Data Must Be Generated to Support Cross-Labeling of Combination Therapies for Cancer
Combinations of targeted therapies (triple, quadruple, or even more) are part of the future of cancer treatment, which means that traditional clinical trials will have to be streamlined and updated to enable greater flexibility and to extract adequate safety and efficacy data. Problems inherent in clinical trial designs for this purpose were discussed by a panel at the 2017 Friends of Cancer Research Annual Meeting.
Roger D. Dansey, MD
As multiple-drug combinations become more the norm in cancer treatment, regulatory and legal issues arise; primary among them is how to list information about all components of a combination, known as cross-labeling. To complicate matters, components often include monotherapies developed by different sponsors, sometimes with market exclusivity or patent protection.
Roger D. Dansey, MD, Senior Vice President, Clinical Research-Oncology, Merck, said that although drug labels are not the only source of information for prescribing physicians, inadequate cross-labeling may limit the amount of product information a physician has, and thus negatively affect patient care.
Kenneth C. Anderson, MD, Kraft Family Professor of Medicine, Harvard Medical School, added that one of the goals of the panel was to develop a framework that informs a level of evidence appropriate for combination therapies by identifying alternative trial designs to generate data and to suggest regulatory modifications in the labeling of combinations—without compromising U.S. Food and Drug Administration (FDA) standards.
Such a framework could help sponsors streamline trials to identify the contribution of each drug in a combination while minimizing data redundancy, as well as keeping the number of patients required for each trial as low as possible.
With a greater number of and more diverse components in future combinations, clinical trials will require increasingly complex designs, more arms, and more patients. Moreover, both sponsors and regulators will have to balance the level of evidence required for approval with speed of development, especially for therapies designated as breakthroughs and headed for accelerated approval.
Revamping and modernizing clinical trial design can confer significant advantages:
- Identifying the contribution of each therapy in a combination while avoiding large randomized controlled trials allows quick advancement to phase III.
- Adding multiple specified time points in a trial to evaluate the contribution of each drug is especially valuable in immuno-oncology.
- Redundancy in data generation can be minimized. Of the 30 most recent oncology therapies to receive accelerated approval, more than half were based on results from single-arm trials.
- Using real-world evidence enhances safety and efficacy data—within certain parameters.
- Using surrogate endpoints can shorten trials, thus reducing the need for overall survival as the only acceptable endpoint. Many novel therapies extend survival to such an extent that it is difficult to measure.
However, as increasing numbers and complexity of combination therapies affect the extent of achievable innovation, the assessment of value and side effects will become more difficult.
Trial Designs for Combinations
Jim Omel, MD, a cancer research advocate and long-time survivor of multiple myeloma, compared various trial designs, all of which have advantages and disadvantages.
[Trials of drug combinations] will have to balance speed with level of evidence and create innovative ways to assess the contribution of components in combination.— Kenneth C. Anderson, MD
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A basket trial is good for matching patients with rare mutations to targeted gene therapies. It compares the efficacy of several drugs simultaneously. But measurement of genotype status does not account for change in tumor composition over time. Trials become increasingly complex as arms are added, and the effect of a mutation in different tumor types can be overlooked.
An umbrella trial tests multiple drugs in a single cancer type and targets patients to the most appropriate therapy based on specific molecular aberrations. Again, measurement of genotype status is static and does not account for change in tumor composition over time. As arms are added, complexity increases.
A common control trial reduces recruitment by comparing several arms to a single control. Its main advantage is speed, but it can be difficult to determine an appropriate control arm that is suitable for all the investigational arms.
An adaptive trial speeds the process by approving modification protocols before the trial starts, and interim analyses provide flexibility to adapt the trial in real time and respond to unexpected events. However, adaptations or trial decisions based on highly uncertain data early in patient accrual can lead to erroneous conclusions, and frequent interim analyses may jeopardize the trial’s integrity.
