or safety of biotherapeutic products.
In this regard, we would like to make the following requests before the ECBS:
We respectfully request the ECBS to start discussing and focus on the entire Part 10 of the 2009 SBPs Guideline, which deals with clinical evaluation of SBPs. We suggest that it be replaced with a language clearly explaining the circumstances that demand in-vitro surrogate efficacy analyses, further comparability analyses for demonstration of non-inferiority and the details of Phase I trial to address safety concerns with an inbuilt PK /PD study.
The most frequent side effects of biotherapeutics are local reactions at the injection site. These side effects are in most cases caused by the formulation and not by the active molecules. Biotherapeutics have lower toxicity because they act by binding ligands either on the surface of cells or ligands that are free-floating in extracellular fluids, including the blood and lymph. Unlike small molecules, biotherapeutic proteins are degraded into amino acids (and sometimes sugars) that are normal constituents of body metabolism. The side effects of biotherapeutics are often the result of the pharmacodynamic effect. Hence, if the SBP has the same potency as the RBP, their side effect profiles will be the same.
The most important development, which justifies the revision of the 2009 SBP Guideline, is the improvement in analytical methods. The methods to analyze proteins have improved dramatically in the last decade reducing the possibility that a difference in the clinical consequences between SBP and RBP is missed. These methods allow full characterization of proteins, in detail, regardless of their size and complexity. For instance, we have seen a ten-fold increase in the sensitivity to identify different glycoforms of glycoproteins such as those shown for epoetins and monoclonal antibodies. This makes it possible to asses the quality and efficacy based on the similarity of the structure without any clinical studies. (1)
However, the 2009 SBP Guideline insists on clinical studies to prove the efficacy of the biosimilar product. The development of SBP is considered a step-wise process. The basis of its development involves an extensive analysis of the different batches of the RBP. Based on the physical, chemical and biological characteristics of the RBP, a manufacturer designs its own process aiming to have a product that is similar to the RBP. Current WHO guidelines demand the confirmation of this similarity via preclinical and clinical studies. However, the logic should be the opposite; preclinical and clinical phases should not be used to confirm findings made during the analytical phase, but to discard any major residual uncertainties remaining from comparative characterization about safety and efficacy. The approach by the regulatory authorities should be that the comprehensive characterization and comparison at the quality level are the basis for waivers or data reduction of the non-clinical and clinical development. In other words, the more similar the product in physical-chemical and in-vitro biological characterizations, the less is the need for a clinical trial. In most cases, those trials are not needed and comparative analytical characterization is enough.
In the light of the above-mentioned advancement in the science around analytical techniques as well as the knowledge gained through the biosimilar development, we propose the following changes in the efficacy data requirements in 2009 SBP Guidelines:
1. Biomolecular structure analyses have now, both technically and empirically, established rigorously that the structural comparability information is sufficient for regulatory purposes. Therefore, all efficacy examination requirements should be removed from regulatory guidelines. Detailed structural characterization requirements should be a part of the guidelines. The demonstration of similarity in quality is sufficient to assure the safety and efficacy of most products. The emphasis on quality testing should focus on impurity profiles and potency.
2. While biomolecules are indeed structurally distinct from small molecules sufficient to cause regulatory uncertainties about structure, their pathways of efficacy are known with certainty at the molecular-cellular levels. Therefore, in-vitro tests examining the triggering of molecular-cellular pathways involved in efficacy are more than sufficient as efficacy analyses for regulatory purposes. Efficacy for biomolecules should be evaluated in-vitro, not in-vivo, for biosimilar macromolecules. All efficacy-directed examinations in-vivo should be removed from the guidelines and be replaced by in-vitro test requirements.
3. Given the demonstration of structural similarity and in-vitro surrogate efficacy analyses, further comparability analyses for demonstration for non-inferiority should not ordinarily be required. However, if and where necessary, evaluation of comparative potency in cellular-molecular analyses in vitro would be deemed sufficient for regulatory guidelines.
4. Immunogenicity studies are only needed if SBP does not match the critical quality attributes related to manufacturing.
5. Interchangeability and extrapolation to all indications should be the default unless there are scientific reasons to deny extrapolation.
We propose the the revision/revamping Section 10 of the 2009 SBP Guideline, which deals with the clinical evaluation of SBP. Since the SBP Guideline states: “Usually, clinical trials are required to demonstrate similar efficacy between the SBP and the RBP. In certain cases, however, comparative PK/PD studies may be appropriate, provided that 1) the PK and PD properties of the RBP are well characterized, 2) at least one PD marker is a marker linked to efficacy (e.g. an accepted surrogate marker for efficacy), and 3) the relationship between dose/exposure, the relevant PD marker(s) and response/efficacy of the RBP is established.”. This usual requirement of clinical studies requires time and resources and effectively compromises access to affordable biotherapeutics. Therefore our proposal in the submission focuses on the revamping of clinical study requirements for efficacy studies through comparative clinical trials.
Once revision /revamping of Section 10 of the 2009 SBP Guidelines is amended, a revision of the whole text will be needed, because the dated underlying reasoning concerning the need for confirmatory clinical trials exists throughout the guidelines.
the teleconference held on October 11th 2019 between the WHO staff,
some members of the ECBS and the Chair asked us to:
In the following weeks, we will provide a document that details the problematic provisions of the 2009 SBP Guidelines and the reasons for the proposed changes from a scientific and access perspective.
We respectfully request the ECBS to examine the document in light of the scientific memo and the scientific evidence we already submitted, and that the committee takes a serious consideration to review the 2009 SBP Guidelines.
In the spirit of informed discussion, we request:
1. To organize an expert consultation of experts free of conflict of interest to be coordinated or in coordination with the Committee on Essential Medicines and Science Division. The purpose of this expert consultation is to have an in depth discussion on the major issues related to 2009 SBP Guidelines especially the requirement of comparative clinical trial, interchangeability and extrapolation etc.
2. To make public the ECBS responses to our above-mentioned proposals as well as those in the memo with supporting verifiable evidence.
Prof. dr. H. Schellekens MD,
Claudia Patricia Vaca González
5. Chetali Rao, Independent Researcher, New Delhi, India
6. K M Gopakumar, Legal Advisor, Third World Network
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