Review process for IVIg treatment

Discussion

There are now more than 20 sets of diagnostic criteria for CIDP and MMN that range from highly specific, where the goal is to select ideal patients for research, to most sensitive, which capture more cases but risk overdiagnosis.^2,–,5 These multiple efforts reflect a neuropathy field characterized by the absence of a gold standard test for diagnosis and diseases with overlapping findings that require a demanding clinical logic to account for phenotypic, laboratory, and electrodiagnostic features. Complicating the situation, bedside decision makers must calculate the downside of missing a diagnosis in a potentially treatable case that might not fulfill diagnostic criteria.^6,–,8 It should not be surprising that clinicians with differing experiences and values, and who may have diverse decision-making capabilities, can approach the same problem differently.

As a specialty pharmacy, NuFACTOR has been a first-hand observer of the use of IVIg in neuropathy. In addition, many of our experts (J.S.K., T.D.L., R.B., and D.S.S.) have consulted for insurance payers as reviewers and arbiters or have published diagnostic criteria. A decade after food and drug administration (FDA) approvals of treatments for these conditions,^9,–,12 our team wondered if the pendulum may have swung toward excessive use. We designed this QA/QI study to learn about clinical practice decisions by mimicking the review processes used by insurance companies. Because of the multiplicity of published criteria that reflect the diagnostic difficulty, we made the assumption that these would be difficult to use alone in making review decisions. Thus, we asked our expert reviewers to rely on real-world records provided to insurers to make individual assessments about diagnoses and expected treatment responses. As the study progressed, it became clear that “ideal” data do not exist to facilitate the required interactions between patients, physicians, infusion companies, and payers.

Using our methods, diagnostic accuracy appears to be even more pessimistic than the report by Allen and Lewis,¹ in which 53% of cases diagnosed with CIDP met electrodiagnostic criteria. In contrast to the earlier work, we included all forms of demyelinating neuropathies, rather than CIDP alone, and focused only on patients naive to IVIg therapy. We found just 15.3% of the cases in which electrodiagnostic studies were provided, all of which were approved by insurance companies, clearly fulfilled electrodiagnostic criteria for a demyelinating neuropathy. In approximately 12% of the provided cases, electrodiagnostic studies were incomplete or could not be interpreted, and no studies were provided in nearly one-third of cases.

In the judgment of our expert reviewers, only 42% of the reviewable cases and 32% of overall cases clearly met diagnostic criteria consistent with an immune neuropathy, whereas nonimmune neuropathies accounted for more than half of reviewable cases. Notably, these values may be an overly optimistic estimation of real-world practice because our cohort solely included patients already approved for IVIg therapy. The a priori exclusion of insurer-denied cases would have had the effect of increasing our estimate if these cases were the clearest examples of conditions other than immune neuropathy.

The overall 36.7% treatment response rate may represent another overestimate. This value would have been lower had we included cases in which the treating physician explained that IVIg had been discontinued specifically because there was no response. Other key biases may also have affected our response rate. IVIg had been reordered, by definition, in all cases the SER examined. We can presume that the treating physicians reordered IVIg because they believed it worked, but anchoring to the original diagnosis might have affected both how they perceived and documented the outcome. This, in turn, could influence the interpretation by our SER. The effect of anchoring could be magnified if a treating physician relied on subjective responses or failed to carefully document examinations. Patient experience may add to this because placebo responses can be as high as 20%.³ Biases may have contributed to the surprisingly high 21.7% “objective” response rate in cases in which our first reviewers diagnosed types of neuropathy that are known not to be immune responsive.

Our panel deemed the records “unreviewable” in more than 20% of cases. This problem typically reflected incomplete, poorly written, or difficult-to-follow notes. Follow-up assessments also often lacked key observations to allow for clear conclusions. The SERs had no way to contact the treating physicians, as could be done in controlled studies, because insurance companies rarely use iterative approaches to track missing information. As a result, we adopted the term “AUNTs” (Analytically Uninterpretable Note Taking) to designate this real-world phenomenon of how experts perceive clinical records.¹³

Even given these limitations, predictions about who would and would not respond to IVIg treatment by our IERs, paired with the interpretation of the SERs, were significantly better than the overall SER-determined base response estimates. This provides evidence that input from neuromuscular specialists, who understand the complex reasoning processes involved in differential diagnosis of neuropathies, could improve on the current review process.

Our findings also suggest that prescribing some IVIg for patients who do not have immune-mediated neuropathy is unavoidable. This likely reflects realities related to diagnostic uncertainty. For example, IERs believed that twice as many patients were appropriate candidates for a trial of IVIg (32%) as were likely to respond (15%). These low numbers continue to suggest that only few cases are sufficiently documented not only to clearly warrant treatment but also to demonstrate how reviewers may at times be open to therapy, despite skepticism about the eventual benefit. We have previously used the term “UNCLEs” (UNcertain CLinical Entities) to describe a differential diagnosis that cannot reasonably be narrowed to exclude a treatable condition.¹³ Two of the more common examples in our study were cases likely to have primary muscular atrophy, in which MMN remained on the differential diagnosis^14,15 or diabetic neuropathies with features that could not be fully distinguished from CIDP.⁶ Weak indications for treatment despite a known diagnosis is another factor. For example, Distal Acquired Demyelinating Symmetric Neuropathy with an Immunoglobulin M paraprotein, which is known to respond poorly to IVIg,¹⁶ and mild Guillain Barré Syndrome, where progression has ceased before treatment was ordered, were considered reasonable for a trial of IVIg by some of our IERs. It may be important to capture these specific clinical entities, to make providers aware of uncertainty, and, therefore, open to discontinuation of therapy when treatment seems ineffective.

Overall, our findings, consistent with earlier reports suggesting that IVIg is overused in immune neuropathy, call for a change from the current approach. Potential areas for improvement include documentation of key observations, inclusion of expertise in review processes, and capturing data to highlight true and perceived uncertainty as it pertains to diagnosis and treatment responses. Given the cost of IVIg, it is worth ensuring that clinicians submit concise information at the onset and at designated intervals during therapy, as has been proven possible in the IGOS study in acute neuropathies.¹⁷ Uncertainty makes it harder to control costs and may foster distrust in communications around treatment decisions. All parties desire to use expensive or scarce resources appropriately and to improve care. Providers might be more enthusiastic about supplying requested documentation and more accepting of decisions to deny insurance coverage for IVIg therapy if they appreciate that decisions were well reasoned, data driven and backed by expert review. Similarly, insurers might be more willing to moderate time-consuming utilization review practices if physicians demonstrate a willingness to participate in a well-validated process to maximize the value of therapy.