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Pink Sheet – FDA's Pazdur Advocates Platform Trials For Cancer Drug Development

Pink Sheet – FDA's Pazdur Advocates Platform Trials For Cancer Drug Development

Executive Summary

US FDA is encouraging common mechanisms of drug testing to enable pharma industry collaboration and avoid redundancy; Pazdur notes that there are many similar PD-1 drugs.


Richard Pazdur, the director of US Food and Drug Administration’s Oncology Center of Excellence, has one plea for industry: work together to develop new cancer drugs. He said the agency is trying to foster this collaboration by encouraging the use of platform trials and common controls.


Speaking at Chasing Cancer, a 17 October event hosted by The Washington Post, Pazdur was asked what his greatest frustrations are in the field. “I would like to see a greater cooperation in the pharmaceutical industry,” he replied.


“For example, we have many PD-1 drugs that are quite similar,” he said. “I would hope companies would work together on the next generation of these immunological therapies rather than have purely a competitive spirit.”


Drugs that target the PD-1 protein on T cells to boost immune response against cancer cells include Merck & Co. Inc.’s Keytruda (pembrolizumab), Bristol-Myers Squibb Co.’s Opdivo (nivolumab) and Regeneron Pharmaceuticals Inc./Sanofi’s Libtayo (cemiplimab-rwlc).


As for what FDA can do to address duplicative trials and redundant drugs, he said the agency tries “to encourage clinical trials that will enable pharmaceutical companies to collaborate with each other, such as platform trials, such as the use of common controls, so they get a common mechanism of testing drugs.”


A platform trial has a single master protocol in which multiple drugs are evaluated simultaneously for treatment of a disease. One such trial is the I-SPY 2 trial, which is evaluating neoadjuvant breast cancer therapies from a variety of sponsors in biomarker identified subgroups. The agency has long advocated the use of such adaptive clinical trial designs. (Also see “Woodcock Hopes I-SPY 2 Trial Is ‘Blazing The Trail’ For Future Adaptive Design Uptake” – Pink Sheet, 12 Sep, 2018.)


Pazdur said patients are not the resource of a pharmaceutical company, but a national and international resource that must be protected. “Their participation in a clinical trial has to be done in a thoughtful way rather than just enrolling patients to answer a relatively mundane question,” he stated.

Detection Vs. Treatment

The moderator asked panelists for their views on a new book by Columbia University oncologist Azra Raza, “The First Cell And the Human Costs of Pursuing Cancer to the Last,” in which she criticizes cancer therapies for targeting advanced disease and being ineffective and calls for a shift in focus to detect changes before a tumor develops.


Ellen Sigal, chairperson and founder of Friends of Cancer Research, commented that there are many diseases that we don’t know how to prevent and treat. While the gold standard is prevention and early detection, she said we can’t stop treating patients.


Pazdur said he agreed with Sigal. “Although drugs are tested frequently initially in a very advanced  population where the response rates, where the efficacy, may be rather modest,  they quickly go into earlier stages of the disease where their effects are greater,” he said. He noted that they also are used in adjuvant and neoadjuvant therapy, treating patients who received curative therapies and are at high risk after relapsing.


“I look at this more of a continuum of drug development” rather than saying here is prevention and there is treatment of advanced disease, Pazdur said. “It’s also important to realize that we really have to address people’s problems” when they are here at our doorstep.

Regulatory Flexibility In Precision Medicine

The moderator cited the criticism FDA’s expedited approval process has received from some people who suggest drugs approved through this route may not be as effective.


Pazdur said he is working on an article, entitled “When Science Collides with Drug Development: the Need for Regulatory Flexibility in the Area of Precision Medicine,” that addresses this topic.


“We have to be realistic that the measurement of overall survival, which many of these people want, simply is not possible always with the development of oncology drugs,” he stated.


He said there are many reasons for this, including having smaller subpopulations of patients based on genetic markers, which makes it impossible to do a survival study. He also noted that natural histories, as well as histories due to therapeutic interventions, are often very prolonged so it may take many years to demonstrate overall survival. Pazdur also cited the reluctance of patients to participate in a randomized clinical trial when they know a therapy may have a much higher response than conventional treatment.


“As we get into a very dynamic environment where many oncology drugs are being developed and the natural history of many diseases are changed,  we have to demonstrate the appropriate degree of regulatory flexibility,” he said. FDA is “responsible to the patients, not to the preservation of a p value in a statistical analysis.”

Trial For One-Dose HPV Vaccine

National Cancer Institute Acting Director Douglas Lowy was asked about the uptake of human papilloma virus (HPV) vaccine and whether it would eventually be approved for one shot dosing.


“The uptake of the HPV vaccine has not been as optimal as one would have hoped or expected,” Lowy said. But he noted that since its approval in 2006 through 2016 there has been a more than 80% decrease in the prevalence of the HPV strains that are targeted by the vaccine.


As for dosing, Lowy noted that data from a clinical trial in Costa Rica suggests one dose might be sufficient. Another large trial in Costa Rica, where there is a high incidence of cervical cancer, is currently underway testing Merck’s Gardasil 9 and GlaxoSmithKline PLC’s Ceravrix to see if one dose is as effective as two. He said trial results are expected in 2024.…