INNOVATION
TYPE OF APPROACH AND BASIS
TRADITIONAL/FRONT-LOADED BASED ON REDUCTION/ MANAGEMENT OF RISK AND PREPARATION FOR SUCCESS
Characteristics • Positioned to de-risk or kill candidate prior to proceeding to later stages of development
• Algorithmic as opposed to case- by-case approach – applicable for some candidates, overkill for others; downplays empirical nature of early development
• Probably driven by quality target product profile (QTPP)
• Selection of enabling API route, based on evaluation of limited range of options
• Full characterisation of molecule is undertaken
• Likely that drug product CTM is formulated
• Not sufficiently flexible – does not allow consideration of potential candidates not fitting algorithm or ways to reduce cost and duration of effort
Potential Consequences
• Front-loading of project (labour intensive) – costs at outset are high, roll-out is not as rapid as more stripped-down approaches
• De-risking results in any problems encountered being truly unanticipated – manufacturing is less eventful, on average; molecule is well positioned for advancement to later stages
• Budgets and timelines can be unsustainable; Prognosis for success is highest, but challenged by lack of speed, high cost –unsustainable for small, emerging companies
ENTREPRENEURIAL/ HIGHLY RISK TOLERANT BASED ON EXPECTATION OF ATTRITION OF NOMINATED CANDIDATE
• Positioned for rapid movement into development and supply of material for preclinical, nonclinical and clinical studies
• Direct scale up of medicinal chemistry route is most often enabling API route, little/no adaptation of synthesis to improve practicality
• Little/no anticipation/avoidance of problems – chemistry limitations, safety, extent of characterisation, impurity profiles, practicality
• Drug product development plan at early stage consists of powder in capsule or powder in bottle, with little or no consideration of BCS classification or delivery challenges
• Virtually all problem solving is “on the fly”
• Too flexible – promotes reactive as opposed to proactive default stance
• Budget and timelines can be adequately managed
• Possible fastest path to Phase 2a POC
• Initial commitments to regulatory agencies are based on poorly understood molecules and processes, very convoluted; limits options for changes needed to address practical capability and performance limitations, required at subsequent stages
• Scope, timeline and budget expansions are regular and significant
• Razor’s Edge: Prognosis for success is less clear and possibly compromised significantly, but success leads to continued investment
Comparison of three models of approaches to early CMC development
successful execution of the plan. Place holders are viewed differ-
ently in traditional and entrepre- neurial development. The traditional approach sees place holders primar- ily as gaps in understanding. The emphasis of the traditional approach is to structure development work to manage risk due to these gaps – to fill them in with knowledge as thoroughly as possible. The entrepre- neurial approach sees place holders primarily as gaps in cost and timing. The emphasis of the entrepreneurial approach in early development is almost exclusively focused on clarify- ing and controlling the costs and durations of development activities. And, ironically, as discussed above,
the unbalanced focus on cost/time- lines, to the detriment of increasing scientific understanding, often results in delays and cost overruns, and can even imperil the success of a devel- opment programme. Both the traditional and
entrepreneurial approaches to CMC drug development have serious limitations that compromise their effectiveness in supporting the advancement of new drugs through the development cycle. Traditional development is too costly and time- consuming, whereas entrepreneurial development is not sufficiently forward-looking and, as a result, carries excessive risk into the latter stages of development.
• Balance between front-loading and rapid roll-out of project
• Enables consideration of “outliers” – molecules that do not fall within screening algorithm criteria, but could be innovative drugs
• De-risking is selective and prioritised –highest impact potential problems are addressed
• Balanced approach results in compromise between extremes of budget and timeline of other approaches
• Approach that is aggressive and practical throughout development cycle, not just in early stages
MIDDLE PATH BALANCES EXPECTATIONS OF ATTRITION AND SUCCESS
• Positioned for speed, but tempered by judicious risk management
• Up-front assessment of candidate’s properties and synthesis, allows prioritisation and definition of risk management-based studies
• Significant (but not exhaustive) effort to anticipate problems that can be avoided
• Careful monitoring of programme needs vs. process knowledge and capabilities drives further investment in risk management and additional studies to enhance processes
Middle path A ‘Middle Path’ approach could be considered as a way to incorporate the most appealing, positively impactful aspects of both the traditional and entrepreneurial approaches into an integrated strategy. The intent of this approach is
to position a given development programme to be leaner than traditional approaches but also to manage enough risk to reduce the likelihood of predictable delays and setbacks. The pursuit of a middle path has its own unique challenges. Any approach that departs from traditional or entrepreneurial approaches requires
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