President Barack Obama has pledged government transparency of his administration. His newly appointed FDA commissioner, Margaret A. Hamburg, MD, has taken up that call, promising a wider view into an entity that has often been perceived as inaccessible. “Over the years, the FDA has been referred to as a ‘black box’ that makes important decisions without explaining them,” Dr. Hamburg said recently.
The FDA has long been criticized as one the most inscrutable parts of the federal government. This opacity has been perceived as particularly vexing with regard to offices that are in charge of the drug approval process.
But the doors are now opening up on the complicated process of oncology drug evaluation and approval. Oncology News International visited the FDA offices for an in-depth talk with Richard Pazdur, MD, who was appointed director of the Office of Oncology Drug Products (OODP) in 2005.
“At the onset of OODP, we have been striving to create an interactive relationship with our stakeholders, including the patients, investigators, the academic community, oncology professional groups, and the industry we regulate,” Dr. Pazdur said. “In short, our office has been working with others to increase the agency’s transparency of the oncology drug approval process so people can better understand how and why we make our decisions.”
Large scope, dedicated staff
The OODP consists of four areas:
• Main office, which coordinates all internal and external activities related to oncology drug approvals
• Biological oncology division
• Drug oncology division
• Hematology and imaging division
A staff of about 160 is responsible for the review and approval of oncology products, including medical oncologists, pediatric oncologists, toxicologists and pharmacologists, and project managers. All of these individuals coordinate with other FDA departments that focus on drug safety and quality processes for manufacturing human drugs.
In the early stages of drug development, decisions are based on the scientific evaluation of clinical data submitted to FDA, and the judgment of potential risks and benefits as determined by the scientific review staff.
“Most people from the outside don’t fully understand the processes involved in reviewing a drug application,” Dr. Pazdur said. “It’s not just clinical trial data. It’s a complex evaluative procedure with many experts representing diverse fields, who must ultimately decide whether a new drug is safe and effective.”
The two OODP review processes that most people are familiar with are the new drug application (NDA) and the biological licensing application (BLA). The NDA or BLA is the drug sponsor’s formal proposal to the FDA to approve a new drug or biologic for sale and marketing.
An NDA is either assigned a priority review (a review timeline goal of six months) or a standard review (a review timeline goal of 10 months) after it is determined whether the entity is an improvement over an available therapy or an existing product. Dr. Pazdur dispelled the notion that the OODP evaluation occurs without meaningful exchanges with the drug sponsor.
“We have a proactive and interactive relationship throughout the entire process,” he said. “We interact with the company in the investigational new drug (IND) and NDA phases. Our major concern in the IND phase is safety, and the studies are generally phase I and phase II trials. We have end-of-phase-II meetings with sponsors to discuss optimal trial designs for registration.” “Before the drug marketing application reaches OODP, a pre-NDA meeting with the sponsor occurs to discuss technical procedures of submission of the application,” Dr. Pazdur continued.
“Shortly after the NDA is submitted, the FDA medical review divisions and other disciplines, including manufacturing, clinical pharmacology, and toxicology have a filing meeting to determine whether the NDA or BLA applications have all the necessary components.”
Rather than focusing solely on the topline results of a clinical trial, FDA reviewers reconstruct the data, producing survival curves, response rates, and tumor responses. Because the FDA has direct access to the data, the agency may perform additional analyses on subsets of patients, looking at geographic, ethnic, and gender differences.
Role of ODAC
Select applications may be discussed at the Oncologic Drugs Advisory Committee (ODAC), a body of 14 nongovernmental advisors that provides independent external advice to the FDA. A medical oncologist, pediatric oncologist, statistician, consumer representative, patient representative, and nonvoting industry representative can serve on the committee.
ODAC meetings are open to the public. Both the drug sponsor and the FDA present their findings, and ODAC members vote on how to advise the agency. FDA usually follows ODAC advice, but the agency is not bound by it.
“We are more interested in the discussions by ODAC members, and their reasons for voting, rather than the numerical tally of the vote. The vast majority of issues discussed by the committee have to do with the evaluation of efficacy rather than any individual safety issue,” Dr. Pazdur said.
Why a drug fails or succeeds
Most oncology drugs are not approved because their trials fail to meet the primary endpoint of proving efficacy. But unlike in other therapeutic areas where toxicity can be the primary grounds for rejecting a drug, the FDA has accepted cancer drugs despite serious toxicities associated with them.
Overall survival remains the gold standard for oncology drug approval. However, the evaluation of overall survival can be confounded by crossover and, perhaps, subsequent therapies. This is one reason that the FDA, in some cases, decided to accept time-to-progression (TTP) or progression-free survival (PFS) as regulatory endpoints.
“Overall survival may not be a practical endpoint in diseases with long natural histories, such as indolent lymphomas. As more novel, targeted drugs are developed with less toxicity, a re-evaluation of endpoints in a risk/benefit analysis should occur. With drugs demonstrating less toxicity than conventional chemotherapy, TTP and PFS may gain greater acceptance,” he said.
The approval process is not merely a screening process for drug activity, he added. “The goal of a registration trial is not merely to obtain a statistically significant result.
“The primary goal is to obtain a statistically reliable evaluation of the drug that represents a clinically meaningful result yielding a favorable risk/benefit evaluation,” he commented.
Dr. Pazdur said that despite shortages in funding and staffing, his office is proactively meeting its charter to advance the development, and ultimate approval of, safe and effective oncology drugs and biologics. “We have numerous interactions with the major U.S. cancer organizations, including ASCO, NCI, Oncology Nursing Society, and ASH, regarding projects that examine approval endpoints, data collection, and clinical trial design issues,” he said.
“Also, when we approve a drug, we send out emails with links to our product labels to cancer organizations within 24 hours of approval so medical oncologists and oncology nurses have access to that important clinical information immediately.”
OODP also has regular interactions with its counterpart in the European Union, the European Medicines Evaluation Agency (EMEA). Joint activities include international staff exchanges, exchange of guidances under development, and discussions of protocols and pending regulatory decisions. Monthly teleconferences are conducted, and regulatory workshops take place during ASCO.
“Drug development is an international business,” Dr. Pazdur said. “Most large randomized trials conducted by pharmaceutical firms have an international accrual. With the internationalization of drug development, it is important for the FDA to interact with other regulatory agencies in Europe, Asia, Australia, and South America.”
Dr. Pazdur chaired a session at ASCO 2009 on the challenges of oncology drug regulation. He pointed out a major difference between FDA and the EMEA: the latter publishes its negative opinions and reviews on withdrawn applications.
“When the FDA does not approve a drug, the review documents, including the complete response letter that outlines the application’s deficiencies, are not released to the public. In Europe, this information on drugs that are not approved is provided to the public,” he said. “Companies could release that information, but the FDA does not. When we approve a drug, all that information goes out on the web. However, for drugs that are not approved, our decision-making process may be unclear to people outside drug regulation. We have been asked by the public to take another look at this in the name of transparency.”