4. DRUG DEVELOPMENT PLANNING: ICH E8(R1) Guideline

This section provides general principles to consider in drug development planning. Drug development planning adheres to the principles of scientific research and good study design that ensure the reliability and interpretability of results. Efficient drug development includes appropriately planned interactions with regulatory authorities throughout development to ensure alignment with requirements for product quality and to support approval in the condition or disease, including possible post-approval studies to address remaining questions. Throughout this process there is critical attention to the protection of the rights, safety and wellbeing of study participants.

Drug development planning builds on knowledge acquired throughout the investigational process to reduce levels of uncertainty as the process moves from target identification through non-clinical and clinical evaluation. Such planning encompasses quality of medicinal product, including chemistry, manufacturing and controls (CMC), and non-clinical and clinical studies (pre and post-approval). Modelling and simulation may inform drug development throughout the process. Planning may also include regional considerations for product introduction into the market, such as health technology assessments.

It is important to ensure that the experiences, perspectives, needs, and priorities of relevant stakeholders relating to the development and evaluation of the drug throughout its lifecycle are captured and meaningfully incorporated into drug development planning.
Clinical development may also feature requirements for co-development of validated biomarkers, diagnostic testing, or devices that facilitate the safe and effective use of a drug.

The types of studies that may contribute to drug development are described in subsections 4.2 and 4.3 and summarised in the Annex.

4.1 Quality of Investigational Medicinal Product

Ensuring adequate quality and characterisation of physicochemical properties of investigational medicinal product is an important element in planning a drug development programme and is addressed in ICH and regional quality guidelines. More extensive characterisation may be required for complex or biological products. Formulations should be well characterised in the drug development plan, including information on bioavailability, wherever feasible, and should be appropriate for the stage of drug development and the targeted patient population. Age-appropriate formulation development may be a consideration when clinical studies are planned in paediatric populations (ICH E11- E11A Clinical Trials in Pediatric Population).

Evaluation of the quality of a drug may extend to devices required for its administration or a companion diagnostic to identify the targeted population.

Changes in a product during development should be supported by comparability data to ensure the ability to interpret study results across the development programme. This includes establishing links between formulations through bioequivalence studies or other means.

4.2 Non-Clinical Studies

Guidance on non-clinical safety studies is provided in ICH M3 Nonclinical Safety Studies, ICH Safety (S) Guidelines and related Q&A documents, as well as in regional guidance. The non- clinical assessment usually includes toxicology, carcinogenicity, immunogenicity, pharmacology, pharmacokinetics, and other evaluations to support clinical studies (and may encompass evidence generated in in vivo and in vitro models, and by modelling and simulation). The scope of non-clinical studies, and their timing with respect to clinical studies, depend on a variety of factors that inform further development, such as the drug’s chemical or molecular properties; pharmacological basis of principal effects (mechanism of action); route(s) of administration; absorption, distribution, metabolism, and excretion (ADME); physiological effects on organ systems; dose/concentration-response relationships; metabolites; and duration of action and use.

Use of the drug in special populations (e.g., pregnant or breast-feeding women, children) may require additional non-clinical assessments. Guidance for non-clinical safety studies to support human clinical studies in special populations should be reviewed (see, e.g., ICH S5 Reproductive Toxicology, S11 Nonclinical Paediatric Safety, and M3).

Assessment of the preclinical characteristics, including physiological and toxicological effects of the drug, serve to inform clinical study design and planned use in humans. Before proceeding to studies in humans there should be sufficient non-clinical information to support initial human doses and duration of exposure.

4.3 Clinical Studies

Clinical drug development, defined as studying the drug in humans, is conducted in a sequence that builds on knowledge accumulated from non-clinical and previous clinical studies. The structure of the drug development programme will be shaped by many considerations and comprised of studies with different objectives, different designs, and different dependencies. The Annex provides an illustrative list of example studies and their objectives. Although clinical drug development is often described as consisting of four temporal phases (phases 1- 4), it is important to appreciate that the phase concept is a description and not a requirement, and that the phases of drug development may overlap or be combined.

To develop new drugs efficiently, it is essential to identify their characteristics in the early stages of development and to plan an appropriate development programme based on this profile. Initial clinical studies may be more limited in size and duration to provide an early evaluation of short-term safety and tolerability as well as proof of concept of efficacy. These studies may provide pharmacodynamic, pharmacokinetic, and other information needed to choose a suitable dosage range and/or administration schedule to inform further clinical studies. As more information is known about the drug, clinical studies may expand in size and duration, may include more diverse study populations, and may include more secondary endpoints in addition to the primary measures of efficacy. Throughout development, new data may suggest the need for additional studies.

The use of biomarkers has the potential to facilitate the availability of safer and more effective drugs, to guide dose selection, and to enhance a drug’s benefit-risk profile (see ICH E16 Qualification of Genomic Biomarkers) and may be considered throughout drug development. Clinical studies may evaluate the use of biomarkers to better target patients more likely to benefit and less likely to experience adverse reactions, or as intermediate endpoints that could predict clinical response.

The following subsections describe the types of studies that typically span clinical development from the first studies in humans through late development and post-approval.

4.3.1 Human Pharmacology

The protection of study participants should always be the first priority when designing early clinical studies, especially for the initial administration of an investigational product to humans (usually referred to as phase 1). These studies may be conducted in healthy volunteer participants or in a selected population of patients who have the condition or the disease, depending on drug properties and the objectives of the development programme.

These studies typically address one or a combination of the following aspects:

4.3.1.1 Estimation of Initial Safety and Tolerability

The initial and subsequent administration of a drug to humans is usually intended to determine the tolerability of the dose range expected to be evaluated in later clinical studies and to determine the nature of adverse reactions that can be expected. These studies typically include both single and multiple dose administration.

