INTRODUCTION What Is Planning?

Planning is the process of producing a plan. A good plan optimizes the process to achieve the target objectives of the project in the shortest possible time with the minimum resources. Planning, therefore, means optimizing the classical project management triangle: performance/time/cost.

In addition, a plan is an essential means of communication between all project participants to achieve transparency, understanding, and commitment. "Planning makes you free" seems to be a contradiction but, in reality, the efforts devoted to creating a good plan provide the reassurance and freedom of mind that everything that could be reasonably anticipated has been thought of and consid- ered. Of course, unexpected events occur and make it necessary to review and adapt even the best plans.

A plan for developing a drug gives answers to three questions:

r What program of experiments and studies need to be conducted and reported to reach the targeted project performance?

a_{This chapter is based upon the original chapter by Dr. Kutzbach from the first edition and has been} revised to reflect contemporary development requirements and planning systems.

58 Kutzbach et al. r What is the minimum time required to execute this program?

r What resources are required to carry out the work and what is the schedule? This article will focus on the aspects of performance and time planning. Time optimization planning should assume, initially, that resources are available as and when needed. In the second step, it may be necessary to adapt a plan according to the available resources and existing priorities.

The planning targets of high performance and short development time present a practical conflict. Performance is defined by the quality of the database to ensure rapid and broad registration approval and good positioning in the market. Adding more and larger studies to improve this performance inevitably adds to the time. Late market entry jeopardizes the commercial return because of shorter patent protection and increased risk of an earlier market entry by a competitor with a similar product. A short time to regulatory submission, however, is worthless if approval failure follows or if commercialization is compromised resulting in the need to add studies during the approval process. Planning, therefore, must carefully define the minimum program required to achieve the target without unacceptable risk and also must minimize the time to complete this program.

Differences of Planning in Research and Development

The development of a new therapeutic drug runs through two major phases: r The research phase of selecting a suitable drug candidate from a large number

of compounds screened for activity in vitro or in animal models

r The development phase in which a single compound is carried through the necessary nonclinical and clinical trials required to prove its efficacy and safety and to obtain regulatory approval

During the research phase, the plans for synthesizing new compounds are constantly adapted to the outcome of the screening assays. Long-term planning in this phase is therefore largely restricted to the overall scope of time and resources applied to the project. This work is managed by the disciplines of chemistry and experimental biology within the research and discovery function.

In the development phase, however, the contributions of many disciplines must be closely coordinated to minimize the time to interim decision points and to the final project completion.

This article will focus on the planning of development projects. Planning is facilitated by the fact that regulatory guidelines and directives are often available to help in designing the development program for a particular disease indication. Generally, development is structured in the phases shown in Table 1.

Planning of the development process is essentially a stepwise, continuous process starting with a defined target and ending with a detailed plan of action. The plan will be continuously adapted in the light of development findings and changing circumstances as shown in Table 2.

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Table 1 Standard Phases of Drug Development

Phase Start Main tasks End

Average duration (mo) Preclinical Development decision Safety evaluation in animals; laboratory and initial scale-up of API; drug product

formulation for phase 1

Approval to treat first human subject 15 1 Start of first tolerability and kinetic study in humans

Safety, tolerability and kinetics in humans; extended toxicology; API process development; drug product optimization/ manufacture for phase 2; establishment of clinical database Approval to start first therapeutic trial 12 2 Start of first therapeutic trial

First proof of therapeutic efficacy; determination of effective dose; long-term toxicology Approval to start large pivotal therapeutic trials 24 3 Start of first large pivotal trial Statistical proof of efficacy and safety in a large, diverse patient population; API and drug product scale-up and validation; compilation of regulatory dossier Completion of documentation for electronic regulatory submission 30 Approval Submission in first country Response to questions and requests of regulatory authorities; production of launch supplies; premarketing and sales force training

Marketing approval

12–48

Abbreviation: API, active pharmaceuticals ingredient. THE BASIS OF THE PROJECT PLAN Defining the Project Target

