Editor's note: Last week, BioWorld Insight examined efforts to improve the efficiency of cancer trials and cited promising examples of adaptive design. In part II, we examine the business, cultural and regulatory challenges to adaptive design in cancer trials.

Frustration borne from thousands of failed clinical trials and the approval of fewer than five dozen new cancer drugs since 2000 – eight of them just last year – is leading to a revolution in designing cancer trials. Two of those protocols, the I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2) trial conducted by Puma Biotechnology Inc., of Los Angeles, and the newly launched public-private collaboration called Lung-MAP, are designed to improve the efficiency of cancer trials, potentially moving therapeutic candidates through the pipeline more quickly and cost-effectively.

But industry experts caution that adaptive design, while the newcomer in cancer trials, will not answer every question or address every need. Breaking through decades of competition and mistrust in the biopharma industry requires the writing of new rules, and not every organization is positioned to be an early adopter.

Seeking orphan drug designation is an existing route to new drug approval and an option for biotechs and big pharmas to consider for cancer compounds, suggested Joshua Cohen, senior research fellow and research assistant professor at the Tufts Center for the Study of Drug Development (CSDD), who studies patient access to approved biopharmaceuticals. The tactic enabled approval of some early cancer drugs, such as Gleevec (imatinib, Novartis AG), which initially was approved to treat patients with chronic myeloid leukemia in the accelerated phase of blast crisis or in chronic phase after failure of interferon-alpha treatment. More than a decade later, the drug is approved to treat many cancers, following the time-tested strategy to expand rare disease therapies into larger populations following initial approval, and gaining wider therapeutic value and a bigger payoff. (See BioWorld Today, July 16, 2014.)

The orphan drug strategy has been used sparingly in cancer, Cohen said, but is worth considering – maybe even more so – as scientific evidence shows that many types of cancer resemble rare diseases. Moreover, payers – at least in the U.S. – are effectively obligated to add cancer drugs to their formularies.

"Companies are more focused on cancer research and getting drugs to market than they were a decade or so ago," Cohen told BioWorld Insight. "Payers have responded to the influx of new, relatively high-priced cancer drugs with increased patient cost-sharing and conditions of reimbursement, such as prior authorization. Yet, few if any new cancer drugs are denied coverage in the U.S. This is partly due to state and federal legislation which protects most cancer drugs from being excluded from formularies."

'EXPLOSION OF OPENNESS TO SHARE PRE-COMPETITIVE DATA'

Still, pursuing the orphan drug pathway, or the even newer breakthrough therapy designation, remains a one-off approach that probably won't change the trajectory of cancer drug approvals.

"Cancer drug development has moved slowly because of the complexity of the genome and the fact that no two cancer tumors on the same organ site are the same," explained Roy Herbst, professor of medicine, chief of medical oncology and associate director for translational research at the Yale Cancer Center, who is helping to spearhead the groundbreaking multidrug, multisubstudy, biomarker-driven squamous cell lung cancer Lung-MAP study (SWOG S1400). Now, he added, "we're breaking up the pie and we're identifying the areas for special studies. Addressing genomic complexity is the key to increasing progress."

Kenneth Getz, director of sponsored programs at the Tufts CSDD and chairman of the nonprofit Center for Information and Study on Clinical Research, or CISCRP, said "the real revolution is occurring in the explosion of openness to share pre-competitive data and to leverage talent wherever it can be found around the world." Although many of those interactions are virtual, through online data-sharing, efforts to assemble physical collaborations that encompass a range of partners are catching on.

"Cancer research has driven a wide range of innovative technologies over the years," Getz told BioWorld Insight, and many of those platforms will help to accelerate drug development. "But what's most remarkable is the way that organizations – both public and private – are interacting and sharing that information."

That openness – the willingness of biopharmas to allow experts even from potential competitors to "peek under the hood" – signals a major change from the industry's standard operating procedure, Getz said.

Lung-MAP is an important early example of how a private-public partnership can take a unified approach to solve a complex thesis, agreed Bill Chin, executive vice president of scientific and regulatory affairs at the Pharmaceutical Research and Manufacturers of America (PhRMA). He also cited Project Data Sphere, an initiative that rolled out earlier this year as a platform to share, integrate and analyze comparator arms of historical cancer trial data sets.

"Historically, because of regulatory and other constraints, cancer medicines and other medicines were always found as single entities," Chin observed. "It was only after the fact that developers learned that putting medicine A and medicine B together produced something better than either one on its own. Lung-MAP, which focuses on adding a number of investigational agents on top of standard chemotherapy to learn which combinations might be better than either agent alone, is extremely exciting."

WITH CANCER, 'YOU HAVE TO TAKE SMART RISKS'

Obviously, a key benefit of successful collaboration in adaptive trials, especially major initiatives such as Lung-MAP, is the opportunity to share the high cost and failure rate of cancer drug development by leveraging knowledge and resources across the industry.

"Pharmaceutical companies no longer have deep enough pockets to go it alone," Getz pointed out. "They need to find ways to spread the innovation risk by engaging a broader community of organizations that all have vested interests in the success of a given new treatment."

Often, the level of risk drug developers are willing to bear is directly proportionate to the severity of the indication. With fatal illnesses like cancer, "you have to take smart risks," said Bahija Jallal, who heads Medimmune, a unit of London-based Astrazeneca plc. "When you're dealing with a disease with high unmet medical need, that's almost an obligation. People are dying from certain cancers, so it behooves us to do something."

Gaining cooperation among stakeholders with competing interests isn't a walk in the park, however.

