Yes, in the dossier an absorption spectrum of the investigational medicinal product in the wavelength range between 290 and 700 nm should be provided. In the case of light absorption >290 nm a statement about photosafety of the IMP in accordance with the “Note for guidance on photosafety testing” (CPMP/SWP/398/01) has to be given.

Please do not present the findings sorted by target organs. Tables are more suitable in reporting noteworthy findings, sorted by species, increasing duration of treatment and increasing dose. Those tables should also contain toxicokinetic data of the dose levels given as well as a statement on reversibility of findings (if investigated).

The discussion (including regards to severity, recovery, and progression of the findings) should include the clinical relevance, the safety margins to the planned dose or doses, the parameters to be monitored, as well as exclusion and stopping criteria.

Yes, it is necessary to present the calculated safety margins on the base of (free) exposure (AUC, Cmax) at the NOAEL in the animals to the expected exposure in the intended clinical trial. The safety margins should be calculated for the starting dose as well as for the maximum dose (single or multiple doses, whatever is planned). The selected doses should be justified.

Yes, according to ICH M3(M) the assessment of embryo-foetal development should be completed prior to phase I trials.

Yes, this is possible in exceptional cases. If in the clinical trial

• a life-threatening disease is treated and the patients involved are using highly effective contraception in accordance with Note 3 of the “Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals” (CPMP/ICH/285/95 modification) or,

• if the clinical trial is investigating gender-specific differences after a single dose application of the IMP and the patients involved are using highly effective contraception in accordance with Note 3 of the “Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals” (CPMP/ICH/285/95 modification), the CTA can be approved.

Yes, the calculation of safety margins should be based on the estimated (upscaled) systemic exposure. In addition please give a statement about the expected therapeutic dose range in humans.

In accordance with the ”Note for guidance on the pre-clinical evaluation of anticancer medicinal products“ (CPMP /SPW/997/96), drug application in repeated dose toxicity studies should be performed as similar as possible to the clinical study design. Particular attention should be paid to critical target organ toxicity and reversibility of toxic effects. Irrespective of daily or intermittend administration in the clinic, the duration of the repeat dose toxicity studies should be at least equal to the duration the clinical trial (not longer than 6 months), unless a benefit for the treated patient is seen.

Yes, in accordance with the "Guideline on the Need for Non-Clinical Testing in Juvenile Animals on Human Pharmaceuticals for paediatric indications" for all clinical trials with children studies of repeated-dose-toxicity, genotoxicity, reproductive and developmental toxicity and, if applicable, studies on juvenile animals are required. If those studies are considered to be not necessary, this has to be justified.

This is necessary if the dose for the use in humans is also declared in mg/m² body surface.

Yes, providing only a brief list of changed sections is usually not sufficient for the assessment. The changes should be marked in the text of the new version (coloured, bold or underlined) or should be listed explicitly in detail.

IMPD layout should be in agreement with the layout suggestions in the 3. Notification on the clinical trial of medicinal products for human use.

Yes, in a simplified submission the preclinical section in the IMPD can refer to the corresponding IB section. In this case the IMPD layout should be used (see 15.). On the other hand, please keep in mind that the preclinical section in the IB cannot refer to the IMPD.

If preclinical data are presented in the IB and the IMPD, both data sets should be equal or comparable. If in doubt, latest preclinical data should be presented in more detail or data in the IMPD.

Relevant differences of data in both documents and updates in one document should be announced in the cover letter.

Currently, a European guideline does not exist. Therefore, the FDA-guidance paper: ”Estimating the Maximum Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) should be used. The dose calculation should be listed explicitly in the preclinical part. More guidance and information for non-clinical safety testing prior to first-in-human studies can be found in the European document “Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products (EMEA/CHMP/SWP/294648/2007).

If possible, the estimated exposure should be taken into consideration.

The following guidelines are at minimum to consider (list is not complete):

• ICH M3(M): CPMP/ICH/286/95

• ICH S6: (Biotechnology) CPMP/ICH/302/95

• ICH S7A: (Safetypharmacology) CPMP/ICH/539/00

• ICH S7B (QT Interval Prolongation) CHMP/ICH/423/02

• „Note for guidance on the pre-clinical evaluation of anticancer medicinal products“: CPMP/SWP/997/96

• „Note for guidance on photosafety testing“: CPMP/SWP/398/01

• „CHMP Draft Guideline on the Limits of Genotoxic Impurities“: CPMP/SWP/5199/02

A clinical trial is possible under the precondition of a careful dose escalation and an appropriate ECG monitoring according to the PK profile of the drug. The ICH documents S7B and E14 should be considered for non-clinical risk assessment and for clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential, respectively.

Yes, tables are more suitable in reporting noteworthy findings, sorted by species, increasing duration of treatment, and increasing dose. These tables should also contain toxicokinetic data of the dose levels given as well as a statement on reversibility of findings (if investigated).

In addition to the table a discussion of the noteworthy findings (including regards on severity, recovery, and progression) should include the clinical relevance of the findings, the safety margins to the planned dose or doses, the parameters to be monitored, as well as inclusion/exclusion and stopping criteria.

Enclosed, you will find an example table of presenting results from preclinical studies of pharmacokinetics, safety pharmacology, and toxicology.