WASHINGTON—The advocacy organization Friends of Cancer Research (FOCR) released a new blueprint document at a forum here designed to improve and expedite the approval process for drugs given the Food and Drug Administration's Breakthrough Designation, along with companion diagnostic tests. Currently, the development of a companion diagnostic may lag behind the accelerated review timeline of a new breakthrough drug.
The new FOCR document follows up on the organization's May 2013 document describing standards for breakthrough drugs and diagnostics, and its November 2012 white paper providing recommendations for the new FDA breakthrough designation.
“A year ago breakthrough therapies became a reality; we are thrilled about that,” said FOCR Chair Ellen Sigal, PhD. “What patients want are treatments that work for them.” She noted that for cancer drugs especially, combining the expedited breakthrough designation with a companion diagnostic holds promise for getting a targeted drug to the population for which it is likely to be most effective more rapidly.
The breakthrough designation has proved popular with pharmaceutical manufacturers: From Oct. 1, 2012 to Sept. 6, 2013 there have been 83 requests for this designation, with 26 approvals of the designation granted and 34 denied, according to FDA statistics. About 99 percent of breakthrough therapy applications have been reviewed within 90 days.
The new FOCR document recommends the following modifications (which speakers said could likely be implemented without new legislation) to standard drug/diagnostic co-development to expedite the development of a companion in vitro diagnostic device (IVD) intended for use with a breakthrough drug:
1. Automatic designation of companion IVDs for use as part of a breakthrough drug approval as eligible for priority review;
2. Use of highly coordinated administrative processes and management commitments for review of IVD companion diagnostics associated with breakthrough therapies that are commensurate with those processes offered for breakthrough therapies;
3. Use of risk-based processes to determine required analytical studies for each assay type at the time of a drug premarket approval application (PMA) filing;
4. Use of risk-based processes to determine requirements for data and testing related to quality systems, manufacturing processes, and software testing and documentation;
5. Use of a “continued access” supplement investigational device exemption (IDE) to enable a broader set of laboratories to be ready for testing immediately upon contemporaneous approval of the companion diagnostic and therapeutic product.
Sigal, FOCR Executive Director Jeffrey Allen, PhD, and coauthors set forth their detailed strategy for co-development of targeted therapies and companion diagnostics for cancer patients in an article, “Considerations for the successful co-development of targeted cancer therapies and companion diagnostics,” available online ahead of print in Nature Reviews Drug Discovery (doi:10.1038/nrd4101). That article (first author is Jane Fridlyand) contains a detailed discussion of whether to include both biomarker-positive and biomarker-negative patients in trials or whether to restrict a trial to biomarker-positive patients, among other issues.
‘Important Escalating Trend’
According to the FDA, co-development of a new breakthrough drug with a companion diagnostic is an important, escalating trend. “Companion diagnostics can play a very important role in breakthrough therapies,” said forum panelist Michael Pacanowski, PharmD, MPH, the FDA's Associate Director for Genomics and Targeted Therapy in the Office of Clinical Pharmacology. He noted that to date about three-fourths of breakthrough-designated new drug applications have had companion diagnostics.
Added William Chin, MD, Executive Vice President for Science and Regulatory Affairs for the Pharmaceutical Research and Manufacturers of America: “Overall, the trend is for companies to be thinking much more about companion diagnostics with new therapeutics.” For example, Myriad Genetics recently announced that it will collaborate with AstraZeneca to provide companion diagnostics for Phase III clinical trials of the investigational poly-ADP ribose polymerase (PARP) inhibitor olaparib, which is being developed to treat various cancers, including BRCA-mutated breast and ovarian cancers.
Speakers at the forum, which was sponsored by FOCR and the Alexandria Center for Life Science, emphasized that breakthrough-designated drugs and their companion diagnostics will be held to the same FDA approval standards as all drugs and diagnostics.
“It remains paramount to maintain adequate product quality for safe patient use,” said Barbara A. Conley, MD, Associate Director of the National Cancer Institute's Cancer Diagnosis Program, Division of Cancer Treatment and Diagnostics.
Added Janet Woodcock, MD, Director of FDA's Center for Drug Evaluation and Research (CDER): “Breakthrough drugs go through the same FDA review process as any other drug. The drugs will be expensive, but they certainly won't have lower approval standards than other drugs.”
But both Pacanowski and Woodcock noted that the clinical trial process used to establish safety and efficacy for breakthrough drugs and their diagnostics needs to be streamlined. “In the breakthrough category there's an interest in enhancing the efficiency of trials,” said Pacanowski.
“In cancer we're right up against a new problem,” Woodcock said. “We're trying to sort out molecular complexity. . . our tools are crude.” Because of this ever-increasing molecular complexity, “we need totally new ways of doing patient evaluation and assessment,” which will require more efficient and adaptive clinical trial designs. To meet the new challenge of molecular complexity, “FDA's CDER is trying to change. It's not going to be like it was a decade ago, and everyone just has to get over it,” she emphasized.
From the standpoint of cancer center oncologists, companion diagnostics for new cancer drugs (whether breakthrough-designated or not) are becoming a key fact of life in patient care, said Keith Flaherty, MD, Director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center.
“We feel pressured to include the approved drugs and the investigational drugs . . . the patients don't have much time. It forces us to make these multi-marker assessments. We are obliged by our patients to perform these [diagnostic] tests; we have to pre-screen. That's the only way we're ever going to make advances in therapy.”
From the standpoint of insurers, said Michael Kolodziej, MD, Aetna's National Medical Director for Oncology Solutions, “we love companion diagnostics—it's value based, since the diagnostic test defines the patient population most likely to benefit from a drug.
In fact, insurers such as Aetna will pay for some drugs only if the companion diagnostic is used first to define whether the patient is likely to benefit, he noted. Kolodziej told OT that when an approved drug has an approved co-diagnostic, “it makes the coverage decision relatively easy.” But, he said, the new FDA breakthrough designation does make insurers nervous. “These drugs are expensive. We want to make sure we are comfortable that the evidentiary standards [for approval] are the same.”
He said insurers such as Aetna are looking to the Centers for Medicare and Medicaid Services (CMS) to see how that federal agency handles the breakthrough therapy designation for its millions of covered beneficiaries. “It is a new pathway to approval; we've had some internal discussions,” he said.
But nervousness about coverage decisions aside, Kolodziej said the breakthrough designation—especially for drugs with companion diagnostics—holds much promise for patients. “We are excited about the possibility of treating hard-to-treat diseases,” he said. “With molecular diagnosis you can more precisely define the population most likely to benefit.”
In July 2012 Congress authorized a new Breakthrough Therapy designation as part of legislation designed to guide effective new drugs through the FDA review process more quickly. The aim of the designation is to identify drugs for serious and life-threatening diseases such as cancer that show early evidence of efficacy beyond that of currently available drugs.
Companion diagnostics define the patient subgroup most likely to benefit from a new breakthrough therapy, often on the basis of one or more specific biomarkers.
In July 2013 the FDA released a draft guidance document that defined the agency's concept of a companion diagnostic and introduced a drug-diagnostic co-development approval process. The agency is expected to soon issue guidance on co-development.