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Due to a shifting landscape because of faster drug approvals, this article offers strategies for sponsors to design clinical trials.
The latest generation of oncology treatments is entering the market faster than ever before, owing much to the emergence of precision medicines and tumor immunotherapies.
This shifting landscape poses complex challenges for sponsors as they design clinical trials. For instance, what does a pharma company do if a competing drug is approved mid-development? Proactive drug developers can adapt by building flexibility into their clinical trial protocols. Below, we offer strategies based on our observations both closely watching and actively managing over 460 oncology clinical trials.
Among those excited about these new therapies is the U.S. Food and Drug Administration (FDA). Over the past several years, the federal agency has significantly quickened its pace for approving drugs, particularly for those that address an unmet need or confer a significant benefit. The first approval for an oncology product under the FDA’s Breakthrough Therapy designation, which can greatly reduce review times and overall time to market, was for ibrutinib in late 2013. The trend continued in 2014, with nearly all of the oncology drugs approved by the FDA falling under some type of expedited designation or status, such as Breakthrough Therapy, Priority Review, Fast Track, and Orphan Drug.
The very next year, the FDA approved 33 drugs in oncology, setting a record high. This brisk pace of approval has made a substantial impact on the standard of care, which has shifted frequently based on emerging clinical data. Practice guidelines for lung cancer, for example, have been revised five times this year alone, according to the National Comprehensive Cancer Network.
The accelerated approvals are taking place in part because the more recently sanctioned drugs create fewer harmful side effects. Patients are now able to receive more lines of therapy and investigators have more metrics available to determine clinical efficacy. As a result, the FDA has relaxed its view on endpoints to demonstrate a drug’s safety and effectiveness. The agency is now more open to embracing measures other than standard survival endpoints as indicators that a drug works and is safe in clinical trials. A non-small cell lung cancer drug, ceritinib, received approval based on Phase 2 trial results showing an overall response rate for more than half of patients over seven months.
Another accelerating factor is that the FDA has shown a willingness to approve based on single-arm cohorts of larger Phase 1 or Phase 2 trials. Durvalumab, for example, was approved based on a 182-patient single-arm bladder cancer cohort from a larger Phase 1/2 multi-arm trial.
Clinical trial design
In response to the FDA’s rapid approvals, pharma sponsors need to quickly generate enough evidence to satisfy FDA requirements. Innovative protocol designs are becoming more prominent in this regard. For example, one can conduct a “basket trial” that tests a new therapy across a variety of tumor types by enrolling patients based on their genetic mutations rather than tumor histology. This concept was validated via the FDA’s recent approval of pembrolizumab in microsatellite instability-high or mismatch repair deficient solid tumors. It was the first approval based on a common biomarker rather than the location in the body where the tumor originated.
In another innovative design, “umbrella trials” allow researchers to test multiple indications and combinations for a given therapy, with the potential to spin any arm off as its own registrational component. Each therapeutic arm is based on different molecular characteristics of the subjects’ cancers. These complex approaches are attractive because they link protocol design to personalized medicine approaches, making it possible to explore multiple indications with similar genotypes simultaneously and observe sizeable effects in small populations.
Although this strategy of using innovative, aggressive study designs speeds up clinical trials, there are risks and trade-offs involved. First, an overly complex clinical trial may not produce enough convincing statistics and require additional studies to demonstrate efficacy. Beyond that, these types of studies are likely to incur additional costs in trial implementation and burden for the clinical sites and their staff. Most importantly, patient safety should remain the number-one priority, so building appropriate safety measures into any clinical trial may save a lot of time with regulatory oversight.
How pharma community can adapt
A major challenge for sponsors planning clinical trials today is to keep up with the latest changes to the standard of care and anticipate future shifts to the competitive landscape while their trials are in progress. To increase their chances of success, sponsors need to design their clinical trial protocols with a degree of adaptability.
For example, sponsors can speed up patient recruitment by adjusting language describing inclusion/exclusion criteria to be less strict. This will allow them to cast a wider net and facilitate easier patient recruitment. However, the downside is that a more heterogeneous population may have ramifications for data quality and statistical efficacy.
In some indications, there is no single, accepted standard of care, or there may be a pending approval which could shift the standard. Therefore, in trials where a new drug is combined or compared with the existing standard of care, and that standard may change, researchers may elect to allow investigators to choose from a list of comparator drugs that have a similar mechanism of action. This decision needs to be considered carefully, as it too might have statistical and logistical implications. Such a move may affect trial timeline, especially if the approval of an agent in an indication does not rapidly become the new standard of care.
Depending on the stage of one’s clinical trial, sponsors might be able to complete crucial portions of the study while presuming the new therapy eventually will become generally available or reimbursed. Without definitive information to guide choices, sponsors can design protocols knowing that changes are likely to take place. Sponsors prefer to avoid making cost- and time-intensive critical amendments to their protocols, but such changes are sometimes necessary and must be used judiciously.
Finally, many drug developers are adding multiple arms to their trials. Novella Clinical recently worked with a sponsor that added an arm to study its drug candidate as a second-line of therapy after noticing a competitor was closer to first-line approval. This strategy took advantage of a potential gap in treatment options, removing the chance of directly competing for a rare patient population and speeding the potential time-to-market as approved second-line therapies are minimal. It also left the window open to compete head-to-head against the first-line therapy later.
The future is promising
are being developed and over 10,000 cancer clinical trials are underway in the United States. To bring new cancer therapies to market successfully, many pharma companies benefit from the insight and guidance provided by an oncology-focused clinical research organization that understands the space and its nuances. Despite a competitive and ever-evolving landscape, this is an exciting time for pharma companies to do their part in advancing therapies that will shape the course of cancer treatment for years to come.
How pharma can adapt
To design flexible clinical trials that adapt to shifting standards of care, pharma sponsors can:
Use innovative trial designs
Adjust inclusion/exclusion criteria
Allow investigator’s choice
Plan for critical amendments
Add multiple arms
Andrew Zupnick, PhD, is Vice President, Oncology Strategy, with Novella Clinical.