Toward Patient-Centered Drug Development in Oncology.

As an oncologist, when I sit with patients to discuss starting a new chemotherapy regimen, their first questions are often “How will it make me feel?” and “How did patients like me feel with this treatment?” Regrettably, this information is generally 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.

In 2011, 15 hematology–oncology drugs were approved by the U.S. Food and Drug Administration (FDA). In only one case — that of ruxolitinib for the management of myelofibrosis — was symptom information included in the portion of the label that manufacturers can legally use for marketing purposes. In fact, ruxolitinib was the first cancer therapeutic in more than a decade for which symptom information was included in a U.S. drug label.

Cancer-drug labels stand in sharp contrast to labels for other types of drugs, about 25% of which list the drugs’ effects on patients’ symptoms or functioning.1 That disparity is surprising, given how common symptoms and functional impairment are in patients with cancer and how toxic oncology drugs can be.

The FDA has taken several recent steps toward encouraging inclusion of the patient perspective in drug development. It issued highly influential guidance on the use of patient-reported outcomes (PROs) in drug development,2 collaborated with the Critical Path Institute and industry to form the PRO Consortium with the aim of developing robust symptom-measurement tools, and obtained support from Congress in the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA) to expand its internal expertise on the methodology of measuring PROs. (Unfortunately, allocated PDUFA funds have been withheld, which substantially impairs the FDA’s ability to implement planned patient-centered programs.)

These FDA efforts are evident in the ruxolitinib label and in the label for abiraterone acetate, approved this year for metastatic prostate cancer, which describes beneficial delays in time to the development of pain and the need for opioid use. Yet in preapproval trials in patients with cancer, symptom or functional-status evaluations that meet the FDA’s standards remain rare.

Some experts have argued that the FDA has raised the methodologic bar too high, whereas others accuse the pharmaceutical industry of paying too little attention to patients’ experiences. The bottom line is that both regulators and industry continue to prioritize survival-based end points rather than patient-experience end points in cancer-drug development.

Yet as patients live longer with cancer, they must increasingly choose among agents with varying efficacy–toxicity balances. And 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. Moreover, payers increasingly seek information about patients’ comparative experiences with different products, because patients with worse symptoms or functional status utilize more supportive services.3

On the industry side, information about the patient experience is sometimes gathered in preapproval “pivotal” clinical trials (trials intended to provide evidence of the safety and efficacy of a product to support regulatory approval) through questionnaires focused on health-related quality of life (HRQOL). Often, this information is gathered to satisfy European regulators as well as payers, who seek a demonstration of economic value. Unfortunately, these end points are generally exploratory, and protocol-specified hypotheses and analytic or statistical plans are lacking. Data are commonly missing, and the results are rarely (or highly selectively) included in primary publications of trial results4 and are generally not intended for inclusion in U.S. oncology-drug labels.

We can, and ought to, aim higher. The examples of ruxolitinib and abiraterone, as well as experiences outside oncology, demonstrate six key steps that can move drug development toward a more patient-centered approach — one in which developers and regulators systematically consider patient perspectives in the design, conduct, and reporting of research .

In the case of ruxolitinib, the sponsor was a small company whose leadership was committed to including the patient perspective in key trial end points. When early clinical experience and published data for the target population revealed a constellation of symptoms related to the disease that were viewed as important by patients (step 1), the company began discussions with the FDA (step 2) and collaborated with academic researchers and a consulting firm to develop a patient-reported outcome measure (step 3). This measure was tested and refined through use with patients representing the target population before it was employed in a pivotal trial (step 4). The questions were loaded into a handheld device that patients used to report their own responses daily, with near perfect levels of compliance — despite their debilitating symptoms. The company had ongoing communication with and feedback from the FDA throughout this process.

Ruxolitinib demonstrates the particular value that PROs provide for understanding clinical benefits when studies are not designed to detect overall survival advantages and instead rely on end points such as tumor response, progression-free survival, or noninferiority. Although overall, ruxolitinib represents a success story, measurement of fatigue and HRQOL decrements — which are prevalent and widely viewed as important to patients — were not included as key end points because the FDA had methodologic concerns about them; these omissions resulted in a label containing an incomplete picture of the patient experience (steps 2 and 6 might have prevented this).

