Thirty years of preclinical safety evaluation of biopharmaceuticals

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1. Introduction 30 years ago the first biopharmaceuticals produced by recombinant DNA technology and other biotechnological methods were introduced. At that time it was already known that the classical preclinical safety evaluation procedure applied to small molecule therapeutics (SMTs) would not predict adverse effects of biopharmaceuticals. The checkbox approaches used in the classical procedure were considered not appropriate. It was suggested, “when developing a biotechnology product, attention should be focused on the unique characteristics of the products itself, rather than on existing testing guidelines”. It was clear that new safety evaluation procedures needed to be developed. However, more knowledge and experience was necessary to design a scientific and rational preclinical safety evaluation procedure for biopharmaceuticals. To gain that experience, the safety evaluation of biopharmaceuticals should be done on a case-by-case basis. Since then the knowledge base has expanded, experience has been gained, and several preclinical safety guidelines for biopharmaceuticals have been implemented, replaced, and updated. But did these advancements in science enable regulators to design a preclinical safety evaluation procedure suited to biopharmaceuticals? 2. The evolution of the preclinical safety guideline Analysis of the evolution of the preclinical safety evaluation procedures of the last 30 years shows how the current guideline, ICH S6(R1), came about. When the first biopharmaceuticals received market approval many experts concluded that biopharmaceuticals have different safety concerns than SMTs and so the classical preclinical safety evaluation procedure would not provide useful results concerning the safety of biopharmaceuticals. Due to the novelty and different safety concerns, scientific progress was necessary to enable the design of a scientific and rational preclinical safety evaluation procedure for biopharmaceuticals. To gain experience, the preclinical safety evaluation would be conducted on a case-by-case basis focused on the unique characteristics of these biotechnology-derived products. However, case-by-case approaches are difficult to apply in practice, because case-by-case approaches require a high level of expertise from pharmaceutical companies and regulators. The absence of standardized rules also contradicted the “safety-first principle” which is a basic principle of drug regulation. Driven by risk-averse behavior, national regulatory authorities requested, and industry used, the classical preclinical safety evaluation procedure to assess the safety of biopharmaceuticals. However, deviating from this standard procedure was possible if the company developing the biopharmaceutical could justify that a different approach was required. In 1997, the national procedures were replaced by a harmonized guideline, S6. The S6 was designed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) with the aim to harmonize the practice of the preclinical safety evaluation of biopharmaceuticals. But while there are differences, as for example that the use of one species can be sufficient and that genotoxicity is not required as a standard, in general this guideline resembled the classical safety evaluation program as this had become the common practice of the regulators and industry. Although S6 provides opportunities for case-by-case flexibility, the checkbox approach remains dominant in S6. This is understandable because harmonization of guidelines is perpendicular to the flexibility needed for a caseby-case approach. The aim of harmonizing guidelines is to create a basic framework, recognized by all parties, that streamlines the regulatory assessment process and reduces the development times and resources for drug development. Flexibility may lead to differing interpretations and inconsistent opinions between regulatory agencies and it therefore does not reduce the development time and does not contribute to a streamlined regulatory assessment process, which is the opposite of what ICH tries to achieve. 3. Status quo Revision of the S6 was considered to be necessary by the ICH because “ clarification (and sometimes amplification) of this guidance (S6) is needed as substantial experience and new information has been gained since Step 4 (the adoption of the guideline) (1997)” . According to the ICH preclinical safety experts clarification was required with regard to species selection, study design, reproductive and developmental toxicity, carcinogenicity and immunogenicity. In June 2011 the revised guideline S6(R1) concerning the preclinical safety evaluation of biotechnology-derived pharmaceuticals (biopharmaceuticals), was approved by the ICH steering committee. Did the ICH design this revised guideline making use of the state-of-the-art knowledge. 4. State of the art knowledge on biopharmaceuticals Experience with biopharmaceuticals has shown safety concerns of biopharmaceuticals to be different from SMTs. The adverse effects of biopharmaceuticals are either caused by exaggerated pharmacology, unintentional tissue cross-reactivity, or by immune system-mediated adverse effects. These insights validate the proposed approach to design the preclinical safety evaluation procedure on a case-by-case basis, driven by product specific questions, such as the cause, mechanisms, and reversibility of adverse effects. Despite the fact that from the start of modern biotechnology in drug development experts have recommended a case-by-case approach, this approach was not used as basis for the preclinical safety evaluation guidelines. Instead a standardized checkbox approach with some case-by-case decisions has been dominant in the preclinical safety evaluation guidelines. The recent update of the ICH S6 guideline was an opportunity to catch up with scientific progress and introduce preclinical safety testing driven by the specific properties of biopharmaceuticals. Instead this update only clarified and complemented the S6, thus still closely resembles the classical preclinical safety evaluation procedure and checkbox approach. S6(R1) is only an update of S6, whereas a total reform of S6 would have been more appropriate. Unfortunately, regulators missed the opportunity to catch up with scientific progress into the toxicity of biopharmaceuticals and design a new preclinical safety evaluation procedure suited to biopharmaceuticals.