Using Subjective Evidence in FDA Review

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Scholars call for greater transparency in how FDA uses subjective evidence in treatments for brain injuries.

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Dylan Williams was reportedly walking through a crosswalk on his way home from the library when a car­ struck him and his head went through the car’s windshield­.

Although Dylan remarkably recovered from the traumatic brain injury he suffered in the accident, over 2.8 million people go to the hospital or die from similar injuries each year, according to recent data. Severe brain injuries can often result in comas and other impairments of awareness that are collectively called “disorders of consciousness.” Even though many patients experience disorders of consciousness from brain injuries, there exists no standard course of medical treatment for these disorders.

In a recent article, four scholars argue that the current regulatory approval process for new drugs and medical devices reduces the likelihood that medical treatments for consciousness disorders will be developed. Megan Wright of Pennsylvania State University Law School, Keturah James and Adam Pan of Yale Law School, and Joseph Fins of Weill Cornell Medical College claim that the U.S. Food and Drug Administration (FDA) demands objective evidence to support the approval of new treatments. For that reason, treatments for disorders of consciousness are disadvantaged in the approval process because the evidence supporting these treatments is largely subjective, Wright and her coauthors argue.

Objective evidence typically includes quantitative measurements such as blood pressure or plasma levels. By contrast, subjective evidence is often gathered through clinician observations or patient reports, such as through structured questionnaires asking if symptoms have improved, Wright and her coauthors explain.

FDA has not been transparent as to how it weighs subjective and objective evidence, but according to Wright and her coauthors, the agency’s practices have shown a preference for objective measures.

FDA guidance documents on its drug approval process indicate that the agency prefers objective evidence of a drug’s effectiveness over subjective reports and observations, Wright and her coauthors say. For example, one guidance document provides examples of objective measures that can be used to determine the effectiveness of a treatment but gives scant attention to the use of subjective evidence.

Studies also indicate that FDA prefers objective evidence of a drug’s effectiveness. One recent study found that 45 percent of FDA approved drugs used objective markers to demonstrate effectiveness, but patient reports and clinical observations only accounted for about 18 percent and 33 percent of approved drugs, respectively.

Wright and her coauthors use the example of disorders of consciousness that occur after severe brain injuries to illustrate why FDA’s preference for objective evidence can be problematic.

The preference is primarily problematic because researchers have not found reliable objective indicators that can be used for determining the effectiveness of treatments for disorders of consciousness. Wright and her coauthors suggest that even if objective indicators exist, researchers would have to use invasive procedures to collect necessary data because the indicators would be within the brain.

Wright and her coauthors also note that objective measurements—like blood sugar or heart rate—do not tell clinicians whether patients are experiencing a clinical benefit from the treatment for consciousness disorders.

Instead, clinicians use subjective evidence­—like patient surveys and observations—to evaluate treatments for disorders of consciousness. By using observations and patient reports, clinicians can learn if a treatment is effective directly from the patient, Wright and her coauthors explain.

For disorders of consciousness, Wright and her coauthors say that sometimes reports or surveys submitted by family members can be useful. Family members may be more familiar with the patient’s level of consciousness and notice small changes in a patient’s behavior after treatment that may otherwise go undetected or unperceived by the patient.

Although Wright and her coauthors highlight the benefits of subjective evidence, they do recognize FDA’s concerns. Subjective evidence often involves clinicians using their own judgment and observations, which allows more room for error than objective evidence gathered by technology. Subjective evidence has also been criticized because it may be interpreted differently by various clinicians. By relying on objective measures, clinicians can often ensure that less bias is introduced, which may make the data more accurate.

But Wright and her coauthors argue that subjective evidence is beneficial because it ensures that clinicians are considering patient preferences when determining if a treatment is effective.

To resolve the tension between subjective and objective evidence, Wright and her coauthors say that FDA should whenever possible require clinicians to submit multiple forms of subjective evidence in addition to required objective evidence. Subjective evidence can include results that show patient preferences, patient-reported outcomes, and patient’s perceptions of treatment effectiveness as part of medical device applications. Wright and her coauthors argue that the combination of subjective and objective evidence is particularly useful for disorders of consciousness treatments.

Admittedly, objective indicators have not been established for disorders of consciousness. But Wright and her coauthors say that clinicians can compare potential objective indicators with observations and patient surveys to determine if the objective evidence could eventually be used as a reliable indicator of whether the treatment is providing a clinical benefit.

Although these measures may put additional burdens on clinicians, Wright and her coauthors argue that both subjective and objective evidence is needed to “promote sound science and regulatory policy.”

In addition to encouraging clinicians to submit more subjective evidence, Wright and her coauthors say that FDA needs to be more transparent about how it weighs evidence. Agency transparency, Wright and her coauthors conclude, “will reduce uncertainty and may also increase all stakeholders’ trust in the regulatory process.”