Efficient R&D process can position a drug candidate for commercial success

Pharmaceutical manufacturers are under increased pressure todifferentiate new drugs from those already on the market. With increasedscrutiny from the U.S. Food and Drug Administration (FDA) and new hurdles forsafety in comparative effectiveness, it is more important than ever forpharmaceutical companies to increase R&D efforts while controlling costs.Speeding up R&D is an efficient way to increase the probability ofachieving clinical and commercial success for a drug candidate. However, theway to achieve this is not often straightforward. Fortunately, several newtechnologies exist that are revolutionizing the drug development process by acceleratingsmall-molecule research.

There are several steps pharmaceutical companies can take tomake the most effective use of time and money spent on drug discovery anddevelopment. First, investigate high-throughput, in vitro profiling technologies to improve innovation cyclesthrough rapid, cost-effective reiterative selection and optimization. Second,enhance the clinical relevance of early stage R&D by making invitro and in vivo data more predictive of clinical outcomes. Third,evaluate each step of the innovation cycle to ensure precise and immediatecontrol over critical path activities. Finally, leverage early cumulative datato get an accurate and detailed knowledge of the drug candidate's attributes atan early stage and help predict its potential market value.

High-throughput, in vivo profiling

Despite the ability of drug developers to rapidly screenmillion of compounds, such speed is irrelevant unless the data provides anaccurate assessment of key attributes, such as kinetics, mechanism of actionand specific effects on key target enzymes. Through strategic use ofhigh-throughput, in vitro profilingtechnologies, researchers can rapidly generate a drug profile, allowingnumerous reiterations until one or more "optimal profile" candidates has beenselected that has a greater chance of surviving the in vivo testing stage and beyond. New technologies such asmicrofluidic-based instruments provide immediate high-quality data with goodsensitivity, thereby allowing detection of low-activity inhibitors, which arepotentially more pharmacologically relevant, while at the same time eliminatingfalse positives.

Every new technology that is introduced into the innovationcycle should ideally be able to keep pace with the preliminary screeningprocess, yield reproducible data across a broad spectrum of compounds, becost-effective in terms of materials and labor and be able to generate multipledata points per compound. These attributes allow drug developers to exploit aphenomenon that has been used by the IT industry for more than adecade—distributed experimentation—whereby the availability of inexpensivemodular technologies has allowed innovation through decentralization ofactivities that were once restricted by necessity to a single system.

By judiciously using new enabling life science tools in areiterative manner, researchers can quickly eliminate candidates likely toscore poorly in terms of safety and efficacy, and select for additionalcriteria such as slower off rates, which are more likely to correlate withgreater therapeutic windows in vivo. Byimplementing distributed experimentation, drug developers can further enhancethe efficiency of the process, facilitating swift decision-making during thedevelopment process.

Enhancing clinical relevance at an early stage

Given that one of the greatest drains on pharmaceutical ROIis the exorbitant cost of clinical failure, it is imperative to ensure that invitro and preclinical in vivo data is predictive of clinical outcome. An abundanceof recent technological developments, including next-generation sequencing,genomic/proteomic biomarker discovery, companion diagnostics and invivo imaging, have helped strengthen thetransition from in vitro to invivo, thereby facilitating more clinically relevantdrug development.

New modalities in in vivo optical imaging, in particular, allow researchers to visualize thebiological effect of a compound within a live animal, in real-time over days orweeks, without the need to sacrifice the animal to obtain data. Not only doesthis reduce cost in terms of animal usage and labor (such as histologyworkload), but it also provides real-time data that is more predictive of thecompound's activity in humans. With engineered mouse and rat models for all themajor disease indications, in vivoimaging is of broad utility to the pharmaceutical industry, and has beenstrategically used by many large companies to generate data for FDA regulatoryapproval of small molecule drugs.

Evaluating critical path activities

While the pharmaceutical industry appreciates the importanceof accelerated drug development, in its eagerness to save on cost throughoutsourcing, it has often overlooked a basic tenet of business strategy: thehigher the strategic value of an activity, the more closely it should be held.Given how essential speed, data generation, analysis, reiteration and swiftdecision-making are throughout the innovation cycle, it is advisable to keepthese activities in-house to ensure proper control over the process.

