Pfizer’s crizotinib development program combined organization, art, and science— and a large dose of unforeseen risk.
The path to commercializing a breakthrough discovery is rarely a linear process. The orderly rationale of the scientific method is often overtaken by the random artistry of passion, personality, business culture, and sheer luck. Each plays a significant role in handicapping success or failure in that wending transition from bench to bedside. The story behind drug development is thus as interesting as a dime-store novel, except what is fiction in the second case is truth in the first—and always the developer’s own dime is at stake.
Pfizer’s crizotinib—a new targeted therapy that blocks progression of a genetic alteration in a subset of patients with non-small-cell lung cancer (NSCLC), extending survival well beyond the current standard of treatment—is revealing on two counts. The compound’s extraordinarily fast development timeline shows that improvements in basic science around molecular biology are bringing more order to the process of moving from POC to confirmatory trials that conform to regulatory requirements for an accelerated NDA. At the same time, the path for crizotinib was littered with unforeseen risks, best exemplified by a chancy decision on clinical testing that, instead of yielding a medical breakthrough, could have shut the door on an entire field of investigation and potentially harmed Pfizer’s reputation.
With reference to the speed of the science, several institutional drivers helped pull crizotinib out of the filing cabinet and into active development. First was a seemingly unrelated commitment by Pfizer to expand its research capabilities in Asia to accommodate the region’s demand for data relevant to local clinical conditions. Governments like Korea were committing significant funds to facilitate home-grown research, particularly in oncology where the disease profile bore distinctive variations compared to the US. As a result, Pfizer began looking at how various tumor suppressing therapies based on the ALK and MET gene alterations could be leveraged against additional tumor types, including those prevalent in Asia.
“During the dose escalation part of the Phase I study of crizotinib in the US and Korea, we observed early responses in patients with advanced NSCLC,” Darrel Cohen, senior director in the Pfizer Oncology Business Unit, tells Pharm Exec. “Given our strong local networks, we were able to connect the dots and apply this knowledge quickly to expand the Phase I clinical trial and initiate a Phase II study of crizotinib in ALK-positive NSCLC. And despite the limited test population evidence, we were able to take the risk of expanding the trial to focus on establishing how crizotinib suppresses tumor growth among those patients with advanced NSCLC harboring ALK rearrangements, a group that represents approximately 3 percent to 5 percent of the entire NSCLC patient population.”
Pfizer contends that crizotinib is not only a potential therapeutic leader, but a benchmark in new ways to facilitate development partnerships across regions and markets. The success of this approach is exemplified by its joint simultaneous filing submissions on crizotinib to the FDA and the Japanese Ministry of Health Labor and Welfare in March of this year.
But there was also real risk in going global. The expanded trial proved more complicated than expected, involving extensive outreach to academic partners and regulatory authorities in Japan and Korea. In both groups there was concern about the generally precarious state of health among the candidate clinical trial population, most of whom were in the late stages of the disease. This was compounded by the cultural and medical practice gaps between the two countries that proved to be a potent challenge in defining and communicating the clinical trial protocol.
In one instance, Pfizer had to make a wrenching choice, says Oncology Business Unit Regional President for Asia, Jorge Puente. “We had a strong test candidate associated with one of our key academic research partners in Japan. The patient was at that point near death but our assessment was that getting him to the trial center in Korea might possibly prolong his survival and enhance the clinical relevance of the data. So we decided to pull out all the stops in registering the patient, including getting the Korean regulatory officials to accept his entry to the country, obtaining approval of the institutional trial review board, ensuring the patient’s informed consent with the government oversight required under Japanese law, and arranging logistics and transport for a subject who by that time was on a respirator.”
Puente notes that there was an acute awareness within Pfizer of the risks involved, but, he says, “by limiting the population to the US and Europe, we decidedly could not have achieved the rich response rate that allowed us to file globally with this early data.” From a societal point of view, the availability of this type of therapy to patients could have been set back years.
As it happened, the 27-year-old patient survived the trip, was administered the drug, and within two days was off the respirator and walking unaided.
In a world where individual accountability has grown opaque, it is still true in science that reputations and livelihoods can be put on the line, often around statistically assumptive outcomes whose interpretation in the clinical setting can deliver life—or death—to thousands of patients.
William Looney, Editor-in-Chief