2. From laboratory and animal studies to patients

A medicine candidate cannot be given to humans until enough information has been obtained on the safety and on the effects that the medicine is expected to have. Non-clinical studies bring important information that can predict the medicine’s profile, such as ‘proof of concept’, a proposed dosage regimen, and adequate safety monitoring. Also, they help define the criteria for inclusion or exclusion of patients/participants in clinical studies.

Non-clinical cell (in vitro) and animal studies (in vivo) should therefore:
  • Demonstrate the efficacy of the medicine candidate.
  • Provide knowledge on the safety of the medicine, for instance studies that examine the maximum tolerated dose.
  • Estimate the effects of the medicine that cannot be studied in humans – for instance, its effect on foetuses or in pregnant women.

Reseachers need to use their professional judgement to apply or deduce information from laboratory and animal studies to human studies. Useful rules for this so-called extrapolation have been developed and described in the guidelines of the Committee for Human Medicinal Products (CHMP) of the EMA and the ICH. These guidelines specify the types of studies that must take place before clinical trials can start. Issues with the non-clinical programme of a development candidate can cause objections when the regulatory authorities review the marketing authorisation application (MAA). Regulators may ask questions on how relevant the non-clinical models are for the proposed indication of the development candidate in humans. If researchers wish to avoid these issues, non-clinical studies must be carefully planned and laboratory and animal studies must be setup so that they can predict how the medicine will work in humans.

Researchers should plan the non-clinical programme based on the following factors:
  1. The type of medicinal product.
  2. The type and severity of the disease.
  3. The population or group of patients that the medicine is intended for.
  4. The phase of the clinical trial (Phase I, II or III).
  5. The expected dose and duration of the treatment in humans.

Many companies seek scientific advice from regulatory authorities (for instance the EMA or national competent authorities (NCAs)). Scientific advice helps the company to make sure that the right tests and studies are done. It will also help avoid any major objections on the design of the tests later when the regulatory authorities evaluate the MAA. If companies seek and follow advice from regulatory agencies, it is more likely that they will obtain a positive outcome for an MAA. The advice is given in the light of the current scientific knowledge, and is based on the documentation provided by the company.

Non-clinical data are most important in the early development of a development candidate (see Figure 1 below). Much of the non-clinical data on safety and efficacy will be replaced later with data from clinical trials in humans and when the medicine is ready to be prescribed to patients. However, in some cases the clinical use of a new medicine will be based on non-clinical data for a longer period of time. This is due to ethical concerns about testing in humans. For example when testing the effect of a medicinal product on cancer development or in reproduction. Eventually these non-clinical data will also need to be replaced e.g. as part of post-marketing life cycle management and pharmacovigilance.

Ideally, the company should make sure that all non-clinical safety concerns are raised in the development period and before the MAA. However, there may still be safety concerns when the MAA is submitted and assessed. Such concerns can include carcinogenicity, genotoxicity, genotoxic impurities, reproductive toxicity, and hepatoxicity.

When the regulatory authorities evaluate the non-clinical programme, they may also ask the company to justify animal models. And they may question if toxicokinetics studies are sufficient to assess safety in humans.