“Fail Fast” Using Toxicology Endpoints in Pharmacology Studies

“Fail Fast” Using Toxicology Endpoints in Pharmacology StudiesSuccessful drug development is increasingly dependent on a robust “fail fast” strategy that includes incorporation of safety / toxicology endpoints into lead optimization pharmacology studies. This early marriage of pharmacology and toxicology will provide insight into the margin of safety that is critical for advancing the molecule, the design of the GLP studies and the clinical plan. Biopharmaceutical companies that employ a “fail fast” strategy can make safety decisions from the integration of toxicology into pharmacology studies, which markedly reduces lead optimization cycle times and overall spend during this phase.

Large Opportunity to Reduce Spend and Time in Lead Optimization

Conducting an optimized toxicology and pharmacology program will improve the probability of technical success of the candidate molecule in both GLP studies as well as clinical development. The capitalized cost of the Lead Optimization phase – the longest, most expensive, and success-determining phase in most drug discovery programs – is $414 million on average for each successfully launched new medicine, according to a 2012 article published in Nature Reviews Drug Discovery from Steven M. Paul, et al. of Eli Lilly. This figure takes into account the opportunity cost over time in each phase. This capitalized cost could be even more of a percentage of overall development costs if Lead Optimization is not done as efficiently as possible. However, improvement in this phase can have a big impact on cost and time.

Evaluating Toxicity & Bringing Forward the Best Candidate

Combining safety assessments into pharmacology studies, when it makes sense, helps you gauge the viability of that molecule for further development by quickly establishing a margin of safety.  At the very least, this data will help you select doses for the toxicology study, since you will have an understanding of whether there’s a safety issue at the top dose used in your pharmacology study.

Here are some situations of when including toxicology endpoints in pharmacology studies makes the most sense: 1) when the target is only expressed during disease, 2) you have many publications on physiology of target 3) the target is conserved across species 4) you have good reason to believe the model represents the disease in the patient, 5) low variability exists, and finally, 5) the model translates to the clinic.

On the other hand, there can be reasons for not including toxicology endpoints in pharmacology studies. For instance, if you have low confidence in the human translation of the safety data in the model, the pharmacology is different in animals and humans, or the physiological knowledge of hitting the target is insufficient, then including toxicology endpoints may not be appropriate.

What to Do with a Potential Safety Finding

Several considerations should be made before you decide to add a safety evaluation into your pharmacology study, including the indication, therapeutic class, and potential translation to the clinic. Furthermore, once a potential safety issue is found, you will need to consider if the finding is linked to pharmacology, if the dose-response potency can be reduced to widen the margin of safety, and if the finding is truly a spurious finding from the model. Finally, you’ll need to determine what else can be done to provide enough data to make a decision based on the finding.

Integrating safety and efficacy can help you solve issues proactively or reactively. Proactive resolution, or dealing with issues before they arise, could include understanding the potential safety issues from a high pharmacological dose and hitting the target too hard.  Examples are blood pressure medicines, where too much can over compensate the desired effect, or diabetes treatments, where blood sugars can be reduced too much. Another example is addressing class effects that might be on or off target for the intended therapy, such as the skin effects seen with some of the EGF inhibitors.  Building safety measurements into pharmacology studies for these potential effects would be proactive and potentially avoid more expensive investments.

Covance can also help you solve issues, such as clinical holds, that happen later in development and are more reactive to a finding. We’ve had many clients come to us for clinical hold issues and we’ve been very successful providing data that helps them better understand the implications of their findings.


Biopharmaceutical companies are increasingly employing “fail-fast” strategies. Overall, selectively placing toxicology endpoints in pharmacology studies can eliminate compounds, provide data for more rapid decision making, and ultimately reduce the cost of your Lead Optimization program.

Covance has a long history of developing new medicines from GLP studies to marketing. Our Lead Optimization Pharmacology & Toxicology is a service that’s designed to select the best molecule for candidate selection and further development. The value this brings to our clients is the ability to integrate service lines, such as pharmacology, biomarkers, imaging and safety, and thoughtfully add endpoints to studies, maximizing the number of questions being answered in each individual study. Alternatively, the client could run multiple studies, which could result in missing an important finding much later in development.

For more information about how Covance can help you develop successful Lead Optimization Pharmacology & Toxicology strategies please contact us or visit our website for more information: www.covance.com/discovery.

Complimentary Webinar: A “Fail Fast” Strategy for Lead Optimization Pharmacology and Toxicology

Speaker: Shawn Heidel, D.V.M., P.h.D. – Executive Directory, Global Discovery Pharmacology & Toxicology, Covance
When: Tuesday, April 16th at 11:00 am Eastern

This webinar will focus on lead optimization pharmacology and toxicology and a fail fast strategy that many companies are using. The advantages and disadvantages of incorporating safety and toxicology endpoints in pharmacology studies will be discussed along with case studies demonstrating their potential value.
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About Shawn Heidel, D.V.M., Ph.D.

Shawn Heidel, DVM, Ph.D. is the Executive Director, Lead Optimization Pharmacology & Toxicology at Covance Inc. Shawn Heidel has extensive experience in small and large molecule drug development, from early discovery to post-marketing. He spent 13 years with Eli Lilly and Company in various roles including eight years as a Director of Toxicology and lead of the Toxicology Project Leader and Study Monitor groups. Shawn has been a member of the BioSafe Leadership Committee for the last eight years and was elected as chair two years ago. He has been active in the ICH process as a member and signatory of ICHS6(R1) and as a current member of the ICHS1 Expert Working Group. His current role at Covance includes setting the strategic direction for the Lead Optimization Toxicology, Pathology, and Molecular and Anatomic Imaging groups.