In the case of abiraterone, the company took a risk in its pivotal trial by expending statistical power to measure the time to opioid use among men with minimal baseline symptoms, when little was known about this end point in prostate cancer (step 4). It would also have been useful to include information about symptoms other than pain that are of interest to men with this disease; according to qualitative research conducted before the pivotal trial and formal patient-engagement activities, these would include symptoms such as tiredness or sleep disturbance (steps 1 and 5). Although a broad HRQOL tool was administered with positive results, there was no protocol-specified analysis plan for it, and it did not meet the FDA’s current methodologic threshold (steps 2 and 6).

For these key steps to be taken routinely, a fundamental shift in cultural orientation among drug developers and regulatory reviewers is imperative. Specifically, the patient experience of treatment with a given drug must be regarded as essential information about the properties of the product, without which our understanding of its risk–benefit profile is incomplete. This requirement applies equally to studies with end points based on survival (such as abiraterone) and those focused on tumor response (such as ruxolitinib).

Methodologic challenges exist but should not continue to be cited as insurmountable. They have been shown to be addressable in many trials,1 and multiple documents offering guidance on methods are available.2,5 Examples include minimizing and analyzing missing data, identifying meaningful score changes for questionnaires, and analyzing PRO data in nonblinded trials. Additional research is warranted both to advance measurement science in these areas and to develop measures in the public domain that meet regulatory standards.

But the principal barrier remains a failure to prioritize the identification and confrontation of these challenges up front. Moreover, when PRO measurement is left until the postmarketing phase, it is often too late to adequately measure outcomes in a comparative trial, which leaves the true effect of a product on the patient experience uncertain. Ideally, moving forward, whenever representatives of a pharmaceutical company and a regulatory agency sit down to discuss a product-development program, they will ask the same question my patients ask of me: “How does this product make people feel?”

Source: NEJM


FDA Approves Abiraterone for Advanced Prostate Cancer

A ball-and-stick model of the abiraterone molecule
On April 28, the FDA approved abiraterone (Zytiga), pictured above, for the treatment of men with metastatic castration-resistant prostate cancer who are no longer responding to the chemotherapy drug docetaxel.

For the second time in a year, the Food and Drug Administration (FDA) has approved a new treatment for men with advanced prostate cancer who, until recently, have had few effective treatment options.

Last Thursday the agency approved abiraterone (Zytiga) for the treatment of men with metastatic castration-resistant prostate cancer (meaning the disease progresses despite low levels of tumor-fueling hormones) that are no longer responding to the chemotherapy drug docetaxel. Last spring, the agency approved cabazitaxel (Jevtana) for the same indication. In both cases, the approvals were based on findings from large phase III trials in which the drugs improved patient survival.

The availability of these two new drugs—as well as the immunotherapy sipuleucel-T (Provenge), which the FDA approved last April as an alternative to docetaxel for some men with metastatic castration-resistant prostate cancer—has altered the treatment landscape for advanced prostate cancer, several researchers said.

With a number of other experimental drugs in clinical trials also showing promise for the treatment of metastatic prostate cancer, it’s almost “an embarrassment of riches” at the moment, said Dr. Ian Thompson, of the University of Texas Health Science Center at San Antonio.

But although the survival improvements produced by abiraterone and cabazitaxel are meaningful, he cautioned, the benefits are still modest: both drugs improve patients’ median overall survival by approximately 2 to 4 months.

In addition, the availability of multiple treatment options creates new—albeit welcome—problems, as researchers and clinicians must now try to make difficult decisions about which drugs to use in which patients and when. Some of these decisions, however, involve so-called “off-label” uses of the available therapies.

Androgens Are Still Important

Abiraterone’s approval was based on findings from a clinical trial, funded by the drug’s manufacturer, Cougar Biotechnology, in which nearly 1,200 patients were randomly assigned to abiraterone in combination with the steroid prednisone or to prednisone plus placebo. The median overall survival was 14.8 months in patients who received abiraterone and prednisone and 10.9 months in those who received prednisone alone, researchers reported last December at a major European cancer conference. Patients treated with abiraterone experienced few serious side effects. (Findings from the trial that led to cabazitaxel approval were reported in March 2010).

Abiraterone and cabazitaxel haven’t been compared in a head-to-head trial, but abiraterone has fewer serious side effects and can be taken orally, which may make it the preferred first option for these patients, said Dr. William Dahut of NCI’s Center for Cancer Research.

