The nature of drug development

Drug discovery, as described in Section 2, is invariably an exploration of the unknown, and successful projects may end up with compounds quite different from what had originally been sought: there is a large component of ‘unplannability’. In contrast, drug development has a very clear-cut goal: to produce the drug in a marketable form, and to gain regulatory permission to market it for use in the target indication(s) as quickly as possible. The work required to do this falls into three main parts, respectively technical, investigative and managerial:

• Technical development – solving technical problems relating to the synthesis and formulation of the drug substance, aimed mainly at ensuring the quality of the end-product:

Main functions involved: chemical development, pharmaceutical development.

• Investigative studies – establishing the safety and efficacy of the product, including assessment of whether it is pharmacokinetically suitable for clinical use in man:

Main functions involved: safety pharmacology, toxicology, pharmacokinetics, clinical development.

• Managerial functions:

Coordination – managing quality control, logistics, communication and decision making in a large multidisciplinary project to ensure high-quality data and to avoid unnecessary delays:

Main function involved: project management

Documentation and liaison with regulatory authorities – collating and presenting data of the type, quality and format needed to secure regulatory approval

Main function involved: regulatory affairs.

An important distinction between the technical and investigative aspects of development is that, in tackling technical problems, it is assumed that a solution does exist, and so the team’s task is to find and optimize it as quickly as possible, whereas in assessing safety and efficacy it cannot be assumed that the compound reaches the required standards – rather, the object is to discover this as quickly and cheaply as possible. In other words, technical development is essentially an exercise in problem solving, whereas clinical and toxicological development is a continuing investigation of the properties of the compound. Although technical problems, such as an unacceptably complex and poor-yielding synthesis route, or difficulty in developing a satisfactory formulation, can result in abandonment of the project, this is relatively uncommon. Failure on account of the drug’s biological properties, such as toxicity, poor efficacy or unsatisfactory pharmacokinetics, is, however, very common, and largely accounts for the fact that only some 10% of compounds entering Phase I clinical trials are eventually marketed. An important aspect of the management of drug-development projects, therefore, is to establish firm ‘no-go’ criteria, and to test the compound against them as early as possible.

Development proceeds along much more clearly defined lines than discovery, and is consequently more ‘plannable’, particularly the non-clinical studies, where standard experimental protocols exist for most of the work that needs to be carried out. This applies also in Phase I clinical studies. Delays can nevertheless occur if unexpected findings emerge, for example poor oral absorption in humans, or species-specific toxic effects, which require additional work to be carried out before clinical trials can proceed. If the drug has a completely novel mechanism of action this often prolongs the technical phase whilst off-target effects are explored (sometimes at the insistence of the regulatory authority).

Beyond Phase I, the route to be followed is generally much less well charted, and success depends to a much greater extent on strategic decisions by the project team as to which clinical indications should be investigated (see Chapter 17). They will need to assess, for example, whether recruiting patients to the trial will be easy or difficult, what exclusion criteria should apply, what clinical outcome measures should be used, and how long the treatment and assessment periods will need to be. To achieve registration as quickly as possible, it may, for example, be expedient to select a relatively low-market, but quick-to-test, clinical indication for the initial trials, and to run these trials in parallel with more prolonged trials in the major indication. Careful attention needs to be given to the patient group selected for the trial, so as to maximize the chance of success in obtaining a clear-cut result. Experience shows that inconclusive clinical trials resulting from poor decisions of this sort are a common cause of failure or delay in drug development. Where the indication allows this an adaptive trial design may allow a more efficient evaluation of the drug (see Chapter 17).

Components of drug development

Figure 14.1 summarizes the main activities involved in developing a typical synthetic compound. It shows the main tasks that have to be completed before the compound can be submitted for regulatory approval, but needs to be translated into an operational plan (Figure 14.2) that will allow the project to proceed as quickly and efficiently as possible. It is obvious that certain tasks have to be completed in a particular order. For example, a supply of pure compound, prepared in an acceptable formulation, has to be available before Phase I clinical studies can begin. Animal toxicity data must also be available before the compound can be given to humans. Deciding on the dosage schedule to be used in efficacy trials requires knowledge of the pharmacokinetics and metabolism of the compound in humans. Because the data generated will be included in the final registration proposal, it is essential that each part of the work should be formally reported and ‘signed off’ by the group responsible and archived for future reference. A typical development project is likely to involve several hundred individuals, expert in different disciplines and working on different aspects of the project, and coordinating their work is a complex and demanding task. For this reason, most companies assign specialist project managers to this task. Their role is to design a project plan, based on input from the experts involved, to monitor progress and to adapt the plan accordingly. As well as being good organizers, project managers need to be excellent communicators, diplomatic, and with a good understanding of the scientific and technological aspects of the project. Figure 14.2 is a much-simplified outline of a project plan of the development of a typical orally active drug. Each ‘task’, represented by an arrow, starts and ends at a circular symbol (representing an ‘event’), and decision points are marked by diamond symbols. This type of graphical format, which is widely used as a project management tool and implemented in many commercially available software packages, is known as a PERT (project evaluation and review technique) chart. By assigning times – shortest possible, maximum, and expected – to each task, the timing of the whole project can be assessed and the critical path – i.e. the sequence of tasks that need to be completed on time in order to avoid an overall delay – defined. In Figure 14.2 the process has been reduced to a bare minimum to allow representation on a single page; in practice, each of the ‘tasks’ shown (e.g. develop formulations, perform Phase I studies, etc.) needs to be further subdivided into a series of subtasks and timings to enable the project to be planned and monitored at the operational level. The complete diagram for a typical drug development project will be of such size and complexity as to frighten all but the most hardened project management professionals. Software tools, fortunately, are available which allow the project to be viewed in different ways, such as Gantt charts, which are barcharts set against a calendar timescale, showing the expected start and completion dates for each task, many of which will be running simultaneously on any given date¹.