4.3.1.2 Pharmacokinetics

Characterisation of a drug's absorption, distribution, metabolism, and excretion continues throughout the development programme, but the preliminary characterisation is an essential early goal. Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites, interactions with metabolic enzymes and transporters, and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. For orally administered drugs, the study of food effects on bioavailability is important to inform the dosing instructions in relation to food. Obtaining pharmacokinetic information in sub-populations with potentially different metabolism or excretion, such as patients with renal or hepatic impairment, geriatric patients, children, and ethnic subgroups should be considered (ICH E4 Dose-Response Studies, E7 Clinical Trials in Geriatric Population, E11, and E5, respectively).

4.3.1.3 Pharmacodynamics & Early Measurement of Drug Activity

Depending on the drug and the endpoint of interest, pharmacodynamic studies and studies relating drug levels to response (PK/PD studies) may be conducted in healthy volunteer participants or in patients with the condition or disease. If there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and efficacy and may guide the dosage and dose regimen in later studies.

4.3.2 Exploratory and Confirmatory Safety and Efficacy Studies

After initial clinical studies provide sufficient information on safety, clinical pharmacology and dose, exploratory and confirmatory studies (usually referred to as phases 2 and 3, respectively) are conducted to further evaluate both the safety and efficacy of the drug. Depending on the nature of the drug and the patient population, this objective may be combined in a single or small number of studies. Exploratory and confirmatory studies may use a variety of study designs depending on the objective of the study.

Exploratory studies are designed to investigate safety and efficacy in a selected population of patients for whom the drug is intended. Additionally, these studies aim to refine the effective dose(s) and regimen, refine the definition of the targeted population, provide a more robust safety profile for the drug, and include evaluation of potential study endpoints for subsequent studies. Exploratory studies may provide information on the identification and determination of factors that affect the treatment effect and, possibly combined with modelling and simulation, serve to support the design of later confirmatory studies.

Confirmatory studies are designed to confirm the preliminary evidence accumulated in earlier clinical studies that a drug is safe and effective for use for the intended indication and recipient population. These studies are often intended to provide an adequate basis for marketing approval, and to support adequate instructions for use of the drug and official product information. They aim to evaluate the drug in participants with or at risk of the condition or disease who represent those who will receive the drug once approved. This may include investigating subgroups of patients with frequently occurring or potentially relevant co- morbidities (e.g., cardiovascular disease, diabetes, hepatic and renal impairment) to characterise the safe and effective use of the drug in patients with these conditions.

Confirmatory studies may evaluate the efficacy and safety of more than one dose or the use of the drug in different stages of disease or in combination with one or more other drugs. If the intent is to administer a drug for a long period of time, then studies involving extended exposure to the drug should be conducted (ICH E1 Clinical Safety for Drugs used in Long-Term Treatment). Irrespective of the intended duration of administration, the duration of effect of the drug will also inform the duration of follow-up.

Study endpoints selected for confirmatory studies should be clinically relevant and reflect disease burden or be of adequate surrogacy for predicting disease burden or sequelae.

4.3.3 Special Populations

Some groups in the general population require additional investigation during drug development because they have unique risk/benefit considerations, or because they can be anticipated to need modification of the dose or schedule of a drug. ICH E5 and E17 provide a framework for evaluating the impact of ethnic factors on a drug’s effect. Particular attention should be paid to the ethical considerations related to informed consent in vulnerable populations (ICH E6 and E11). Studies in special populations may be conducted during any phase of development to understand the drug effects in these populations. Some considerations of special populations are the following:

4.3.3.1 Investigations in pregnant women

Investigation of drugs that may be used in pregnancy is important. Where pregnant women volunteer to be enrolled in a clinical study, or a participant becomes pregnant while participating in a clinical study, follow-up evaluation of the pregnancy and its outcome and the reporting of outcomes are necessary.

4.3.3.2 Investigations in lactating women

Excretion of the drug or its metabolites into human milk should be examined where applicable and feasible. When nursing mothers are enrolled in clinical studies their babies are usually also monitored for the effects of the drug.

4.3.3.3 Investigations in children

ICH E11 provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of drugs in paediatric populations.

4.3.3.4 Investigations in geriatric populations

ICH E7 provides an outline of critical issues in developing drugs for use in geriatric populations and approaches to their safe, efficient, and ethical study.

4.3.4 Post-Approval Studies

After the approval of a drug, additional studies may be conducted to further understand the safety and efficacy of the drug in its approved indication (usually referred to as phase 4). These are studies that were not considered necessary for approval but are often important for optimising the drug's use. They may be of any type but should have valid scientific objectives. Post-approval studies may be conducted to address a regulatory requirement.

Post-approval studies may be performed to provide additional information on the efficacy, safety, and use of the drug in populations more diverse than included in the studies conducted prior to marketing authorisation. Studies with long-term follow-up or with comparisons to other treatment options or standards of care may provide important information on safety and efficacy. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies and studies designed to support use under the approved indication (e.g., mortality/morbidity studies, epidemiological studies). These studies may explore use of the drug in the real-world setting of clinical practice and may also inform health economics and health technology assessments.

4.4 Additional Development

After initial approval, drug development may continue with studies of new or modified indications in new patient populations, new dosage regimens, or new routes of administration. If a new dose, formulation, or combination is studied, additional non-clinical and/or human pharmacology studies may be indicated. Data from previous studies or from clinical experience with the approved drug may inform these programmes.

Source: ICH Expert Working Group