The increasing role of toxicology in early decision making processes

Clinical development costs are rising at an alarming rate. There is a decreasing success rate for new drug candidate approval and the duration of development is increasing. In other words, industry is spending more and getting less from current drug development efforts. In 2010, 21 new drugs were approved in the U.S., the fewest since 2007, as the Food and Drug Administration showed more willingness to delay or reject medicines with potential safety risks1. Along these lines and according to a study conducted by the Biotechnology Industry Organisation and BioMedTracker, the success rate in bringing new drugs to market has fallen. The study looked at drugs moving from early stage Phase I clinical trials to Food and Drug Administration approval between 2004 and 2010. The researchers found that the overall success rate is about one in 10, down from one in five to one in six, seen in reports involving earlier years2.

Looking at these trends, it is obvious that pharmaceutical companies need to re-evaluate their strategies to make more effective and informed go/no-go decisions as early as possible, in order to reduce attrition rates and shorten drug development timescales. In this context, the increasing pressures on R&D productivity have identified early development as a key phase to sift through the available drug candidates to identify those with the potential to become ‘winners’ and to eliminate the ‘losers’ prior to any significant expenditure (‘fail early and cheap’). Toxicology is playing a pivotal role in this process, because the main causes for attrition during development are toxicity (nonhuman) and clinical safety3.

Looking in more detail at these failures, the following toxicological findings most frequently lead to the termination of a project:

• a narrow therapeutic window in relation to the intended indication or in connection with a potential for drug interactions
• critical findings such as genotoxicity, liver toxicity, cardiotoxicity
• the inability to clinically monitor certain toxicities

The possibility that toxicological findings may lead to late failures during drug development underlines the necessity for predictive tools which allow an early assessment of the potential liabilities of a new drug candidate. Cardiac toxicity (including arrhythmias), hepatic toxicity and CNS toxicities (neuropsychiatric effects, abuse liability, dependency) have been the leading reasons for drug withdrawals over the last decade. Strategies to reduce predictable toxicities are central to improving the quality and viability of new therapeutic agents.

To date, standard non-clinical toxicity studies remain the cornerstone of the prediction of toxicity in humans. However, new approaches as well as the refinement of existing methods are necessary to improve the prediction of potential side effects in humans. Various promising investigative approaches are currently being evaluated for potential screening purposes or use on a case-by-case basis following safety alerts in standard non-clinical toxicity studies. The hope is to find a few simple measures that will tell whether a drug is likely to cause serious side effects.

In this context, combined efforts between drug developers, regulators and academia are necessary to improve our current diagnostic methods. New and more sensitive diagnostic tools (‘biomarkers’) may facilitate the development of promising drug candidates that have the potential to address unmet medical needs but were previously thought to be ineligible for development because the current diagnostic tools fall short in their ability to detect early development of injuries in humans.

As an example, for many years, only serum creatinine and blood urea nitrogen were used to measure kidney damage and these two biomarkers are not very accurate, not very sensitive, and they indicate a possible kidney problem far too late. It is thus re-assuring to note that a group, called the Predictive Safety Testing Consortium (PSTC), has been successful in choosing a panel of novel biomarkers to predict kidney injury from experimental drugs. The unprecedented collaboration includes the U.S. Food and Drug Administration, the European Medicines Agency, and scientists from 17 pharmaceutical companies and academic researchers4.

Coming back to the high attrition rate of drug candidates during development and in particular during the preclinical phase, while it is the clear intention to eliminate the losers prior to any significant expenditure, there might be a significant number of potential drug candidates which fail during preclinical development due to toxicological findings in animals. The relevance of this for humans is not known but they cannot be tested safely in humans due to the lack of specific and sensitive mechanistic safety markers. What is needed is a broad panel of biomarkers that demonstrate that organ injury can be monitored at both the point where toxicity begins and when it reverses after withdrawal of treatment.

 The successful qualification of such biomarkers will encourage their adoption by pharmaceutical companies in non-GLP and GLP animal toxicology studies as well as in certain clinical trial settings. In non-GLP studies the biomarkers can support the selection of drug candidates or help to provide a better mechanistic understanding of drug-induced side effects. In GLP studies, the biomarkers can help in assessing the safety of drugs to provide support for translation of drugs into early human studies. In such a case, the biomarker would permit the development of a drug formerly not thought to be viable because of the inability of available tests to adequately detect and monitor early injuries in humans. For example, a drug development candidate may cause toxicity in animals, but the relevance for toxicity in humans is unknown. If a sponsor can provide preclinical evidence that the biomarker signal can detect early signs of injury when full reversibility upon cessation of the drug is possible, the progression of the drug candidate into human trials might be facilitated after careful evaluation of the risk/benefit ratio, in discussion with health authorities. In that case, the biomarkers would be carefully monitored in first-in-human studies, and appropriate actions could be taken on the basis of the biomarker signals and established decision thresholds.

One may ask why it takes so long for regulators and industry to agree upon standards for biomarkers. One explanation is the inadequacy of biomarker research and development. The literature is full of new potential biomarkers but too many of these studies lack sufficient rigor for translation into drug development. Too often, studies lack adequate description of the sampling, data generation or statistical analysis. But a larger part of the answer lies in the fact that cooperative relationships between regulators and drug companies are a relatively new development. Until the formation of FDA’s Critical Path Initiative, the Predictive Safety Testing Consortium (PSTC) and the Innovative Medicine Initiative which all have a clear mandate to address toxicity markers, industry had no framework to engineer cooperative initiatives.

As stated in the beginning, the increasing pressures on R&D productivity have identified early development as a key phase to make more effective and informed go/no-go decisions. This development is not surprising because in relation to the overall R&D expenditures, the costs are relatively low in this phase. On the other hand, there is an enormous potential to save costs by eliminating drug candidates which are not suited for development. Not only in this context, investments in the early development phase pay off very quickly. Importantly and based on new diagnostic tools, there might be the chance to develop drug candidates formerly thought not to be viable because of the inability of available tests to adequately detect and monitor early injuries in humans. The productivity crisis of R&D is expressed by a decreasing number of development candidates. While it may be difficult to find ways to numerically increase the output from research because the low hanging fruits are all gone there might be a chance to increase the number of development candidates successfully passing the preclinical phase by applying new technologies and diagnostic tools. In this context, Toxicology will even play a more important role than in the past.

References

 1. Larkin, Catherine (2010): New Drug Approvals Fall in 2010 as Safety Concerns Slow U.S. FDA Decisions, Bloomberg News (December 30, 2010)

2. Berkrot, Bill (2011): Success Rates for Experimental Drugs Fall: study, Reuters (February 14, 2011)

3. Federsel, Hans-Jürgen (2008): Handing Over the Baton: Connecting Medicinal Chemistry with Proccess R&D, Drug News Perspect. 21(4), 193-199

4. Dieterle, F. et al. (2010): Renal Biomarker Qualification Submission: A dialog between the FDA-EMEA and Predictive Safety Consortium, Nature Biotechnology 28, 455-462

About the Author

Eckhard von Keutz has held several positions at Bayer Healthcare since he joined the company in 1982, before being appointed Senior Vice President, Head of Global Early Development in 2007. He is a member of the European Society of Toxicology and Chairman of the Board of Trustees for the Fraunhofer Institute of Toxicology and Experimental Medicine.