Cancer Drug Co-Development Roundtable at Ohio State University May 4th 2011

On Wednesday May 4th, a Cancer Drug Development Roundtable took place at the Ohio State University Comprehensive Cancer Center. The roundtable consisted of high-level stakeholders and the topic was the co-development of two or more experimental drugs for cancer treatment. The objective of the Cancer Drug Development Roundtable was to set up a framework of recommendations for the FDA that address the current hurdles for co-drug development for the industry. The recommendations will be revealed later this year, but the broad long-term goal is to bring novel and more effective cancer treatments to patients faster and with more efficiency.

SLIDESHOW

Cancer Drug Development Roundtable at Ohio State

The Ohio State University Comprehensive Cancer Center –  Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Friends of Cancer Research gathered Janet Woodcock (Director, Center for Drug Evaluation and Research (CDER), FDA); Jim Doroshow (Director of the Division of Cancer Treatment and Diagnosis at the NCI; Ellen Sigal, (Chair and Founder, Friends of Cancer Research); and Eric Rubin, (Vice President, Oncology Clinical Research, Merck) and asked each to present their view on the co-development process. For the rest of the day, the working group participants were engaged in a closed session to carve out recommendations for the FDA. Dr. Caligiuri and Ellen Sigal were the co-hosts for the event.  Dr. Robert Brueggemeier, (Dean, College of Pharmacy at Ohio State) was the moderator for the Q&A portion of the public session.

The Background
The FDA is in the process of revamping its regulations for drug development. The focus is specifically on the co-development of two or more distinct investigational drugs intended to be used in combination, but not in fixed-dose combinations.

Currently, the only way to combine two treatments is after each has been approved by the FDA: Combining two experimental treatments in clinical trials is not allowed under the current U.S. regulatory framework. This slows and thwarts our knowledge on how to best approach cancer treatment and progress in the treatments available for cancer patients.

As we outlined in “An FDA Perspective on Developing Novel Combination Therapies” published on this site on March 23, 2011, the U.S. Food and Drug Administration (FDA) first requested public comments on the co-development of investigational drugs.

The FDA specifically requested comments on both the methodology and regulatory issues that arise when developing investigational drugs in combination, particularly for oncology and other therapeutic areas in which co-development is more likely to occur. Next, the FDA released the “Guidance for Industry Co-development of Two or More Unmarketed Investigational Drugs for Use in Combination” in December 2010. The guidance is to ensure that regulatory expectations are transparent and provides recommendations on preclinical testing, safety, pharmacology studies, and phase 1 through 3 efficacy studies for co-development. Importantly, the guide carves out the type and amount of data that the FDA requires to demonstrate the contribution of each drug to the overall efficacy of the combination. The result is a road map for co-development for appropriate therapeutic categories. However, non-clinic and lab hurdles like legal, liability, business, and intellectual property issues were not examined in detail.

The impetus for the new guidance is the idea that the current oncology research and patient treatment data show that combination therapies for cancer will be more efficacious in destabilizing tumor growth. Cancer is complex, and most patients see at least two types of treatment in their course of therapy. Some of the latest cancer treatments being developed are targeted therapies that often lead to resistance as redundant or alternative pathways are activated due to selective pressure from targeted agent exposure. This is why it is becoming more and more apparent that combination therapies for cancer will be more efficacious in destabilizing tumor growth.

New drug development has historically been pursued linearly, one agent at a time.  Add-on clinical trials have been used to test the efficacy of combination treatments in which a standard regimen plus a new drug is compared to the standard regimen alone. “Successful development of future targeted therapies will require modernizing this paradigm to provide the flexibility needed to rapidly evaluate combination regimens involving new targeted agents in a single development program.” Stated Janet Woodcock, the head of the CDER stated in her March, 2011 NEJM perspective.

Uncertainties Ahead
One caveat of co-development is the lack of full characterization of the effect of a single drug component, resulting in less information on both safety and efficacy. Janet Woodcock previously stressed that co-development should be used only for treatment of life-threatening disease for which there is no satisfactory standard of care and stressed the FDA’s commitment to safety.  Co-development will likely mean increased collaboration, increased private-private and private-public partnerships. How these relationships will play out between two private drug developers remains uncertain.