Several years ago, a trend emerged in drug discovery anddevelopment, whereby many pharmaceutical companies began to outsource keyR&D activities to third parties. The high cost of capital equipment andlabor, combined with the high levels of radiation that required costlycontainment, could justify outsourcing, even though it means losing control ofsome core competencies. A recent study of 359 U.S.-based companies measuredtheir outsourcing practices and innovative performance and found that: 1) the conventionalwisdom that outsourcing saves on cost appeared not to apply in all situationsand, in fact, in some cases the cost of outsourcing dramatically exceeded thecost of internal product development; and 2) an inappropriate level ofoutsourcing (too much or too little) decreased innovation, as evidenced by thefact that 1 percent too much outsourcing resulted in an 11 percent decrease inthe expected number and influence of resultant patents.¹ Given thatmanaging costs while maximizing innovation is critical to the success of allpharmaceutical companies, these findings underscore the importance of applyingcareful discretion when choose which activities to outsource.

Importantly, there have been many key technological advancesin the life science tools industry in recent years, many of which have beensufficiently game-changing to warrant bringing key activities back-in-house.High-throughput profiling is a case in point given its low cost point in termsof capital and labor, speed and critical position in the innovation cycle interms of being able to generate high-quality data within hours versus days orweeks. With new technologies like these that are enabling swift "Go/No Go"decision-making, the impetus for outsourcing has almost entirely dissipated. Infact, the enhanced speed, efficiency, cost benefit and control at key decisionpoints that it affords the drug developer strongly argue that such enablingtechnologies should be kept in-house and fully leveraged in the early stagedrug discovery process. Simply put, maintaining control of the innovation cycleis too important to warrant surrendering control to third parties, particularlywhen there are cost-effective solutions at hand.

Positioning a drug candidate for commercial success

While most early drug discovery and development is primarilyfocused on generating leads that are likely to be clinically effective and safein humans and hopefully gain regulatory approval, success in meeting these twoparameters is not sufficient to ensure a positive ROI. To increase the chanceof commercial success in terms of market share, reimbursement and pricing, agood drug candidate must be sufficiently differentiated from existing andupcoming marketed drugs with which it will compete.

Pharmaceutical companies can introduce an early "commercialsuccess hurdle" into the R&D process by using the innovation cyclereiteratively to seek a compound that has an aspirational profile based on whatthe attributes of the ideal product should look like. While the ideal profilemay or may not be attainable, the drug developer can compare the ideal profilewith a baseline profile (i.e., the minimal attributes for a commercialproduct), and make the decision to continue reiterative screening or to proceedwith the product in hand. With an accurate and detailed knowledge of the drugcandidate's attributes at an early stage, a drugmaker can quickly predict itsmarket value, and proceed along the path that will maximize the chance ofcreating a drug that is both clinically safe and effective and welldifferentiated from the competition.

While there is no single solution to the pressures weighingon the pharmaceutical industry, it is important that drug manufacturers seizethe opportunity to reexamine the drug discovery and development process. Toimprove R&D efforts, it is essential that drug manufacturers evaluate theway in which they adopt and deploy new life science technologies in order toallow nimble, reiterative drug development. In addition, the pharmaceuticalindustry needs to rethink the process of indiscriminate outsourcing and insteadbolster its internal control of critical path activities that ultimately helpdetermine the speed and efficiency of the entire drug development process. Thecurrent cost of enabling tools, both in terms of capital equipment and labor,has reached an attractive price point that renders this a compelling valueproposition. Given the long timeline and high cost of drug development comparedwith the relatively modest cost of keeping key technologies in-house, thebenefit of being able to make swift decisions at critical junctures is asimple, yet tangible way of improving the ROI and ultimately creating moresuccessful drug candidates.

Kevin Hrusovsky was appointed President and CEO of CaliperLife Sciences in 2003, following the acquisition of Zymark Corp. by Caliper.Hrusovsky served as president and CEO for Zymark and president of thepharmaceutical division at FMC Corp., and ran the Teflon and other specialtybusinesses at Dupont. Hrusovsky is on the Global Research Council forChildren's Hospital in Boston and is a member of the Association of LaboratoryAutomation's steering committee. He received his B.S. in Mechanical Engineeringfrom Ohio State University, an M.B.A. from Ohio University and an honorarydoctorate from Framingham State University for his contributions to lifesciences. He has served on several public life science companies' board ofdirectors.

References: 1.Stanko, M., J. Bohlmann & R. Calantone. "Outsourcing Innovation." WallStreet Journal. Nov.30, 2009.