Several issues must be considered when planning the preclinical development program of a novel investigational compound such as the nature of the target, the mode of action, the choice of suitable animal models, the identification of pharmacologically effective doses levels, the design of preclinical proof-of-concept studies, and the adequate design of toxicology studies in at least two animal species that are predictive for the situation in humans, et cetera. But there are even more important aspects that are related to regulatory affairs issues. The early elaboration of a good integrated project plan offers the opportunity to identify the critical path, and an efficient project management can streamline the developmental period. This paper focusses on three major items that should be considered to manage a smooth transition from pre-clinical to clinical research with intent to commence the clinical development program in good time and have it adequately designed to make sure the planning targets Several issues must be considered when planning the preclinical development program of a novel investigational compound such as the nature of the target, the mode of action, the choice of suitable animal models, the identification of pharmacologically effective doses levels, the design of preclinical proof-of-concept studies, and the adequate design of toxicology studies in at least two animal species that are predictive for the situation in humans, et cetera. But there are even more important aspects that are related to regulatory affairs issues. The early elaboration of a good integrated project plan offers the opportunity to identify the critical path, and an efficient project management can streamline the developmental period. This paper focusses on three major items that should be considered to manage a smooth transition from pre-clinical to clinical research with intent to commence the clinical development program in good time and have it adequately designed to make sure the planning targets will be met.

Extent of the non-clinical program and timely completion of essential documents

Make sure the extent of the non-clinical program is appropriate to support the conduct of clinical studies in humans. In this context, make sure the quality and type of documentation and presentation of results follows the requirements of the Investigational and Medicinal Product Dossier (IMPD).

"Due consideration should be given to a good central project coordination reaching across target groups"

The IMPD is an essential document that will need to be submitted to the regulatory authority BfArM at the time when the application for the first study in humans is filed. If non-clinical reports originate from different institutions, it may be useful to centrally keep track on the contents, quality, technical preparation and compilation of the documents. To put it another way, due consideration should be given to a good central project coordination reaching across target groups during the transitional period from non-clinical to clinical research.

Among other things, regulatory affairs aspects and scientific/medical writing skills with regard to the production of the essential documents are important. If the investigational compound has a novel mechanism of action, it is recommended to run through a scientific advice process at the regulatory authority some time prior to commencement of the clinical development program. Experience has shown that this may streamline the later approval procedure of the First-in-Human (FIH) trial.

General considerations regarding the clinical development program

Identify your target product profile at an early point in time and make sure the clinical development program is appropriately designed to meet the development goals. However, do not stick to static project paradigms during the course of the program, but re-evaluate your developmental premises at regular intervals on the basis of the current research results.

For biotechnology firms and venture capital-driven companies there is usually some focus on the next milestone to be reached, and the early clinical development program should be adequately tailored to achieve that goal. "Go/No-Go criteria" should be defined. The identification of the critical path in project management is always crucial to minimize the development time and related cost.

As always, scientific aspects related to the mechanism of action, disease-specific issues, aspects related to market size and pricing as well as pragmatic considerations (e.g., feasibility to conduct clinical trials in the target patient population) should be taken into account when planning the clinical development program. Even though those aspects may have limited impact on the design elements of the FIH trial, it is important to set up the clinical development plan as a whole at an early stage because there may be important issues that could interfere with some design aspects of the FIH trial (e.g., investigation of surrogate parameters as secondary objectives).

"Make use of external expertise"

As a matter of course, the project team must be adequately staffed during all project phases with a focus on those items that are of particular importance at a certain stage. Make use of external expertise, e.g., with regard to scientific advice, interpretation of research results, regulatory affairs issues, clinical project planning or writing of study protocols or research reports. Get in contact with an experienced contract research organization (CRO) at an early time. The ideal CRO will not only organize a clinical study, it will provide valuable scientific input in the well-understood interest of the sponsor and will provide solutions during all stages of clinical development. The selection of the right CRO is therefore of paramount importance.

Special considerations when planning the First-in-Human (FIH) trial

On general, FIH trials are conducted in healthy subjects, but in certain indications, e.g., oncology trials, the phase-I program is commonly conducted in patients; some special considerations apply to those cases. The following general recommendations apply to the standard approach, but, depending on the nature of the compound, its mechanism of action, and the galenical formation, variations of the following design features are possible:

A FIH study typically follows a single ascending dose-group design (escalating single doses) with sequential subgroups of healthy subjects. There are commonly 6-9 dose steps. A placebo control is regarded as state of the art. A common ratio of active compound to placebo is 3:1.

The primary objective of the ascending single-dose study is the identification of the highest dose that is safe and well-tolerated after single dosing (or confirmation of safety and tolerability of all doses investigated, if even the highest tested dose is well-tolerated). The assessment of the systemic exposure (pharmacokinetics) of the investigational compound and relevant metabolites is also important. This should be done as a so-called online-pharmacokinetic evaluation during the course of the study to make sure there is an adequate exposure control prior to proceeding to the next dose step.

"Make sure there is an adequate exposure control prior to proceeding to the next dose step"

Data on pharmacodynamics or biomarkers are collected, if possible. The maximum recommended safe starting dose must be calculated based on the animal toxicology study results obtained in two appropriate species taking into account possible additional factors of risk. In this context, an important issue is determining the "Human Equivalent Dose" (HED) to the "No Observed Adverse Effect Level" (NOAEL) obtained in animal toxicology studies via normalization to body surface area. A summarizing table with a simplified process chart is given below. Scaling factors are given in pertinent guidance documents. For every early development program, a concept of risk mitigation should be developed.

"It is therefore useful, or even mandatory, to consult an expert for early clinical development"

As mentioned above, only a very general outline on the study design features can be given here as the individual design elements and demands on the clinical study protocol will depend on the special peculiarities of the investigational medicinal product.

It is therefore useful, or even mandatory, to consult an expert for early clinical development to manage a smooth transition from pre-clinical to clinical research to adequately design the FIH trial to have a solid base for upcoming clinical trials in patients and achieve the developmental objectives in a timely and efficient manner.