INNOVATION
to the empirical nature of the science that is encountered throughout the development cycle, and the sometimes paradoxical reluctance to invest in programmes that have yet to prove their worth.
Approaches to early development Three idealised approaches to early development of chemistry, manufacturing and controls (CMC) are discussed here, two of which, ‘Traditional’ and ‘Entrepreneurial’, are well- established. The third approach, described as ‘Middle Path’, has been emerging, and has been implemented to a limited degree. A ‘Traditional’ approach is most often undertaken by well-resourced companies, because this is risk-averse, and labour and cost-intensive. As a result, candidates developed using this approach are carefully considered, from the point of view of API process development and manufacturing , characterisation and dosage form development and manufacturing. Risk is mitigated to a fault, and there is a reasonable likelihood that the Phase 1 clinical dosage form is formulated based on the candidate molecule’s biopharmaceutical classification system (BCS) category. Candidates are advanced
or killed based on relatively fixed criteria, which are usually part of an algorithm. Algorithms are devised as the result of experience, so another prerequisite for the approach is the possession of sufficient depth of experience to inform it. Use of an algorithm to select development candidates can result in a rather rigid, ‘one size fits all’ approach to any early development effort. Limited flexibility in the consideration of potential candidate compounds, as well as the approach to the development of selected candidates can give rise to inefficiencies of several sorts. Potentially valuable candidates may not be considered or nominated, because they are excluded by the algorithm(s).
Traditional approaches to nominated candidates may be susceptible to excessive attention to detail that may not be appropriate or necessary for earlier stages of development. The limited flexibility
characteristic of traditional development approaches means that there are few grey areas – it is rare that compounds possessing challenging physicochemical properties, but very compelling activity are considered for advancement. If these types of molecules, which are increasingly typical in general, are chosen to be developed, they are likely to have a tentative status that may not give them a legitimate chance for evaluation. Overall, traditional
approaches to drug development are highly strategic, and they successfully deliver de- risked candidates into early development. As a result, the candidates selected and advanced from this approach tend not to have predictable problems associated with them. Drug candidates developed using the traditional model are poised for success, in the event of continued positive clinical and nonclinical data. However, the budget and time investment associated with traditional development efforts is prohibitive for most small companies that are increasingly becoming innovators responsible for advancing new drugs to the market. In addition, even companies that have historically taken traditional approaches to development are looking for ways to streamline their approaches.
By definition,
‘Entrepreneurial’ development approaches are highly tolerant of risk. This comes with the niche that entrepreneurial companies occupy – they are focused on innovation. The innovation may be in the form of a new target or modality or technology, or it may be a result of in-licensing of a candidate that was not chosen for development at a company using the traditional model. Most candidates developed using the
entrepreneurial approach are not de-risked to nearly the same degree as those developed using the traditional approach. Due to the lack of risk mitigation for entrepreneurial development candidates, such candidates are more susceptible to attrition. The priorities associated with
entrepreneurial efforts are rapid entry into development and supply of material for preclinical and clinical studies. The philosophy of this approach is that survival of the programme is essentially only dependent on preclinical and clinical study results, and that early development does not merit careful consideration, since it can be deferred and ‘fixed’ later in the development cycle, if the candidate survives to that point. The impact of early CMC development on ability to obtain meaningful early animal model and human in vivo data is seldom sufficiently considered. There are numerous notable instances in which such daring gambles pay off, ie compounds make it through Phase 2a proof of concept and into late development. However, significant liabilities are often carried into late development as a result: • As a consequence of inadequate characterisation and production by poorly understood processes that are more typical for molecules developed using an entrepreneurial approach, regulatory commitments are made at investigational new drug (IND) filing that limit scientific and technical flexibility. Such flexibility is needed to develop practical, economical processes and sound analytical methods. Regulatory commitments based on insufficient understanding are usually convoluted.
• There is often no comprehensive, coherent narrative of the path from early to late development that allows understanding of why certain choices were made. This adversely affects the ability to provide
background and articulate rationales and justifications when interacting with regulatory agencies, particularly at later stages of the development cycle.
• Expansion of the scope of development activities (analytical, process R&D, pilot production, QA investigations and corrective and preventive actions (CAPA)) often occurs at a juncture when both cost and time are at a premium, and the impact of setbacks and failures is at a maximum. Such scope expansions work against the primary objective of time to market. This sort of scope expansion not only potentially offsets any time and cost savings realised in early development, but usually results in a programme that is much more costly and time-consuming than originally projected and communicated to sponsor leadership and stakeholders. The paradox of entre-
preneurial development is that, although it can seem flexible in its earlier stages, the initially imposed time, budget and resource limitations can eventually result in a constriction of options, which makes negotiating the later stages of development particularly difficult.
Traditional vs entrepreneurial At candidate nomination, the beginning of a development programme, relatively little is known about the molecule selected. As a result, many assumptions and projections need to be made to create strategies and plans, regardless of the type of approach taken. ‘Place holders’ are used to designate gaps in knowledge or understanding when initial development strategies and plans are devised. These place holders are expected to be refined and replaced as actual data and knowledge are obtained, and this allows revision, clarification and refinement of both the strategy and the plan. This process is an index of the progress of the
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