ASH Clinical News spoke with Richard Pazdur, MD, director of the U.S. Food and Drug Administration’s (FDA) Oncology Center of Excellence (OCE), about the scope of the new center and its efforts to accelerate the drug-approval process.
In January 2017, the FDA formally established the OCE as part of the national Cancer Moonshot Initiative. Can you describe the OCE’s responsibilities, as well as your role as its director?
The OCE unites experts across the FDA and its agencies (including the Office of Hematology and Oncology Products [OHOP], the Center for Devices and Radiological Health [CDRH], and the Center for Biologics Evaluation and Research [CBER]) to expedite the development of medical oncology products. Its operations support an integrated approach to the clinical evaluation of drugs, biologics, and devices for the treatment of cancer.
As the director of the OCE, I work in close coordination with the FDA commissioner and the directors of the various centers to make this happen – and to help patients get faster access to safe and effective cancer treatments. I also continue to serve as acting director of OHOP. These positions are a natural complement to each other; the majority of the FDA’s oncologists work in OHOP, and OHOP oversees most of the applications for products that treat cancer. In these dual roles, I am able to bring together experts in OHOP with other cancer experts across the agency to help advance the goals of the new interagency center.
One way in which the new OCE organization can affect cancer drug development is that I, as the director, can mobilize and deploy internal review resources within the FDA to promote the more rapid completion of marketing for drugs for which there is an urgent need.
The FDA currently has several approval pathways to help move these types of therapies through the regulatory process (i.e., breakthrough-therapy designation and fast-track designation). How will the OCE’s operations complement these pathways?
The OCE’s scope includes the clinical review of applications for products undergoing expedited review, such as those granted breakthrough-therapy designation, accelerated approval, or priority review.
Trial sponsors will submit product applications to the same relevant FDA product center as in the past: CBER, CDRH, or the Center for Drug Evaluation and Research (CDER). If an application is granted expedited review, the OCE will form a clinical review team comprising representatives from OCE, OHOP, and the relevant product center. The review team will make its recommendations on the clinical portion of the application and, as OCE director, I will review and approve their recommendations. Once approved, the application will be returned to the product center, where other aspects of review – such as quality, toxicology, statistics, manufacturing, and facilities inspection – will take place and the final approval determination will be made.
The OCE carefully weighs the risks and benefits of new products prior to approval, including obtaining external consultation at an Oncologic Drugs Advisory Committee meeting or with special government employees (patients and clinicians who have undergone conflict-of-interest screening and who can provide an opinion about the new product) on an as-needed basis.
“We encourage clinical trial designs that allow for enrollment of patients who reflect the real-world population likely to receive the therapy under investigation … and who, traditionally, might be excluded from clinical trials.”
How will the OCE handle post-marketing surveillance and the monitoring of drug safety?
The lifecycle of a new product does not end with approval, and post-marketing surveillance will remain a key feature of ongoing safety reviews. The FDA has mechanisms in place at the time of approval to ensure patient safety, such as an accurate description in labeling of the adverse reactions observed during pivotal clinical trials.
If a safety signal arises, CDER will follow these issues through the Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) module. DARRTS was established in January 2007 as a centralized system that ensures a team of safety experts weighs in on the significance of new safety signals, shares recommendations for regulatory action, and more. Again, because the OCE brings together various centers across the FDA, the OCE director will be able to manage the disposition of resources to address the review of new safety signals.
Additional studies or registries may be required to address areas of concern that regulators have identified, and these requirements can be found in the approval letter.
Are there special considerations unique to the review and approval of hematology products compared with products for solid-tumor oncology and other diseases?
The clinical trial considerations for hematology products are slightly different than for other disease states because most hematologic disorders are rare – making large, randomized trials difficult to conduct. Therefore, occasionally, non-randomized, controlled trials are used in the approval process. In these situations, FDA reviewers may also rely on patient-reported outcomes data to make approval decisions – as was the case in the 2015 approval of ruxolitinib for the treatment of myelofibrosis.
Hematologic malignancies also are often treated with combination chemotherapy, particularly in patients with newly diagnosed disease. Drug development, however, frequently emphasizes the use of single agents in patients with relapsed or refractory disease, after other standard treatments have failed. So, in the case of hematologic malignancies, researchers and regulators must consider the complete lifecycle of the investigational agent and that it will eventually be used as part of combination therapy.
