Off-Label Drug Research Generates 'Medical Uncertainty'

Damian McNamara

December 13, 2018

A number of small studies that explored additional, off-label indications for pregabalin (Lyrica, Pfizer), and were promoted as promising, were never confirmed in subsequent, confirmatory research, a new systematic review shows.

Investigators from McGill University, Montreal, Canada, say they fear physicians are placing too much weight on findings from these small, early studies.

In the review of 238 total trials of pregabalin for nonapproved indications, 63% of 27 studies "potentially generated uncertainty about the efficacy of pregabalin that was not addressed" within 5 years in any subsequent confirmatory study, they write.

"Physicians typically might pick up a journal or even a magazine and see reports of a positive trial. What they may not realize is that trial is one of many, many other trials testing that same drug. By chance alone, many trials will be 'positive' and show an effect," study co-investigator Jonathan Kimmelman, PhD, professor and director of the Biomedical Ethics Unit in the Department of Social Studies, told Medscape Medical News.

"If the study is small and of short duration, they should be careful about thinking the drug probably works for the condition tested in the trial. In fact, unless the drug has been tested in a large and confirmatory trial, or unless the drug shows huge effects and the small trial had a rigorous design, chances are the drug does not work," he added.

The findings were published online November 26 in JAMA Internal Medicine.

Pregabalin an Attractive Target

Some of the smaller studies in the review appear to be funded without industry support.

Investigators conduct these trials to find treatments for new conditions, for the prospect of getting a publication for themselves or their trainees, or for the collection of pilot data for a more ambitious and larger clinical trial, Kimmelman said.

"Physicians should realize that when they do this, even if the trial is positive, the odds that the intriguing findings will be rigorously tested in a subsequent confirmatory trial are low.

"This means that, unintentionally, physicians who run these small trials are often creating more medical uncertainty than they are resolving," he said.

The investigators chose pregabalin as part of a series of studies they are conducting to examine the relationship between preclinical, exploratory, and confirmatory evidence in the development of drugs for pain.

"We seized on this particular analysis after we saw the volume of exploratory clinical trials that had been conducted in pregabalin," Kimmelman said. Knowledge of widespread prescription of this agent also "made selection of pregabalin for this particular analysis very attractive," he said.

Pregabalin was first approved in 2004 in Europe and the United States for various neuropathic pain conditions and as adjunctive therapy for adults with partial onset seizures. Subsequent official indications included generalized anxiety disorder in Europe and neuropathic pain associated with spinal cord injury in the United States.

The agent is also "widely used off label in acute, subacute, and chronic noncancer pain," the researchers note.

Interestingly, as reported at the time by Medscape Medical News, Pfizer paid a $2.3 billion fine for promoting pregabalin's off-label use in 2009.

The action involved charges of illegal marketing, misbranding, and payment of kickbacks to physicians for prescribing the COX-2 inhibitor valdecoxib (Bextra), which is no longer marketed.

'Clinical Agnosticism'

For the study, the investigators classified the 238 studies used in the current review as either exploratory or confirmatory. They considered Phase III trials confirmatory and Phase I and II trials exploratory. Nearly three quarters of the included trials were exploratory (74%).

The researchers also found that a higher proportion of primary endpoints in exploratory trials were statistically positive compared with confirmatory trials (107 [61%] of 176 studies vs 34 [55%] of 62 studies, respectively).

"If such trials are not followed by confirmatory trials, health care providers who draw on this literature can be left perceiving, but not knowing, that a drug could be clinically useful, a state we have defined elsewhere as 'clinical Agnosticism,' " they write.

About half of the 33 indications were assessed in exploratory trials only. Of the 16 new indications subsequently tested in confirmatory studies, five (31%) ultimately received European Medicines Agency and/or US Food and Drug Administration (FDA) approval.

A majority of all included trials (79%) evaluated pregabalin for a new pain-related indication. The remaining 21% included 19 potential neurologic and psychiatric indications.

Clinical agnosticism was addressed immediately in seven of the 27 indications (26%) within 5 years of follow-up because the initial publication was a positive confirmatory trial.

