INNOVATION
a shift in thinking, from ‘either-or’ to accommodation of elements of both approaches. An increased investment of effort on the part of those responsible for the creation, refinement and execution of the development plan is necessary. The middle path approach is more dynamic and nimble than the traditional approach, but also more proactive and less reactive than the entrepreneurial approach. As with a traditional approach, a critical assessment of the API synthesis would be performed, with the intent of determining how an enabling process would be pursued. Characterisation of the candidate molecule would also be done, to inform the selection of the target form of the API, and the dosage form development approach. What distinguishes this work , as opposed to a traditional effort is how this initial information is used and implemented. More attention is given to the empirical nature of development and prioritisation of possible activities. On the basis of such an initial assessment, the studies that have the most impact on managing the biggest risks associated with the candidate’s development are selected to be performed. This results in a more focused, narrow-scope R&D plan that manages risk more than is done in an effort that is purely entrepreneurial, while having a budget and duration that is significantly reduced, as compared with traditional plans. As with any approach to CMC
development, the middle path approach must address the question of when the transition from expedient, enabling processes to processes with enhanced capabilities occurs. The answer is variable, and it relates to the empirical nature of the science of drug development. This transition is costly and potentially temporarily disruptive to ongoing development activities, particularly manufacturing, and therefore its strategy and timing need to be carefully considered. The complexity of this transition decision-making process has multiple dependencies: • Budget, related to funding situation of company and other activities and programmes competing for resources, both of which are variable;
• Culture of company – risk tolerance philosophy, ability and inclination to identify and manage risk;
• Technical, logistical and strategic challenges associated with manufacturing of API and dosage form and establishment of a supply chain;
• Clinical trial data and planned future clinical study design assumptions affecting demand for drug product;
• Gap between current capabilities of drug substance and drug product manufacturing processes and those required to meet clinical and regulatory milestones; and
• Target dates for regulatory filings Taking the middle path requires preparedness to monitor the current state of knowledge of the development effort, and determination of if and how the programme needs to change to accommodate foreseeable drug supply needs.
Summary In comparing traditional and entrepreneurial approaches to development, the differences between the two is a matter of what is emphasised (Figure 1). Traditional approaches focus on risk identification and mitigation, from the outset of candidate nomination, by systematically increasing knowledge.
The issue of attrition for predict-
able reasons is managed by algo- rithm-based exclusion of potential candidates from further considera- tion, based on pre-determined crite- ria. Less development time is spent on the critical path for traditionally developed drugs. The drugs devel- oped by the traditional approach tend to be ‘better behaved’ than their entrepreneurial counterparts, due to systematic de-risking. In contrast, entrepreneurial
approaches focus on minimisation of costs and durations of activities, due to limited resources and the likelihood of attrition. Risk identification and mitigation is usually an afterthought, if done at all. Much more development time is spent on the critical path, as compared with traditional development efforts. Entrepreneurial companies tend to develop drugs
that have significant challenges associated with their properties – this is risky, but the potential payoff is that innovative, differentiated drugs of high value result. Middle path approaches are more
expensive and time consuming than typical entrepreneurial approaches at the outset, but the real costs of entrepreneurial approaches are rarely fully assessed or apparent until later stages. These approaches are less thorough than traditional approaches, but the most significant predicted risks are identified and addressed.
Budget and time investment associated with traditional development efforts is prohibitive for most small companies that are increasingly becoming innovators
Neither traditional nor
entrepreneurial approaches, at their extremes, are sustainable in a pharmaceutical industry under continually increasing pressure and scrutiny, from regulators, investors and patients. Cost and time to market needs to be reduced, as does the failure rate. Middle path approaches proceed from a holistic perspective that considers drug development as an integrated, interdependent undertaking, requiring more interaction between different functions of a development team. The expectation is that such an approach will anticipate and avoid the most significant foreseeable problems, while providing flexibility that allows adaptation to changing circumstances that are typical for development of innovative molecules. The most useful aspects of
traditional and entrepreneurial approaches do not need to be mutually exclusive. The hope is that, by using a middle path approach, elements of both risk management and risk-taking innovation result. The intended outcome is that molecules chosen to advance into development have a reasonable opportunity to succeed, with a manageable price and development cycle time.
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