The field of hematology has long been at the forefront of scientific discovery and uncovering the mechanistic basis of disease processes. With technology advances such as chimeric antigen receptor T-cell therapy, checkpoint inhibitors, and other forms of cell and molecular immunotherapy, the treatment landscape and development pathway for newer agents will inevitably evolve.
With the greater ability to collect genetic data – from several initiatives launched with the Cancer Moonshot program, biorepositories, and electronic medical record systems – this information will play a greater role in developing treatments for hematologic malignancies, as well as selecting the appropriate patient population for those agents. The growing evidence about the role genetic mutations (particularly driver mutations) play in cancer risk and prognosis has also provided easily identifiable targets for new product development – for instance, the approvals of imatinib, which targets BCR-ABL, and the recent approval of midostaurin, which targets FLT3.
How do you see drug labels/indications changing within hematology as more targeted approaches become available?
Targeted approaches have certainly progressed and, as precision medicine moves forward, the targets of therapy have evolved from a tissue- or organ-based approach to a gene- or pathway-based targeting paradigm.
Product indications and labeling will have to evolve accordingly. As the OCE director, I hope to be able to integrate FDA resources to support regulators and researchers in this transition.
For instance, approval decisions will increasingly describe the use of complementary and companion diagnostics – tests that identify patients whose cancers harbor the targeted abnormalities – for the safe and effective use of these drugs. Companion diagnostics also will provide information about how a drug might be used or which patients should receive a particular drug. The FDA has typically approved companion diagnostics under a “one drug, one diagnostic” paradigm, but advances in molecular sequencing mean that we are likely to shift to a “one drug, a panel of diagnostic markers” paradigm.
How could the development and approval of targeted therapies impact registration trial designs?
For decades, the clinical development of cancer treatments has followed the conventional phase I, phase II, and phase III paradigm. One of the OCE’s ongoing initiatives is an effort to modernize eligibility criteria and patient selection for oncology clinical trials.1 It has become clear to us that, far too often, the eligibility criteria for enrolling patients in cancer clinical trials appear to be simply cut-and-pasted from one trial to another, without a scientific or justifiable basis. We need a more thoughtful approach.
We encourage clinical trial designs that allow for enrollment of patients who reflect the real-world population likely to receive the therapy under investigation, including patients with HIV or a history of prior cancers and older patients who, traditionally, might be excluded from clinical trials.2
Recently, researchers have discovered early biomarkers of disease prognosis, which has facilitated better patient selection for drugs. These discoveries have prompted a move away from the sequential, three-phase design to a more seamless approach – adding cohorts to a first-in-human trial to investigate doses and activity in a variety of cancers.
This type of approach proved successful with the investigation of the PD-1 inhibitor pembrolizumab, as we described in a perspective article in the New England Journal of Medicine.3 Pembrolizumab was initially studied in a first-in-human trial to determine the safety and recommended dose of pembrolizumab. When investigators observed early impressive response rates and durations of response, particularly among patients with metastatic melanoma or non-small cell lung cancer, cohorts were added to assess efficacy in these two patient populations, as well as to evaluate alternative dosing regimens and predictive biomarkers. This resulted in the enrollment of more than 1,200 patients in the trial and, 3 years after the trial began, data from a cohort of 173 patients supported the initial accelerated approval for the use of pembrolizumab in melanoma. Subsequent data from this trial have also supported accelerated approval for other indications and approval of a companion diagnostic test.
This type of seamless development could provide earlier access to highly effective therapies and could complement the FDA’s expedited regulatory programs.3
With targeted therapies, specifically, there is a great opportunity to explore alternatives to the conventional, three-phase paradigm. Using large, simplified trials with easily measurable endpoints could reduce the amount of data needed to determine clinical benefit. In addition, common control trials that share a control arm and can involve multiple drugs for the same indication can decrease the total number of patients who need to be enrolled in a pivotal trial.
Taken together, these initiatives will potentially reduce drug-development time, optimize clinical trial resources, and allow us to get products to patients more efficiently.
- Beaver JA, Ison G, Pazdur R. Reevaluating eligibility criteria—balancing patient protection and participation in oncology trials. N Engl J Med. 2017;376:1504-5.
- Singh H, Beaver JA, Kim G, Pazdur R. Enrollment of older adults on oncology trials: an FDA perspective. J Geriatr Oncol. 2016 December 22. [Epub ahead of print]
- Prowell TM, Theoret MR, Pazdur R. Seamless oncology drug development. N Engl J Med. 2016;374:2001-3.