FDAʼs Richard Pazdur (2003)

PALM BEACH, FL—At a fitting opening presentation to the First International Colorectal Cancer Conference, the FDA's Richard Pazdur, MD, told the audience here that the Agency's approval of new agents for colorectal cancer entails a thorough discussion and evaluation of benefit and risk to patients. “Approval involves not just endpoints, but also the impact of the endpoints on patients' lives,” said Dr. Pazdur, Director of the FDA's Division of Oncology Drug Products at the Center for Drug Evaluation and Research. The process can require a discussion of factors ranging from survival rates and symptom relief to time to progression, duration of response, toxicity, and quality of life, he said, adding that the views he was expressing throughout his presentation were not necessarily those of the FDA. Although the laws governing FDA approval stipulate that a new agent demonstrates efficacy and safety in adequate, well-controlled clinical trials, laws are interpreted by the agency, he noted. Approval of an oncology drug is not always straightforward, Dr. Pazdur said. It's important to realize that when the FDA makes a decision about a drug, we have a tremendous amount of internal discussion for any application that comes before us. When we look at the risk/benefit [ratio], the benefits are not always clear-cut. “Many oncology drugs have a narrow therapeutic window relative to toxicity. Most clinical trials in oncology are unblinded because of the toxicity issue.” Other variables are whether full or accelerated approval is sought and the endpoints that are used, he said. “Many issues are involved in how the FDA defines success in treating colorectal carcinoma.”Figure: Richard Pazdur, MDProduct Labels Urging oncologists in the audience to carefully read the product labels of new drugs, Dr. Pazdur said, “One of the aspects that is unique in oncology compared with other medical areas is the role of the product label. We spend a lot of time on the product label, which most of you probably don'tread and throw out.” Approval is not for a drug per se but for a marketing application, and drug labeling is a licensing agreement that defines the appropriate patient population for the drug, Dr. Pazdur explained. The labeling contains information, including dosage, indications and contraindications, and side effects, for the practicing physician and the patient. Full or Accelerated Approval There are two types of FDA approval—full approval and accelerated approval. Full FDA approval requires intense discussion about whether a drug demonstrates not only prolonged time to progression and improved response rates, but also improved survival and symptom relief compared with standard treatment—in short, endpoints that are meaningful to patients, Dr. Pazdur said. “These benefits would go beyond shrinking a tumor or inhibiting an enzyme.” The accelerated FDA approval process instituted in the late 1990s is based on surrogate endpoints, such as response rate and time to progression, “reasonably likely to predict clinical benefit,” he said. “[It] allows us to get out important new drugs for oncology, AIDS, and other life-threatening diseases on an accelerated basis.” Colorectal cancer drugs that have been approved on an accelerated basis include the first approval of irinotecan based on greater than 50% response rates and approval of oxaliplatin. Commonly Used Endpoints “What endpoints should the FDA demand from sponsors and clinical trials?,” Dr. Pazdur asked rhetorically. “Survival is the gold standard.…It doesn't change, and there is no ambiguity. Survival is not vulnerable to bias and is assessed daily from time to randomization until death.” Survival can be improved or equivalent (i.e., non-inferior). “This endpoint assumes that a survival advantage over standard therapy will not be lost with a new agent,” he said. “Survival is an issue that haunted approval of capecitabine in the US, [since the pivotal studies showed improved response rates and time to progression in patients with advanced colorectal cancer, but not improved survival compared with fluorouracil/leucovorin].” Use of survival as the primary endpoint of a clinical trial does have some drawbacks, including the need for large sample size and long follow-up, he said. Additionally, there can be a confounding effect of crossover treatment in clinical trials for patients whose disease progresses during a study, he said. “Crossover therapy can wash out the effect of the originally assigned treatment.” In large part due to the crossover effect, the FDA will be discussing use of time to progression as an endpoint, he said. “This will become more important as more drugs are developed and crossover becomes more common in clinical trials.” Time to Progression Time to progression has both advantages and drawbacks compared with survival as a primary endpoint, Dr. Pazdur noted. Advantages include the need for a smaller sample size and shorter follow-up compared with survival as well as the absence of a crossover effect to obscure any differences between the treatment arms. European regulatory agencies routinely accept time to progression as the primary endpoint, the rationale being the lack of confounding effect, he said. Potential drawbacks are the subjective nature of this assessment and expense. Most trials in oncology are unblinded, which introduces a degree of bias, and it is not clear how much improvement in time to progression constitutes a true treatment effect for the patient, “especially when considering toxicity and benefit in an asymptomatic individual,” he emphasized. For example, a small improvement in time to progression may appear to benefit an asymptomatic individual even when the risk of toxicity is unacceptable. Also, cost can be high if all sites of disease are measured. The FDA does not use time to treatment failure as an endpoint, because this is a “hybrid” endpoint and can reflect toxicity as well as efficacy, Dr. Pazdur said. Instead, the agency measures toxicity and efficacy as separate endpoints. Response Rate “Response rates are an extremely interesting phenomena,” he said. “We have had a lot of discussion about response rates. What do response rates mean? How low can response rate be to predict clinical meaning?” While time to progression and survival partially reflect the natural history of the disease, all the treatment effects measured by the response rate can be ascribed to effects of therapy, Dr. Pazdur noted. “Response rate is complicated,” he continued. Duration of response is important to patients, but response rate does not include stable disease, which is measured in time to progression. The number of complete versus partial responders needs to be considered. Location of response is also important, as is whether response is associated with improved symptoms. Despite a high degree of measurement bias, “response rate is a meaningful endpoint for medical oncologists and patients because it provides immediate gratification. You can show that information to patients,” Dr. Pazdur commented. Oncology agents that have been approved on the basis of response rate and duration of response include goserelin, anastrozole, letrozole, and toremifene. Once an afterthought, quality-of-life measures are increasingly being considered in the drug approval process, he noted. Valid quality-of-life measures with predefined questions should be carefully integrated into the protocol. In the end, though, survival is still the most important endpoint, Dr. Pazdur said. “Even though the FDA may accept other endpoints for approval of a drug, we will probably require that survival be demonstrated eventually.”