Protecting people in clinical trials The preclinical phase: The first step towards safer medicines

On average, the development process for a new medicine takes ten years. The preclinical phase is a crucial step in this process, since its aim is to guarantee that substances have an acceptable safety profile and the desired mode of action before they are tested in humans.

Preclinical studies give researchers an opportunity to investigate a new active substance's properties in detail. They use various methods – animal studies (“in vivo”), cell cultures (“in vitro”) or computer simulations (“in silico”) – to simulate use in humans so they can assess the substance’s effects and potential side effects and obtain a first indication of dosage.

“The preclinical phase is an essential step on the road to safe and effective medicines”, says Elisabeth Klenke. “However, the term is often misunderstood. It does not only cover the time leading up to the first clinical trial. Preclinical data are collected throughout the development process and, if need be, after authorisation too.” Swissmedic has adopted international terminology by calling the Division responsible for the preclinical phase “Nonclinical Assessment” (NCA). The nine-member team combines expertise in veterinary medicine, pharmacy, biology, biochemistry and immunology with professional backgrounds in the pharmaceutical and food industries, academia and research. Additional qualifications, such as ERT (European Registered Toxicologist) recognition, are regularly renewed.

NCA’s core tasks are:

• Assessing the preclinical documentation for authorisation applications
• Assessing data for approval of the first clinical phase
• Assessing or preparing expert toxicological reports when impurities are found in authorised medicinal products
• Inspecting compliance with Good Laboratory Practice (GLP) in conjunction with other federal offices

“The preclinical phase is an essential step on the road to safe, effective medicines.”

The preclinical programme

Before a new medicine is tested in clinical trials in humans, the applicant – in other words, the research-based pharmaceutical company – must submit preclinical data from investigations of the safety and mode of action of the medicinal product to Swissmedic.

The scope of the data depends on the indication for the medicine, the patient group, duration of treatment and physical and chemical properties of the substance. “The requirements vary”, Elisabeth Klenke explains. For example, the conditions for a diabetes medication are different from those for a cancer medicine intended for advanced-stage patients. In the latter case, a higher level of risk can be accepted in the interests of giving seriously ill people faster access to new treatments.

Many potential active substances fall by the wayside in the early stages of medicine development because their safety cannot be adequately demonstrated in their intended application. Only the most promising make it as far as the first clinical investigations in humans (phase 1). At the same time, preclinical trials continue with the aim of assessing possible side effects that cannot be investigated in the clinical environment, such as the dangers to unborn children or the risk of the treatment causing cancer.

Once the clinical trials have been completed, the company submits an authorisation application that includes an extensive data package containing information on the indication, duration of treatment and patient group. Swissmedic has recently adopted the SEND (Standard for Exchange of Nonclinical Data) format, since this increases efficiency and consistency in data evaluation and makes it easier to compare trials.

Preclinical data can still be relevant after a medicine has been authorised, for example in new patient groups such as children.

Promoting a responsible approach to animal testing

Animal testing is still necessary to obtain crucial safety data for the risk assessment in humans. However, there is a worldwide drive to reduce animal testing in the preclinical phase and to make it as ethically acceptable as possible. This is an area where the “3Rs” provide guidance.

Swissmedic is actively involved in national and international projects to promote the development of alternatives to animal testing – what are known as new approach methodologies, such as organoids and organs-on-chips. The weight of evidence approach, which aims to use existing preclinical data more effectively, has already been implemented.

A further contribution to reducing the number of animal experiments is made by the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The Council’s aim is to standardise testing requirements in all member countries. Moreover, safety studies have to be conducted to GLP quality standards. This means that preclinical tests can be recognised worldwide, thus minimising animal use in research. “In other words, one animal experiment applies for the entire world”, says Elisabeth Klenke, putting it in a nutshell.

International cooperation improves global medicinal product safety

“We attach great importance to international cooperation”, Elisabeth Klenke emphasises. “We have an extensive network and have good links to the preclinical assessors at our partner authorities, for example in Canada, Australia, Great Britain or Singapore.” Not only that, there is an opportunity for in-depth dialogue with the European Medicines Agency (EMA) at preclinical assessor meetings.

“The areas covered by the NCA Division are truly diverse, ranging from international projects to assessing new active substances in detail”, says Elisabeth Klenke. “They can also affect you personally, for example when you’re looking at cancer treatments for children. A team that gets on well with each other is hugely important then.” The same applies when several different tasks have to be dealt with at the same time and under time pressure. The time involved can range from several weeks for the first-time authorisation of an active substance to days for the approval of clinical trials and just a few hours for corrections to Information for healthcare professionals. “However, because we have such a cohesive team, we are able to complete our work professionally and on deadline – and even enjoy it too!”