Is Safety a Strategy in Cancer Drug Development?

The ASCO meeting led me to a number of general themes but my attempt to summarize turned into a novella. Since we are in this endeavor to help patients, I decided to write about a patient-centric issue: quality of life for patients being treated with cancer. Given that I am on the business end, I reframed the issue to ask whether safety could be a competitive advantage in oncology drug development.

In oncology drug development, could a differentiation strategy rely on the ability to distinguish two drugs that provide similar overall survival by their side effect profile? Under CFR 312.84, the FDA will consider “whether the benefits of the drug outweigh the known and potential risks of the drug”. Going after a safety benefit is risky, including the unknowns of what measures will the FDA accept in determining which drug has a “better” risk:benefit ratio. However, the search for surrogate markers and assays to evaluate target presence/inhibition are also proving to be less straightforward than anticipated.

One of the interesting posters (6044) was essentially a market research study of breast cancer patients. The authors surveyed the patients on their preferred option (treatment vs. no treatment) for a variety of hypothetical drugs with defined likelihood of benefit and side effect. While potential benefit was more powerful,  patient decisions about treatment were impacted by the probability of side effects. The authors found a variety of factors, including age and the presence of children under the age of 12, impacted acceptance of side effects. The specific type of side effect, such as fatigue vs. heart toxicity, was also important. The development of predictive markers for side effects of cancer drugs would provide patients with tools they may use to guide their treatment decisions.

Continuing the theme of safety biomarkers, a genome-wide association study (1000) of breast cancer patients was presented. The authors were looking for markers related to neuropathy (nerve damage), a side effect reported for many cancer drugs such as paclitaxel, which was evaluated in this study. Two genetic variations were found to be associated with a higher risk of neuropathy. While this work is still early, the discovery of specific biomarkers that impact patient safety could greatly impact treatment regimens. The genetic safety markers that I am aware of in oncology (UGT1A1 and irinotecan, CYP2D6 and tamoxifen, and TPMT and thiopurine drugs) are associated with drug metabolism and thus the safety and efficacy are linked.

Another poster (6102) that caught my eye was a study looking at the use of Health-Related Quality of Life (HRQoL) as an endpoint in Phase III randomized controlled clinical trials. I recently heard a talk on methods to understand QoL during clinical trials. One of the things that struck me is that to have a good survey/questionnaire by Phase III, you really need to have tested the measures and evaluated the data from earlier stage trials. Perhaps this need to start early was part of the reason these authors found that this area needs significant improvement in oncology.

A few posters (9096, 3634) were presented using the EQ-5D survey from EurQol, a network of researchers in Europe. The tool is general but seems be widely used in oncology. Five areas are evaluated:  mobility, self-care, usual activities, pain/discomfort and anxiety/depression. In addition to the clinical information, EQ-5D also provides a valuation model that can be used in comparative effectiveness research. An interesting talk at ASCO by David Cella on using patient reported outcomes to measure toxicity in clinical trials may provide another option. One of the topics he discussed was the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) being developed by Dr. Basch at Memorial Sloan Kettering. Eighty one symptoms in the CTCAE, which is already standard for reporting adverse events, have been identified for patients to report. While PRO-CTCAE doesn’t appear to incorporate the value component in EQ-5D, the similarity to the CTCAE could provide an advantage in uptake of the instrument.

At a time when pressure for differentiation of products in biotechnology is mounting, distinguishing drugs with similar overall survival by their side effect profile may be a viable opportunity in cancer drug development.