Each plan describes the route to a target. A good plan requires and helps to clarify an exact definition of the target. The general target of drug development is an

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Table 2 Steps in the Planning Process

1. Define the target

2. Prepare a list of necessary work packages (studies) 3. Determine the logical sequence and estimate durations 4. Determine the critical path

5. Optimize the plan to reduce critical path length

6. Plan resources and costs and adjust for resource and budget constraints and priorities 7. Adjust plan during execution to new data, as required

approved and commercially successful drug product. Drug performance targets are commonly described by the target indication and the route of administration. This is further specified in terms of efficacy, safety, and patient convenience parameters. Parameters such as socioeconomic benefit, unique selling proposition, and maximum cost of goods may be added. Early in the development process, some companies use draft (patient information) PI-sheets covering most of these parameters. Others start with a less detailed target product profile (sometimes also called project target profile or similar). In any case, it is essential that the efficacy and safety parameters are defined as quantitatively as possible so that they can serve as design parameters for clinical studies. Of course, the minimum requirements must describe a product that has a good chance to be competitive when entering the market several years in the future. If these minimum requirements are not met in the study program, then discontinuation of the project must be considered (see example of a target product profile in Fig. 1).

Often a development candidate offers the opportunity for development in more than one therapeutic indication or in different formulations. These constitute different subprojects that require their own fully detailed target profiles.

Prior to the initiation of the planning process, the selection of subproject(s) to be developed initially and those that present options for future line extensions or licensing opportunities should be made. A parallel development of all possible options, in most cases, would require too many resources and increase considerably the development time to first marketing approval. The selection of the target for the first development may be based on the chance for clinical success, on an expected shorter time to market, or on other valid reasons. Parallel development of two indications is made easier if they use the same formulation and therefore can use the same nonclinical and phase 1 program. On the other hand, the potential of consecutive or combination therapy by intravenous and oral routes may be important enough to justify its parallel development, for example, with certain antibiotics.

If broad international registration and marketing are intended, it must also be investigated if identical targets are appropriate in all countries or regions. There are significant differences in medical practice, definition of indications, and acceptance of application routes by the patient in different regions to be taken into account. The intent must be to cover as much as possible with a shared core program and studies added for specific local requirements wherever necessary.

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Project Target Profile

Project Attributes Realization

Project: AZ 1000 Date: Formulation: Tablet >60% >8 mm Hg * * * * * * * * * * * * Quan- titative cer- tain pro- bable not clear Hypertension

All attributes are minimum requirements

1. Efficacy 2. Tolerability

* Significant responder rate (long-term treatment) * Dose dependant efficacy

* One well-tolerated dose should reduce diastolic blood pressure at trough compared to placebo by

* Risk/benefit ratio and incidence of adverse events at least comparable to ACEIs or Ca antagonists e.g.:

metabolically neutral no narrow therapeutic index

no negative effects on electolyte balance

no restrictions when combined with common drugs, particularly CV and MD

no major contraindications no CNS side effects

* (a) in contrast to Ca antagonists no clinically relevant peripheral edema or increase in heart rate * (b) in contrast to ACE inhibitors no negative impact on lung (particularly no cough induction) and those renal conditions negatively affected by ACE inhibitors Indication:

3. Convenience

* Once-a-day application

* Small, easy to swallow oral formulation

4. Innovation (USP)

* Demonstration of 2a) or 2b) without additional adverse effect

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Legal and Regulatory Requirements

The plan must also take into account government laws, guidelines, and points to consider of the regulatory authorities in the target countries as well as rules of ethical committees or institutional review boards (IRBs). If clear guidelines do not exist, it is useful to obtain the advice of key opinion leaders in the field, for example, on choosing therapeutic targets and clinical end points. Furthermore, every opportunity to present the plan to a regulatory authority should be taken to obtain its opinion or consent.

PREPARING THE PROJECT PLAN