The Public Session at Ohio State
Each speaker highlighted the overall goal of the co-development program, which is to be able to bring better treatment to cancer patients.  Janet Woodcock spoke about recent progress of the targeted therapy approach to cancer with the major hope of successful treatment lying in combination treatments. She emphasized the need for predictability in treatment developments and testing agents in well-developed assays before exposing patients in first in-human trials. Dr. Woodcock also gave drug developers and researchers an agenda for better understanding the mechanisms of toxicity of new agents in order to have a more "systems" perspective of treatments.

Her presentation emphasized the many aspects of development that are currently lacking: a lack of classification assays to identify subpopulations of patients and a lack of pharmacodynamic assays for many agents. In terms of logistics, Dr. Woodcock acknowledged that ongoing trials need to have agents fed into them rather than having a single agent as the center of a trial. Two other major barriers that the new guidance will aim to overcome are competition between pharmaceutical companies in co-developing two agents as well as the regulation hurdle. She reassured the audience that the FDA is indeed supporting the need for innovative combination treatments and new roads to attain these treatments. She noted that regulation “is usually at the top of everyone’s list [of hurdles], but this shouldn’t be the case.”

Dr. Woodcock made a call for early adopters of the yet-unofficial co-development program. “The future is really bright, despite the barriers,” she stated.

The Director of the Division of Cancer Treatment and Diagnosis at the NCI, Dr. Doroshow began his presentation by listing the challenges to developing combination targeted treatments. He saw the following as the major co-development challenges: 1) incomplete understanding of mechanisms of action for targeted agents, 2) the inability to assess target effects, 3) a lack of preclinical models for combination, 4) questions about which clinical trial methodologies to apply to such a trial and 5) the intellectual property (IP) and regulatory challenges of novel combination developments.

Emphasizing the progress that has been made in these areas, Dr. Doroshow spoke about the developments at the NCI to facilitate the identification of promising cancer treatment combinations, including the development of novel assays that are to be in the public domain as well as biomarker assays.  Even if an assay is well-developed within a laboratory, a major hurdle in identifying responder subpopulations is the translation of an assay from the laboratory to a patient setting.  He also discussed the hurdles of access to compounds for doing combination research in the lab. As a first step, the NCI has created a way to test, in an automated fashion, all possible commercial compounds that the research institute is providing to research laboratories at no cost. The platform is a “Combo Plate” of 87 compounds with diverse mechanisms of action that is “intended to enable cancer research, drug discovery and combination drug studies”.

A major point of apprehension from a drug developer’s perspective is IP. The guidance will need a way to allow two companies and an investigator to come together to develop a licensing strategy. The NCI may very well be the mediator in these two-company combination trials.

A representative from the pharmaceutical industry, Dr. Eric Rubin from Merck discussed the company's approach to the “combination problem”.  He presented the resonating scenario of 10 novel compounds that would require 45 trials to test all two-drug combinations. Under our current, linear drug development system, this would require 90 years to complete. Dr. Rubin’s solution is to identify the most promising combinations from pre-clinical studies and to combine these early in the clinic. Dr. Rubin spoke about Merck’s new branch-adaptive trial approach including involvement in the BATTLE lung cancer and I-SPY breast cancer clinical trials.

Finally, Dr. Michael Caligiuri commended Dr. Woodcock for the bold initiative of the draft co-development guidance. He listed questions that the panel would discuss in its closed session. How do we define rules for intellectual property, pricing, profiting, and rights to commercialization for drug co-development? An integral part of the guidance will have to be a way to prevent a drug developer from being penalized in its single-compound or other combination development when one particular combination trial fails. Drug companies may be hesitant to venture into a co-development agreement due to the real or perceived higher risk of adverse outcomes that may accompany such a trial. Better and thorough pre-clinical research and subpopulation targeting via molecular marker assays, however, should result in sound rationale for combination trial execution that each panel speaker stressed in their presentation.

Finally, Dr. Caligiuri raised the important question of the responsible party for financing biological mechanisms of a combination treatment. One solution may be NCI as a mediator in trial execution and a link between each collaborator, as highlighted in Dr. Doroshow’s presentation. He also stressed the utility of comprehensive cancer centers and academic institutions of bringing drug developers together and addressing their IP issues and facilitating pre-clinical research.

The panel of speakers had more questions than answers. The one certainty, it seems, is forward movement by key regulators, clinicians, and researchers. The major stakeholders here have acknowledged that rigorous science and sound rationale must be the foundation for combination treatments if they are to come about with more efficiency and provide better options for patients. Stay tuned for the full FDA guidance later on this year.