Friends of Cancer Research White Paper: FRAMEWORK TO GUIDE APPROVAL OF SUPPLEMENTAL NEW DRUG APPLICATIONS
A framework to streamline the approach and expedite approval of a supplemental new drug application should take the following factors into consideration:
- Unmet clinical need
- Rarity of the disease and the feasibility of accruing enough patients for a randomized controlled trial
- Existence of early data or strong justification suggesting that a randomized controlled trial for the supplemental indication may lack equipoise
- Disease etiology, epidemiology, molecular profile, evolution, and mechanisms of resistance
- Relationship of the supplemental indication to the original
- Drug mechanism of action, pharmacokinetics, and pharmacodynamics and the ways they perform similarly in different cancer types
- Possible dose and regimen changes for the new indication
- Adverse events and safety management derived from randomized controlled trials
- Outcomes that compare the drug with the standard of care
- Magnitude of benefit vis-à-vis risk
- Contribution of each component in a combination to efficacy, safety, and outcomes
- Reliability of an intermediate endpoint and sufficiency of proof of clinical benefit
- Availability of established and reliable diagnostics for targeted therapies
Dr. Omel also compared modifications among arms in trials for combination therapies. “An add-on trial streamlines the process by requiring patients to stop current treatments,” he explained. “But the possibility of drug resistance must be considered during the first phase before adding a second therapy. It is difficult to select the best endpoint to demonstrate benefits and risks in the various trial phases.”
He continued, “A parallel trial allows direct comparison of multiple therapies for combinations vs individual components—or in different cancers. It may, however, require additional investigational arms and more patients.”
Whatever trial design is used, said Dr. Anderson, its complexity will require more arms and more patients. “It will have to balance speed with level of evidence and create innovative ways to assess the contribution of components in combination.”
Master Protocols in Cancer
Adaptive trial designs, such as umbrella and basket trials, are innovative and may be the wave of the future. The panel discussed several of these designs.
- Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) was an umbrella trial that used adaptive randomization to assign patients with a single cancer type, advanced non–small cell lung cancer, to a trial arm for a targeted therapy based on the presence of one of several tumor biomarkers. Completion of the trial signaled a pivotal shift to innovation in streamlining clinical trials.
- The Lung Master Protocol (LUNG-MAP) minimizes patient screening and accruals in trials in advanced squamous cell lung cancer. It assigns patients to trial arms based on biomarkers, but the arms are more diverse than in BATTLE and include drugs of different manufacturers or an immunotherapy for patients with unmatched biomarkers. The trial established a master protocol that minimizes patient attrition at screening.
- National Cancer Institute–Molecular Analysis for Therapy Choice (NCI-MATCH) is a basket trial that studies targeted therapies in patients with specific biomarkers whose cancers have progressed or did not respond to standard treatment. It streamlines trials by assessing treatment efficacy in patients with diverse cancer types that share a biomarker.
No matter how streamlined clinical trials become, FDA still requires essential components for the label. “Labels are designed to inform—mainly clinicians but also patients to a lesser extent,” said Dr. Anderson. “They identify safety and efficacy data, of course, but they also encompass regulatory modifications and provide marketing data.”
Cross-labeling of new combinations that expand existing indications is particularly problematic. Dr. Dansey said that combination trials with results sufficient to support labeling of one component of the combination should support labeling for the other -components.
Regulations already mandate that a sponsor must update labels when new safety and efficacy information becomes available, but a framework or guideline is needed for cross-labeling in combination therapies, which includes:
- Standards for the type and level of evidence necessary
- When new information for patient care must be added
- Expansion of indications for marketing purposes
- New safety information
- Countries where the label is used for reimbursement determination.
Currently, the drug sponsor is legally responsible for maintaining and updating the label, but one sponsor may not have access to the proprietary data belonging to another sponsor of a drug in combination. The mechanism to obtain these data is cumbersome enough to discourage some not to go through the process.
Standard of Care as a Trial Arm
Standard of care has been used as the control arm in randomized controlled trials, but this may no longer be appropriate or ethical. Standard of care can easily change in less time than it takes for the trial and regulatory approval process to be completed—on average, 8 years in oncology. If the standard of care for an indication changes during this process, use of the investigational drug may no longer be appropriate for the trial population. In that event, an entirely different patient population would have to be recruited.
Moreover, oncologists may disagree about what constitutes standard of care. When there is great disparity, comparisons with standard of care, as well as trial accrual, create discord between practice and research. Dr. Anderson noted that historical data could have a stronger role in trials, especially regarding surrogate endpoints such as progression-free survival. ■
DISCLOSURE: Drs. Dansey, Anderson, and Omel reported no conflicts of interest.
- Moderator: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Harvard Medical School
- Roger D. Dansey, MD, Merck
- Ann T. Farrell, MD, U.S. Food and Drug Administration (FDA)
- James Myers, FDA
- Jim Omel, MD, Cancer Research Advocate
- Marc J. Scheineson, Esq, Alston & Bird LLP
* For the 2017 Friends of Cancer Research Annual Meeting session, “Data Generation to Support Cross-Labeling of Indications for Combination Products.”