Upcoming FDA-AACR-ASA Workshop to Examine Overall Survival in Oncology Clinical Trials 

Patients who receive a cancer diagnosis frequently wonder,” How long will I live?” What medical procedures will extend my life the longest ?& nbsp,

Although no one can accurately predict the outcomes of any given patient, doctors can make educated guesses about the potential efficacy of specific therapies based on the findings of clinical trials. In addition, & nbsp,

Overall survival has long been regarded as the gold standard for determining a therapy’s efficacy and safety in an ongoing clinical trial. It measures how long patients live after undergoing an intervention. However, this metric has grown more challenging to assess in recent years. & nbsp,

What causes this? And how can statisticians, regulators, and researchers collaborate to get past obstacles? & nbsp,

Stakeholders from across the drug development spectrum will come together for an upcoming workshop co-hosted by the American Association for Cancer Research ( AACR ), the U.S. Food and Drug Administration ( FDA ), and American Statistical Association( ASA ) to discuss the difficulties in determining overall survival in clinical trials and potential improvements to collection and analysis of this crucial endpoint. In addition, & nbsp,

On July 18, 2023, outside of Washington, D.C., and virtually for those unable to attend in person, will be the FDA-AACR-ASA Workshop: Overall Survival in Oncology Clinical Trials. & nbsp,

To learn more, we spoke with the chair of the workshop, FAACR Kenneth Anderson, MD, a researcher at Dana-Farber/Harvard Cancer Center, a professor of medicine at Harvard Medical School, and an oncologist at Brigham and Women’s Hospital. 

What purpose does overall survival serve? In addition, & nbsp,

Because the ultimate objective of cancer treatment is to extend the patient’s life, overall survival has historically been the preferred endpoint for clinical trials. Overall survival reveals not only the treatment’s effectiveness but also its safety because some treatment toxins have the potential to be fatal. The gold standard for researchers and regulators when evaluating an investigational therapy is whether it outperforms the current standard of care in terms of overall survival. In other words, do patients who receive the new therapy have a longer lifespan than those who do not? In addition, & nbsp,

What is the purpose of the FDA-AACR-ASA Workshop? & nbsp,

The workshop will bring together the entire community — including the FDA, biotech and pharma, clinical investigators and scientists represented by the AACR, statisticians, and patients — to discuss the problems with overall survival in clinical trials and address the numerous questions about how to measure it most effectively. In addition, & nbsp,

What is the best paradigm for creating and assessing novel agents in terms of the design of clinical trials and the use of overall survival, in particular? How should we approach evaluating overall survival in various patient subgroups, according to potential drug developers? When discussing the advantages and disadvantages of a novel treatment with patients, how can we consider overall survival and safety? What information about the usefulness of various metrics should we convey to the FDA? In addition, & nbsp,

What difficulties exist in determining overall survival in clinical trials? & nbsp,

Although new drug approval has historically been based on overall survival, its utility has become challenging in recent decades. Due to the remarkable advancements we &# 8217 have made in the treatment of many cancers, it simply takes too long to measure now. & nbsp,

More than ever, we have a better understanding of the diagnosis, prognosis, and treatment of cancer. The development of therapies that more precisely target cancer cells and spare healthy cells has resulted in better responses, fewer side effects, and longer overall survival in clinical trials as a result of the incredible bench-to-bedside translation and progress we’ve made. In fact, cancer is now a chronic illness in many patients, whether they have cancers that are inactive or have been successfully treated. Patients are also aging and passing away from other causes. & nbsp,

Surrogate endpoints are other metrics that, while they provide crucial data about drug efficacy in a shorter amount of time, have their own drawbacks and cannot truly replace general survival. The main surrogate endpoint that has been used thus far, progression-free survival, doesn’t always correspond with overall survival. In some cases, patients who received the study treatment outlived the control arm by a longer margin, but in larger trials, the overall survival rate was the same for both arms. & nbsp,

Minimal residual disease measures, which enable one to detect a single tumor cell in 100, 000, or one million healthy cells to evaluate the efficacy of therapy, may be the best surrogate markers currently being investigated. Although minimal residual disease has not yet been used for new drug approvals, it may be used in the future as a starting point to forecast progression-free or overall survival. & nbsp,

What subjects will be covered in the workshop? & nbsp,
 
There are five sessions in the workshop on various subjects. & nbsp,

The first discusses a variety of aspects of clinical trial design that could affect how overall survival is judged. Should we assign patients to the experimental and control treatment arms at random, for instance, or should we do so based on specific criteria? Should there be an equal number of patients in each treatment arm if patients are assigned at random? How do we evaluate overall survival in those circumstances when patients in the control arm may be allowed to” cross over” and receive the experimental treatment before the trial’s conclusion in some cases where it shows benefit? Do we permit the administration of a different therapy later in the course of therapy? How do we deal with negative events and their effects on overall survival, perhaps most importantly? Does maintaining overall survival give you the ability to spot long-term negative events that might not otherwise be noticed? & nbsp,

The trial was intended to measure overall survival when it &# 8217, a prespecified endpoint, is the focus of the second session. How do you prepare statistical power in these situations to have a reliable assessment of overall survival? Crossover from the control arm to the experimental arm and the effect of unfavorable events on overall survival are just a few of the problems I just mentioned that apply here. How do we also take into account the effect of subsequent treatments on the primary drug being tested’s overall survival assessment? & nbsp,

The third session talks about problems with overall survival when it &# 8217 isn’t a predetermined outcome. Because it involves carrying out analyses that were not originally planned when the trial was designed, this scenario may be even more challenging to manage. How much uncertainty should we plan for when conducting such analyses? When should these post hoc overall survival analyses be conducted? & nbsp,

The fourth session looks at how to assess the overall survival of various subgroups. Cancer has a wide range of symptoms. Clinical and genetic factors account for variations in outcomes between various cancer types as well as within the same cancer type. When determining overall survival, how should we approach this? In addition, & nbsp,

The last session looks at how overall survival affects the benefit-risk analysis of cancer treatment. How long does it take for us to have enough faith in a drug’s effectiveness and safety? What are the best ways to talk about overall survival when discussing the overall benefit-risk ratio of a particular therapy with one another or with patients? In addition, & nbsp,

To evaluate the overall advantages and risks of measuring overall survival at early or late timepoints, this session will also look at topics from the previous four sessions. Overall survival analyses’ benefit-risk ratios may vary depending on the type of cancer, the level of aggressive and indolent disease, or the size of the patient population. & nbsp,

What do you hope the workshop attendees leave with? & nbsp,

We hope that participants leave the workshop with a sense of the importance of overall survival and the knowledge of how to assess it effectively. The FDA has acknowledged that in order to move forward with new drug development and approvals at such a rapid pace, it is necessary to address the issues surrounding overall survival measures. I predict that the discussions and recommendations from this workshop will likely serve as the foundation for the FDA’s recommendations for new drug development in cancer. & nbsp,

I &# 8217, I’m honored to be speaking on behalf of the AACR and collaborating with researchers from the FDA, ASA, clinical, and biotech / pharma on this important subject. Most importantly, we have included patients in this workshop, and their presence and real-world experiences serve to serve as a constant reminder of the true meaning behind everything we do. & nbsp,

The FDA, AACR, and ASA Workshop on Overall Survival in Oncology Clinical Trials is available to the public and is free to attend. Sign up <a href="https://www.surveymonkey.com/r/OSWkshp2023″ target=”_blank” rel=”noreferrer noopener”>here. & nbsp,