Lung-MAP "certainly has taught me about leadership and how to build an organization," Herbst said, acknowledging that every company participating in the trial has internal priorities and development goals. "But when the common principle is helping the patient with cancer, that's a laudable goal and a pretty good glue."

In fact, companies, increasingly, are partnering directly with patients and advocacy groups and soliciting feedback about whether to revisit candidates that failed earlier trials in other indications or how to gauge troubling side effects as a mitigating factor in clinical trials participation.

"Patients have probably the greatest vested interests of all," Getz said.

But experts caution against relying too heavily on the patient perspective in designing cancer trials, even using adaptive approaches. Feedback is one thing, but scientific rigor is imperative. The FDA has cast a wary eye at clinical trials with muddled designs, even when patients plead for approval. A classic example of that stance was the tivozanib debacle, which saw a drug with promising potential in multiple cancer indications crash and burn largely due to flawed trial design.

When the drug, developed by Aveo Oncology Inc., of Cambridge, Mass., came before the FDA's Oncologic Drugs Advisory Committee last year, members voted 13-1 against approval despite moving testimony from patients about the need for more options to treat advanced kidney cancer. At the time, Richard Pazdur, director of the FDA's Office of Hematology & Oncology Products, sympathized with the community's desire for new therapies but said the agency can't approve a drug because of "wild enthusiasm not based on data." (See BioWorld Today, May 3, 2013.)

Aveo's new drug application for tivozanib subsequently received a complete response letter and the company halted the kidney cancer program. The VEGF receptor tyrosine kinase inhibitor later failed a phase II study in colorectal cancer, prompting a split from pharma partner Astellas Pharma Inc., of Tokyo. (See BioWorld Today, June 11, 2013, Dec. 16, 2013, and Feb. 18, 2014.)

Even with well-designed studies, patients – and advocacy organizations, for that matter – should never assume that all cancer drugs in development should advance to the next phase of testing, cautioned FDA spokesperson Stephanie Yao. "This is a dangerous assumption as there could be serious safety or efficacy issues that do not warrant a drug's advancement," she pointed out.

Because so much progress has been made in cancer research, patients – and even researchers – sometimes forget that "there are still a great number of challenges relative to our knowledge of what causes the diseases," Chin said. "Any given cancer may be caused by many different molecular mechanisms. We actually don't understand the disease as well as we need to."

But the fact that academic and industry researchers are contending with a steep learning curve about cancer, sometimes with discoveries on the fly of drug development, doesn't excuse the need to keep regulators in the loop.

"If we've learned one thing, it's definitely to have an early dialogue with the FDA," Jallal told BioWorld Insight. "They're open to adaptive design, and they have several pathways for development. But we can't sit in our silos, come with a package and then start to interact with the agency. That's too late."

'WE HAVE TO REDUCE COMPLEXITY'

On top of applying master protocols to the scientific underpinning of cancer and examining which drugs have the greatest potential to tamp down given targets, adaptive design faces other potential challenges.

"There are very long-established perceptions and even misperceptions of the motivations of the other parties" in large public-private collaborations such as Lung-MAP, Getz said.

"You have to have flexibility," Herbst agreed. "You have to work with everyone. Within the master protocol, not every arm has the same statistical designs. Some groups want a higher bar than others to go from phase II to III."

A model like Lung-MAP only works "if you have targets and you have drugs," he added, noting that squamous cell lung cancer was a good starting point, using data culled from the comprehensive sequencing project known as The Cancer Genome Atlas, or TCGA. In addition to advocacy organizations and academic researchers affiliated with the National Cancer Institute and the National Clinical Trials Network, Lung-MAP encompasses industry partners Astrazeneca plc and its Medimmune unit as well as Amgen Inc., Roche unit Genentech Inc., Pfizer Inc. and Foundation Medicine Inc.

"You need a big network to find the 5 percent of patients with the FGFR mutation or the 10 percent with PI3 kinase," Herbst emphasized. The questions raised when studying cancers that affect relatively small populations go beyond an evaluation of safety, efficacy and pharmacokinetics, he said. Such investigations also explore whether a mutation present in a tumor is a "driver or passenger" of the disease.

Ed Bradley, senior vice president of R&D and head of oncology innovative medicine at Medimmune, observed that trials like Lung-MAP must be driven by the science. The effort to design such trials is not unlike that of internally developed protocols, with careful patient selection based on biomarker data or hypotheses and the selection of clinically meaningful endpoints that will pass muster with the FDA.

The appeal of those partnerships is even greater today, given what cancer drug developers now understand about combination therapies, he pointed out.

"The biology often suggests that a combination approach will be best, and that's particularly the case with immunotherapy," Bradley said. Because it's important to move as quickly as possible to test combinations, adaptive trials such as Lung-MAP enable companies to test drug candidates in an overlapping fashion rather than sequentially.

"We tend to do that faster now than we did five or 10 years ago," Bradley said.

But the amount of data generated in trials with open platforms also can be problematic for the partners, Getz cautioned.

"It tends to be unwieldy managing so much input, and there are times when the tendency is to gather too much data and to try to do too much," he said. The result is that certain patient cohorts may be disproportionately excluded from trials or forced to drop out.

"We have to reduce complexity and try to accept the fact that there are some tests and some data that we may have to gather at a later date – maybe even after the drug has been approved," Getz said.

As more coalitions assemble to pursue cancer trials using adaptive design, PhRMA's Chin expects to see an upsurge in creative arrangements. Although launching the initial efforts has been challenging – "maybe even painful," he admitted – biopharmas, academic institutions and other partnering organizations are optimistic about their progress and prospects for success. Once those stories are told, "adaptive trials may become the model for how we do drug development work in the future," Chin said.