“The ease of administration [of abiraterone] and the favorable side-effect profile will obviously play a role in which treatment clinicians and patients choose,” agreed Dr. Maha Hussain of the University of Michigan Comprehensive Cancer Center.

Patients who have already been treated with the drug ketoconazole may be an exception. (Although not approved by the FDA for use in men with advanced prostate cancer, ketoconazole has proven beneficial for some patients.) “Patients with prior exposure to ketoconazole probably don’t respond as well to abiraterone” as those who haven’t received it, Dr. Dahut explained.

Whereas cabazitaxel is a next-generation drug in the class of chemotherapy agents called taxanes, abiraterone is the first in an approaching wave of new agents for prostate cancer that, directly or indirectly, target testosterone—a wave that represents a “paradigm shift” in the treatment of this disease, according to Dr. Dahut. (See the box at the bottom of the page.) Abiraterone works by inhibiting an enzyme, CYP17, that plays a central role in allowing the body to produce testosterone from cholesterol.

Drug-induced castration with luteinizing hormone-releasing hormone agonists—which rob prostate tumor cells of the testosterone they need to grow—has been a standard and successful treatment for prostate cancer for several decades. But in many patients the disease eventually progresses despite very low levels of available testosterone.

“Fifteen years ago, it was largely believed that once a patient’s disease progressed on hormone therapy, he was hormone refractory and there was really no point going on to second- and third-line hormonal therapies,” Dr. Dahut said. But tumor cells, studies have shown, adapt to a low-androgen environment, in part by increasing the expression of the androgen receptors on their surfaces. So, while the overall amount of testosterone in the body may be very low, it’s still being produced, and tumor cells develop the ability to take in as much as they can get.

Abiraterone’s efficacy, he added, signals “the importance of targeting testosterone” even in patients in whom the hormone “is at castrate levels.”

Which Drugs, Combinations, or Sequences?

The availability of several new treatment options for advanced prostate cancer has created a situation in which patients and their doctors may need to make difficult clinical decisions when there isn’t necessarily sufficient clinical evidence. For example, some doctors will likely want to use abiraterone in patients with advanced disease who are no longer responding to standard hormonal therapies but who have not yet been treated with docetaxel.

Patients are likely to have responses to abiraterone at this point in their disease, Drs. Dahut and Hussain agreed, although, Dr. Dahut cautioned, there is no evidence yet that this treatment approach will improve survival. And, Dr. Hussain added, insurance coverage of this off-label indication is unlikely at this time. A phase III trial testing this approach is under way.

If the FDA eventually approves abiraterone for use in patients with castration-resistant disease who have not yet been treated with docetaxel, there will also be questions about whether abiraterone or sipuleucel-T should be used first.

More research is needed to determine the best sequence of therapies, or which combination of therapies might be more effective, Dr. Thompson said. The goal is to “conduct adaptive trials that use multiple agents that are most likely to benefit the individual patient,” he added.

Efforts in this area need to proceed with serious deliberation and care, Dr. Hussain stressed, particularly when it comes to testing combinations of drugs. “Smart, rational approaches supported by scientific mechanistic data to justify testing these agents in combination are needed,” she said, “not just because they’re available and we can do it.”

Doubling Down on Testosterone

In addition to abiraterone, two other drugs are in phase III clinical trials in men with castration-resistant prostate cancer that is no longer responding to docetaxel: TAK-700 and MDV3100.

In addition to testosterone, abiraterone affects production of other hormones that can lead to side effects such as hypertension; steroids are used to protect against or mitigate such side effects. Steroids can have their own long-term side effects, though, so the need to combine abiraterone with steroids could limit use of abiraterone in men with earlier-stage disease and longer life expectancies, Dr. Thompson noted.

Like abiraterone, TAK-700 also targets CYP17, but TAK-700 may be more selective in suppressing androgen production and does not appear to have a dose-response effect, Dr. Hussain explained. As a result, the drug can potentially be used at doses that won’t require concomitant steroid supplementation.

MDV3100 works differently, disrupting tumor cells’ ability to use testosterone. It does this in part by clogging up androgen receptors. Because of its mechanism of action, MDV3100 does not have to be used in combination with steroids.

Regardless of each drug’s strengths and weaknesses, the availability of efficacious second- and third-generation androgen-targeted agents represents “major progress,” Dr. Hussain said. “Each new agent appears to be better than the prior ones. This is great for patients.”

source: NCI bulletin