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How precision medicine, immunotherapy are influencing clinical trial design for cancer drugs

As treatments target increasingly specific disease states, clinical trial design must evolve to generate enough data from relatively small sample populations

Newfound understanding of the biology of cancer has spurred a wave of oncology drug approvals, creating previously unheard of treatment success. At the same time, this degree of success leads to a rapidly shifting competitive landscape, presenting unique challenges for pharma companies planning cancer clinical trials. What steps can the pharma community take to remain flexible and responsive in this new Golden Age of smarter therapies?

An accelerated pace of approvals

Oncology research and improvements in technology have ushered in a new era of more targeted therapeutics based on the mechanisms that drive cancer. Technological advances in tumor imaging and next-generation sequencing have sped the development of precision medicines, treatments that target specific genetic markers rather than relying purely on cytotoxicity. The decreased cost of analysis has led to increased accessibility of genetic data, allowing leading cancer hospitals to use NGS to guide treatment decisions for new cancer patients based on their cancer’s specific genetic makeup. In addition, the field is seeing tremendous strides in immunotherapy approaches, which seek to activate the immune system to defeat cancer cells.

In response to the early success of precision medicines and immunotherapies, the U.S. Food and Drug Administration is approving drugs faster and more frequently. In 2014, all but one oncology drug approved by the FDA received some form of expedited designation. By the following year, more oncology drugs were approved by the FDA than ever before.

The rapid pace of new drug approvals has, in turn, increased the pace of changes to the standard of care, now determined as much by biomarkers as by histology. New data continues to shape the current clinical practice guidelines. The National Comprehensive Cancer Network has updated guidelines for lung cancer five times since they were first issued in late 2016.

The impact on pharma

The accelerated pace of drug approvals for cancer has created a flurry of activity in the pharma community. As of 2014, there were nearly 800 cancer drugs in development. and in 2017 more than 12,000 active cancer clinical trials. Looking just at the field of immuno-oncology and checkpoint inhibitors, which have exploded onto the market in recent years, there are over 750 active studies with checkpoint combinations today. Conducting cancer clinical trials has always been complex, but planning successful clinical trials amid a rapidly shifting oncology landscape presents unique challenges for pharma sponsors.

To provide useful results, clinical trials should use the highest standard of approved care for their participants, but the standard of care in oncology is constantly shifting. As treatments target increasingly specific disease states, clinical trial design must evolve to generate enough data from relatively small sample populations. In an increasingly competitive space, pharma sponsors are tasked with finding the quickest ways to gather safety and efficacy data that satisfies FDA requirements.

Now more than ever, the pharma community must become flexible and responsive to a rapidly changing marketplace. Although sponsors can attempt to anticipate future treatment approvals and incorporate them into statistical models, there is a limit to how far into the future they are able to forecast. Sponsors may, therefore, wish to consider the following ways to design their clinical trial protocols with a degree of adaptability to have the greatest chance of success.

Adjust inclusion/exclusion criteria 

In order to recruit patients more quickly, sponsors can adjust the inclusion/exclusion criteria to be less strict. However, this approach may yield a heterogeneous population, which might have an undesired effect on data quality and statistical efficacy.

Allow investigators choice

For trials that combine or compare an investigational drug with the existing standard of care that is likely to change, sponsors may need to consider letting investigators choose from a menu of comparators. The statistical and logistic implications, as well as the timeline, are important to consider.

Plan for critical amendments 

Portions of a clinical trial can be completed before a new therapy is generally available or reimbursed. Although making changes to the protocol during the course of a clinical study are generally not desired because of added time and cost, there are certain cases where making critical amendments is necessary.

If first-line approval for a drug is already being pursued, sponsors can take advantage of a gap in therapeutic options by adding another arm to their trials that demonstrate effectiveness as a second-line therapy.

Use innovative trial designs 

Changes to protocol designs are also influencing how quickly enough evidence can be generated for the FDA to grant approval. Two innovative new designs are “basket trials” and “umbrella trials.” In a basket trial, patients are recruited based on the genetic makeup of their tumor rather than tumor histology. The recent FDA approval of pembrolizumab was the first approval based on a common biomarker rather than the location in the body where the tumor originated. 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.

It’s an exciting time to be in cancer research and to watch some of these therapies move rapidly from clinic to improving the lives of patients. Sponsors play an important role during development by spearheading innovation, staying flexible, and planning accordingly for the rapid pace.

Photo: DrAfter123, Getty Images

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