Our ultimate success will be defined over the coming years, when we’ve produced transformative new medicines that can be delivered to patients more quickly and at a lower cost than the current paradigm.— Ronald A. DePinho, MD
For several years now, the American health-care system has been undergoing a transformation. Innovative ideas are being explored, new systems continue to be created, and millions of lives have been impacted. As health-care providers and research engines, academic institutions have an opportunity not only to push the frontiers of knowledge but also to test new organizational paradigms to drive those discoveries to new treatments for our patients.
At The University of Texas MD Anderson Cancer Center, starting in 2012, we made it a priority to address the challenges of the process of drug discovery and development, with a focus on reducing the 95% failure rate for drugs entering clinical trials and the enormous cost of the rare drug approval, which ultimately contributes to the overall price of drugs. A root-cause analysis of these failures pointed to several factors, including insufficient validation of targets; lack of rigorous preclinical testing of drugs in sophisticated model systems; poor coordination, communication, and handoffs among biologists, drug developers, and clinicians; and lack of strong responder hypotheses prior to entering the clinic and throughout the process of clinical development.
We identified silos within and across academic, industry, and clinical circles that are misaligned with long-term success and impede the transfer of information as projects move from the preclinical to clinical stage. We hypothesized that, through the integration of academic and industrial best practices, where projects are prioritized by clinical need and subject to stringent validation, it might be possible to vastly decrease inefficiencies within the system, yielding improved validation of drug targets earlier and at substantially reduced costs. We also would have the opportunity to better define precise responder subpopulations to inform the design of early-stage “killer” clinical trials, which would more efficiently facilitate clear outcomes.
Institute for Applied Cancer Science Established
To test our concept, we established the Institute for Applied Cancer Science (IACS). The platform, which is part of MD Anderson’s Cancer Moon Shots Program, fully integrates deep basic science and professional drug discovery capabilities directly with the world’s largest cancer clinical trials program and care enterprise at MD Anderson.
Our mission was to create an internal drug discovery program to identify high-quality clinical candidates aimed at unprecedented targets for both orphan indications and high unmet medical needs. Our prime focus is to deliver these molecules into successful early proof-of-concept phase Ib clinical trials informed by biologic and clinical insights to identify those patients most likely to benefit from specific therapies.
Although we started with an emphasis on small molecules, the MD Anderson Cancer Moon Shots Program added the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform, which expanded our capabilities to develop biologics, capitalizing on our exceptional scientific and clinical expertise in immunotherapy. Recognizing the limitation of an academic lab in conducting stringent preclinical validation, we also created the Center for Co-Clinical Trials (CCCT), a platform dedicated to the identification and rigorous validation of novel cancer drug targets. At CCCT, we use the latest breakthroughs in the development of integrated-omics technologies and functional, primarily in vivo, screening technologies, which take advantage of sophisticated genetically engineered mouse models of cancer as well as fully annotated patient-derived xenograft models.
New Model of Cancer Drug Development
This model of cancer drug development relies on rigorous integration of components along the drug discovery–development–clinical testing continuum to accelerate scientific breakthroughs, increase stringency in decision-making, and enhance operational agility by leveraging expertise and resources across our institution and national network. By reducing risk in truly transformative projects and using clinical and translational medicine early and throughout a molecule’s life cycle, we have the potential to substantially impact patient health and decrease drug costs.
In this model, this coordinated multidisciplinary approach required embedding a highly experienced team of professional drug discovery and development scientists to enable real-time access to the knowledge and insights of our leading cancer biology and genetics programs as well as our physician-scientists and clinicians leading patient-oriented research programs. These industry-seasoned professionals, numbering approximately 100, have collectively participated in the discovery of many drugs over their careers, with the leadership alone having more than 200 years of experience in drug development and 40 drugs developed under their watch. These professionals interact with MD Anderson’s critical mass of 1,700 accomplished faculty, which is supported by an approximately $800 million annual research budget focused on cancer.
On the issue of drug costs, although the past 2 to 3 years have witnessed an increase in the number of therapies being approved by the U.S. Food and Drug Administration (FDA), this has come at the expense of immense sunk costs. Several hundred agents have failed in clinical trials, culminating in a currently estimated $2.6 billion investment to bring a single new therapy to the marketplace.
To address this issue, objective decision-making lies at the heart of our philosophy, and a significant number of our drug discovery projects are discontinued early in their life cycles, when time and funding investments are lower. With a large number of projects during the past 5 years, we have calculated that an IACS lead clinical drug candidate costs 31 cents on the dollar relative to industry standards. Furthermore, armed with a strong clinical hypothesis, we anticipate that conducting early-stage “killer” clinical trials holds the potential for even greater savings incurred by costly late-stage clinical trials.
This model of integrated science–driven, clinically informed drug discovery has the potential to impact all stakeholders: pharmaceutical companies, payers, academic health-care entities, and patients. Drug developers would realize returns on their investments more quickly through a faster, science-driven FDA-approval process. Payers would benefit from decreased drug costs due to increased competition. Academic health-care entities will see value in investing in these efforts, as health-care expenditures become increasingly regulated and clinical reimbursements decline. And, most important, patients would realize gains through access to lifesaving drugs faster and, most likely, at lower costs.
All stakeholders must be involved in the solution, including policy makers who have an opportunity to impact the issue on many levels. Philanthropists also play an important role in making work like this a reality. Philanthropic support is critical in that it allows us to prioritize our portfolio based on science and clinical need, not commercial opportunity.
Defining Future Success
In less than 5 years, we have developed drugs that are now in clinical testing in lethal cancers. We’ve also expanded our capabilities by deepening integration within MD Anderson, feeding our pipeline and providing critical support to our academic and clinical colleagues, who are eager to understand whether their own research may hold clinical potential. Through extensive prioritization to select our projects, rigorous independent target validation, and objective assessments to ensure only the best projects move forward, we aim to detect early a large portion of the 95% of “doomed” projects that otherwise would move into late stages of drug development, typically costing more than $100 million for each phase III asset.
Our ultimate success will be defined over the coming years, when we’ve produced transformative new medicines that can be delivered to patients more quickly and at a lower cost than the current paradigm. In the end, we aim to develop drugs that will reach the marketplace and transform the lives of patients at MD Anderson and across the globe for generations to come. ■
Disclosure: Dr. DePinho reported no potential conflicts of interest.