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International Clinical Trials

Quick Win, Fast Fail

Cyril Clarke at ICON Development Solutions goes in search of methods to reduce uncertainty in the outcomes of research and to improve investment returns

Few products can compare to pharmaceuticals in terms of their development costs, testing complexities, regulatory requirements and potential safety issues – although we could argue that passenger aircraft are in the same league. Consider, then, what a shock it would be to an aircraft designer if during the flight certification, the new aircraft couldn’t get off the ground. In contrast, many pharmaceutical manufacturers get to a similar stage in their own products’ development only to find that they won’t ‘fly’. We understand the physical laws that govern aerodynamics better than we understand the biological laws of drug action and disease response.

Consequently, as an industry, we’ve had to accept relatively high degrees of uncertainty in our outcomes, and our ability to produce molecules that make it into regulatory review has been declining for the past decade. This is not for lack of effort in discovery, but for a lack of molecules that ultimately engage with or modify their target to produce a clinically proven outcome that is differentiated sufficiently from other alternatives. Too many drugs either fail in expensive Phase III trials or do not produce a data package that demonstrates their value to healthcare payers.

To prevent late-stage failures, drug developers and service providers are shifting work to prove the concept of a molecule as a potential medicine to earlier phases of development. This change is being driven by the need to be more efficient and faster (the two are not always the same) in determining the fate of a molecule. To strengthen their case for payers, drug developers are incorporating health economics and outcomes research into early-phase studies, and are thus doing a better job of quantifying and articulating the value that their products will add.

Emerging biotechnology companies and academic researchers have been leading the charge in recent years, with traditional ‘big pharma’ companies following suit more gradually. The corporate ‘drive to produce’ in traditional big pharma companies does not lend itself to accepting a ‘no-go’ decision on a molecule early on as a form of success, even though it does limit the company’s investment and frees up resources for other areas of exploration. An increasing trend is the outsourcing of innovation, both in terms of discovery and increasingly development.

THE QUICK WIN/FAST FAIL APPROACH

Biotechnology companies have been attempting to decrease the technical uncertainty surrounding a product before it enters the expensive stages of development – in particular Phases II and III, when there are significant costs associated with recruiting patients and monitoring them for extended periods. Known as ‘quick win/fast fail,’ this alternative to the traditional development method shifts the proof of concept (POC) stage from Phase II to just after the start of clinical development. As a result, fewer new molecular entities (NMEs) advance to the later phases, but those that do have a higher probability of success and launch. The savings realised by avoiding late-stage R&D failures are re-invested in R&D to further enhance R&D productivity through work on candidate selection (CS), first efficacy dose (FED), first human dose (FHD), and product decision (PD).

Key to the quick win/fast fail approach is a feedback loop in which data gathered at the early proof of concept stage are fed back to discovery scientists for future benefit. This exchange is a microcosm of the feedback loop between the bench, the patient’s bedside, and back to the bench that is integral to translational medicine as a whole. Thus, development is not a one-way road in which research findings enter a production line and emerge at the end as drugs or diagnostics; it is an iterative process that makes use of a ‘virtuous loop’ of information.

FINDING THE R&D ‘SWEET SPOT’

The goal of the POC stage is to determine, with confidence, whether or not a molecule has the potential to become a therapy. Note that we are talking about POC as it relates to a company’s internal decision on advancing to the next level of investment, not about POC for regulatory purposes (admittedly though, the two do tend to converge in some cases, as with orphan drugs or therapies that address high, unmet, medical need). Optimal study design may allow both to be addressed.

Making this determination means that the following two questions need to be considered:

  • Can we produce enough information to support further development (either by ourselves or with a development partner) of this molecule for a given indication?
  • Do we understand the drug dose response sufficiently to design an efficient, laterphase strategy that will support regulatory approval?

For answers, companies are finding clever ways to get more definitive results with a smaller number of subjects or by dosing for a shorter period with a larger number of subjects. They are making use of biomarkers, advanced bioimaging and other tools to make informed go/no-go decisions and then focusing their resources on the most promising candidates. The ideal POC stage will give sponsors total confidence that they have:

  • Identified the desired pharmacological activity
  • Characterised the undesired pharmacological activity
  • Found the links between dose and exposure and desired versus undesired activity
  • Made a preliminary assessment of safety, tolerability and disease response in a small population

Interestingly, we have seen an increase in interest in so-called ‘umbrella protocols’ that allow the first in human (TFID), single ascending dose (SAD), multiple ascending dose (MAD), food effect and patient/pharmacodynamic cohorts in a single protocol. This allows dose escalation to proceed to a pre-specified exposure or pharmacodynamic response and then to be tested in patients at that exposure.

BENEFITS

In adopting the quick win/fast fail approach, drug developers can remove some of the uncertainty in the outcomes of their research and improve their return on investment substantially. The savings to be realised from earlier go/no-go decisions depend, of course, on the indication being studied and the length of the clinical programme. Finding a way to, for example, demonstrate in the course of a year that a drug to treat Alzheimer’s does or does not alter the progression of the disease before it becomes symptomatic would produce an astronomical saving over having to wait perhaps five years for the conclusion of a later-phase study. In contrast, the benefit of an early POC over running a relatively short clinical trial for temporary pain relief would not be nearly as dramatic.

At the same time, by using the quick win/fast fail approach, developers can improve the likelihood that a therapy will perform in the real world as expected, without unforeseen risks. While it is impossible to alter the fact that demonstrating safety is a function of exposure to large populations, the quick win/fast fail approach does accelerate an understanding of both desired and undesired responses to the molecule. A lot of effort is put into predicative biomarkers for safety by both individual companies and precompetitive consortia to allow better extrapolation from these small studies.

CONCLUSION

It is noteworthy that many companies now seek to include proof of concept, or proof of clinical activity, into licensing or co-development agreements.The definition of POC requires great clarity in this setting. Proof of concept is a high added value increment for any company to achieve. The overarching benefit of pushing molecules toward early attrition is that it improves the success rate of those that do proceed along the development path. And that is clearly good for all.


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Cyril Clarke is a Clinical Pharmacologist with over 17 years’ experience in clinical research; 14 of these are within industrial clinical pharmacology. Cyril received his BSc in Immunology and Immunopharmacology and in 1989 his MBBS from University College, London. After training in internal medicine, he joined ICON Development Solutions in 1994 as Clinical Research Physician. He then moved into the roles of Associate Medical Director, Medical Director, and then Medical and Scientific Vice President prior to taking up his current role as Vice President of Translational Medicine. He has acted as Principal Investigator for over 300 Phase I studies, and is also Deputy Chair of the ABPI Experimental Medicine Expert network. He has extensive experience in the development of glucose lowering agents and the development of glucose clamp methodology. Cyril is an Honorary Senior Lecturer in Translational Medicine at the University of Manchester.
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