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Managing the pain of clinical trials
With Kalorama Information estimating the worldwide market for pain management drugs and devices at about $35 billion last year, the stakes for bringing therapies for pain conditions to market are higher than ever—and clinical trial sponsors in this space are working to address some of the challenges inherently involved in investigating what can be highly subjective patient outcomes.
In response to these concerns, diverse players across the drug development spectrum are working to achieve greater clarity and sounder measurement of patient response. Of equal concern to trial sponsors is staying up-to-date on the growing body of industry-authored literature as well as regulator guidance on the subject, all with the aim of differentiating their analgesia products in the competitive pharmaceutical marketplace.
And the conditions that may be affected by their efforts are just as diverse, with both chronic and acute pain conditions like osteoarthritis, lower back pain, diabetic neuropathy, fibromyalgia, whiplash injury and complex regional pain syndrome all standing to benefit from industry consensus on the way trials in this space are conducted.
"Pain is subjective. It's what the patient tells you it is, and there is no objective way of measuring that," says Dr. Robert H. Dworkin, a professor of anesthesiology, neurology, oncology and psychiatry at the University of Rochester School of Medicine and Dentistry.
In 2002, Dworkin co-founded the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, colloquially known as IMMPACT. Seeking to develop consensus reviews and recommendations for improving the design, execution and interpretation of clinical trials for pain treatments, the interdisciplinary group, IMMPACT's participants included academia, regulatory agencies, consumer support and advocacy groups as well as industry.
"We met to discuss a wide range of issues involving design, analysis, conduct and interpretation of clinical trials," Dworkin says. "We thought about the heterogeneity of evaluating pain treatments and doing meta-analysis, and that it would help the field if there was some consensus on dealing with outcomes in clinical trials. We went into that first meeting thinking it would be a one-off kind of thing, but the group quickly decided to meet on a regular basis."
Subsequent meetings yielded a set of standards by which trials could be more effectively conducted for a wide range of disciplines such as anesthesiology, clinical pharmacology, internal medicine, law, neurology, nursing, oncology, outcomes research, psychology, rheumatology and surgery. Now, coming off its 16th meeting in June, IMMPACT's recommendations and systematic reviews have been widely cited and have guided the design of clinical trials, other types of clinical research and a national survey. Additional consensus meetings are planned, and research initiatives involving the assessment of pain and the design and interpretation of clinical trials are ongoing.
The main outcome of these efforts has been the development of Patient Reported Outcomes, or PROs, which is an umbrella term covering a range of consequences of a disease condition and/or its treatment as reported by the patient, including symptom experience, sense of wellbeing, functional status, treatment adherence and treatment satisfaction.
"For the assessment of pain, PRO measures are often the only viable clinical endpoints because there are no objective physical or psychological markers of disease or treatment activity that can be observed or measured," writes Michael Kuss, vice president of analgesia at Premier Research in a recent white paper, "Patient-Reported Outcomes in Analgesia Clinical Trials." "Evaluation of analgesic efficacy requires the assessment of multiple PRO domains in order to adequately characterize treatment impact."
"PROs need to be primary endpoint, and PROs should also be very well represented in secondary endpoints," Dworkin says. "One of the things people have thought about is more objective measures of physical function, such as patient activity levels during the day, and even while sleeping. If a drug is efficacious and reduces pain more than the placebo, does the drug also increase a patient's activity level over the course of the trial? That would be an interesting secondary outcome."
Dworkin notes that data generated by a PRO instrument can provide evidence of a treatment benefit from the patient perspective, but for this data to be meaningful, there should be evidence that the PRO instrument effectively measures the particular concept that is studied. Generally, findings measured by PRO instruments may be used to support claims in approved product labeling if the claims are derived from adequate and well-controlled investigations that use PRO instruments that reliably and validly measure the specific concepts at issue.
The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have imposed standards that call for a higher degree of scientific rigor in the development and evaluation of PRO measures, as well as the level of documentation required to support use and content validity of these measures in confirmatory clinical trials.
"If you're going to bring novel PROs to the FDA, you better be sure to have crossed your Ts and dotted your Is. Seek guidance from the FDA as soon as possible," Dworkin advises.
Many sponsors seeking expert consultation from contract research organizations (CROs) with expertise in PRO best practices and instrument validation—and in fact, Kuss' white paper advises companies to do just that. One such CRO, Chapel Hill, N.C.-based Rho, recently published its own white paper, "The Minimal Clinically Important Difference in Efficacy Trials of Analgesics," on the subject.
"Various PROs will likely remain the gold-measures in clinical trials for analgesics … but they do not indicate whether the magnitude of the improvement would be meaningful to patients," writes Dr. Brian Boehlecke, medical officer at Rho. "Small differences may be statistically significant, but not indicative of a change in pain intensity which many individuals would consider important and worth the expense and possible risks associated with taking that medication. Therefore, for trials of the efficacy of analgesics, it is necessary to determine the smallest change in a PRO pain scale score that would be considered important by patients—i.e., the minimal clinically important difference (MCID)."
The most commonly used quantitative scales for a patient's rating of pain intensity are numeric rating scales (NRS) and linear visual analog scales (VAS). The former often has choices ranging from 0 to 10 representing "none" to "the worst pain imaginable, respectively. The latter requires a respondent to mark a point along a 100-mm line indicating pain intensity, with the extremes having the same descriptive anchors as the NRS.
There are two general approaches to estimating the MCID: anchor-based and distribution-based. Anchor-based methods compare the changes in pain scale scores with an independent external criterion or anchor. The latter is usually some type of global assessment rating in which the patients rate the change in their pain status under treatment into one of several subjective descriptive categories such as "very much worse," "slightly worse," "no change," "slightly better," "much better" or "very much better."
"You want to establish a result that is meaningful for the patient, something that is anchored to some other thing a patient is reporting—a change from baseline improvement to the more meaningful improvement of, 'yes, I feel better.' You want a tight enough estimate that you have statistical significance," explains Ben Vaughn, a statistical scientist at Rho.
The average change in pain scale score for the subjects who rated their change in pain into the chosen category (e.g., "much better") is considered to be the MCID.
"Although reductions of 30 to 35 percent from baseline scores on an 11-point NRS or a 100-mm VAS have been found to be reasonable estimates for the MCID in a variety of studies of both acute and chronic pain, there is no 'one-size-fits-all' level of MCID in all settings and for all purposes. Patients' assessments of the importance of a given reduction in pain intensity may be influenced by whether it has allowed them to reach a tolerable level of residual pain," concludes Boehlecke.