For restless legs syndrome and itch, researchers addressed agnosticism within 5 years with the publication of a positive confirmatory trial. For an alcohol-dependence indication, there was an inconclusive confirmatory trial in the same time frame.

For the remaining 17 studies (63%), potential agnosticism generated in initial publications was not addressed by confirmatory testing within 5 years.

No Proven Benefit, Widespread Use

"Whether measured in number of trials or indications, much of this activity appears aimed at exploring the efficacy of pregabalin rather than proving it," the researchers write.

Clinical agnosticism may be sufficient to support off-label prescription. For example, since initial publication of an inconclusive exploratory low back pain trial, no confirmatory trials have been published nearly a decade later.

In addition, a study published in the New England Journal of Medicine and another published in Pain demonstrated no beneficial effect in this population compared with placebo.

Nevertheless, pregabalin is widely used off-label for this indication.

Essential tremor and migraine are two additional off-label indications where the authors report prolonged agnosticism.

Kimmelman and colleagues acknowledge that the motivations and funding for off-label indication trials are often not robust.

"Because confirmatory trials are expensive and concentrate resources among a small number of principal investigators, public funding bodies are often reluctant to sponsor them," they write.

"Moreover, because physicians can prescribe approved drugs off-label, incentives for companies to advance promising treatments into confirmatory trials weaken after drug approval," they add.

Legal Promotion

Physicians should also be aware that companies "may be using small clinical trials as a backdoor and legal way to market their drug for off-label uses, since a published positive trial is, in effect, the equivalent of an advertisement and FDA allows companies to distribute reprints of trials testing off-label uses," Kimmelman said.

The results of this review using pregabalin can be generalizable to other, but not all, drugs, he added. For example, he and colleagues previously demonstrated a similar dynamic for two anti-cancer drugs, sunitinib and sorafenib.

In general, drugs that target a mechanism shared by multiple conditions, such as a general process in metabolism or immune system function, are more likely to experience a similar research pattern. In contrast, drugs that target a process unique to a single disease carry a lower risk for a number of exploratory trials not backed by confirmatory studies.

In addition to expanding the research to additional medications, the investigators would like to explore the ethics of "what we call the 'generation of agnosticism,' " Kimmelman said.

The current research is a component of a larger research program designed to ask: "How much does society get for all the human welfare invested in drug development, and where are the greatest inefficiencies in this process?" he noted.

The current findings also complement previous work by the same researchers to assess "the huge volume of findings that never get published or circulate in the literature."

"The ultimate aim here is to discover ways that our research systems can better serve patients and healthcare systems," said Kimmelman.

Call for More Confirmation

In an accompanying editorial, Joseph S. Ross, MD, Section of General Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, writes that for official approvals, "the FDA generally requires that companies complete numerous clinical studies," including one or two pivotal trials, of which more than 80% are randomized; and that the trials use double-blinded allocation and include a placebo or active control comparator group.

"But then how do we know whether a drug works for non–FDA-approved clinical indications?" Ross asks.

"This question is quite a bit more complicated, because any company or noncompany researcher, such as an investigator based at an academic institution, can test the drug in a clinical study for any indication, and there is no requirement to establish safety and efficacy if FDA approval is not solicited," he writes.

"A medical literature replete with small, short clinical trials that suggest clinical benefit but are neither generalizable nor replicated creates even greater uncertainty among clinicians," he adds.

Once published, these studies "can generally be distributed as part of companies' physician-detailing and marketing efforts, potentially encouraging off-label prescribing for uses that may not benefit patients and may cause harm," Ross writes.

Better coordination of testing drugs for indications outside of official FDA approval is warranted, he notes. This will "ensure that any studies suggesting clinical benefit and safety are confirmed, ideally in a generalizable patient population."

The study was funded by the Canadian Institutes of Health Research and the Louise and Alan Edwards Foundation. Dr Kimmelman has disclosed no relevant financial relationships. Dr Ross receives research grant funding from the US Food and Drug Administration as part of the Centers of Excellence in Regulatory Science and Innovation program and from Johnson & Johnson.

JAMA Intern Med. Published online November 26, 2018. Abstract. Editorial

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