When Incyte Corp.’s Jakafi (ruxolitinib) was approved in 2011 for the rare bone marrow cancer myelofibrosis, the use of a patient-reported outcome as a secondary endpoint was headline news.

While Jakafi’s primary endpoint was spleen shrinkage, Incyte also used a modified Myelofibrosis Symptom Assessment Form 2.0 diary to measure patient-reported outcomes like night sweats, itching, bone/muscle pain and abdominal discomfort. Also see "Incyte’s Jakafi Gets Additional Claim Based On Patient-Reported Outcomes" - Pink Sheet, 21 November, 2011.

At the time, Richard Levy, Incyte’s chief of drug development and chief medical officer, said that the Jakafi approval marked the first cancer treatment to successfully use FDA’s patient-reported outcome guidance, which had been finalized two years before. Even more notable, Levy said, “it’s been probably more than 10 years since any oncology drug had any endpoint based on anything related to symptoms or quality of life.”

Since Jakafi, the only other oncology drug with patient-reported outcomes in the approved label is Janssen Biotech Inc.’s Zytiga (abiraterone) for metastatic prostate cancer. Labeling language for Zytiga’s supplemental indication – for use in metastatic castration-resistant prostate cancer in men with mild or no symptoms who have not been previously treated with chemotherapy – describes improvements in the time to development of pain and the need for opioid use. Also see "FDA Approves Zytiga In Earlier Prostate Cancer Setting" - Pink Sheet, 11 December, 2012.

There have been a few earlier examples of labeled PROs for oncology products, like mitoxantrone’s 1993 approval for prostate cancer (the PRO was pain and analgesic use), and the Gemzar (gemcitabine) approval in 1996 for prostate cancer (the PRO was pain, analgesic use and weight gain). But for the most part, the use of symptom or functional-status evaluations in pre-marketing studies in cancer patients remains quite rare.

Ari Gnanasakthy, MD, head of patient reported outcomes at Research Triangle Park, N.C.-based RTI Health Solutions, says while everyone points to Jakafi and Zytiga as evidence that patient-reported outcomes can be included in oncology trials, those aren’t typical approvals.

While most cancer treatments leave patients feeling worse with nausea and fatigue, Jakafi isn’t chemotherapy, so the patient outcomes are easier to track, the former Novartis AG exec says. And Zytiga treats prostate cancer, where pain is a “very discrete outcome that can be clearly measured.” In short, when it comes to PROs in oncology, Jakafi and Zytiga should be the exception, not the rule.

On the face of it, the lack of PROs in oncology seems surprising, given the commonality of side effects and functional impairment in cancer patients, and the toxicities associated with many treatments. After all, when faced with a cancer diagnosis, patients want to know how various treatment options will make them feel: How tired will they be? Can they continue to work? How much pain can they expect to experience?

But generally speaking, information about the patient experience with oncology treatments is “missing from U.S. drug labels and from published reports of clinical trials – the two information sources most commonly available to people trying to understand the clinical effects of cancer drugs,” Ethan Basch, MD, director of the Cancer Outcomes Research Program at University of North Carolina-Chapel Hill, notes in a “Perspective” piece published in TheNew England Journal of Medicine in August 2013.

Is a “Sea Change” Coming?

There are some good reasons for the general lack of PROs in oncology.

First, there is a lack of validated PRO instruments, and it’s challenging to develop new ones. Most oncology studies are unblinded, and it’s difficult to measure symptom endpoints in unblinded studies due to the potential for bias. Missing data due to patient drop-out rates is a problem, and most oncology patients are on concomitant medicines, which make it difficult to tease out a symptom effect.

Historically, FDA and industry have focused on survival-based endpoints in oncology. But with patients now living longer with their cancer diagnoses, they are being asked to choose among many treatments with different efficacy-toxicity profiles. “As approved drugs continue to yield only tiny median survival benefits (often measured in weeks), patients understandably want to know how their peers felt during and after a treatment,” Basch says.

In diseases like lung cancer, “we know that treatment effectiveness is associated with alleviation of symptoms such as cough, shortness of breath and difficulty breathing,” Genentech Inc. Global Head of Patient-Centered Outcomes Research for Oncology Alicyn Campbell says. “Patient-reported changes in lung cancer symptoms are an important component for assessing the impact of new medicines.”

“This can be particularly helpful in the absence of overall survival, which becomes increasingly difficult to achieve as patients receive numerous lines of therapy,” Campbell says. Comparative tolerability – how treatments impact patients in their daily life – is also important to document, and is useful in diseases like renal cell carcinoma or breast cancer, “where patients don’t experience tumor-related symptoms that can be readily measured.”

“We know from patients and patient advocates that side effects can be the most burdensome aspects of treatment, so we are developing better patient-reported tools for use as endpoints to measure what is of most importance to patients in clinical trials,” she says. Genentech is working on a PRO measurement for future first-line lung cancer trials that could potentially result in patient-reported claims in approved labeling.

That sentiment isn’t universal across industry. In fact, overall PRO use has declined since FDA released its final guidance on patient-reported outcomes. Part of the reason, sponsors say, is that the guidance has been so restrictive as to make it incredibly difficult to get a new measure validated and approved for use. The time and cost involved have resulted in more sponsors deciding not to spend the effort on patient outcomes.

The good news is that there seems to be a shift at FDA toward accepting “good-enough” PRO measures, and in oncology, a few “champions” have emerged that are working with sponsors to get more patient-reported outcomes in labeling. ([A#2015500002])

There have even been rumblings of an oncology-specific PRO guidance document.

Patient advocates are optimistic. American Cancer Society Deputy Chief Medical Officer Leonard Lichtenfeld, MD, predicts a “sea change” away from the current focus on extension of life in cancer trials and toward increased attention on quality of life issues. “It’s not just the length of our lives, but the quality of our lives that is important to patients.”

Centers for Medicare & Medicaid Services official Louis Jacques, now chief clinical officer at the reimbursement and heath policy firm ADVI, agrees that things need to change. Jacques used his last public statement as a federal employee to suggest that every cancer trial have a patient-identified, clearly adjudicated quality of life endpoint as a primary pre-specified outcome.

The problem right now, he acknowledged, is that “no one conducts those trials.”

Patient-Reported Outcomes in Oncology: The Jakafi and Zytiga Exceptions

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