Interesting Comparative Effectiveness Research (CER) Case Study: “Real World Data” Hypothetical Migraine Case and Lack of PCORI Endorsement

Interesting Comparative Effectiveness Research (CER) Case Study: “Real World Data” Hypothetical Migraine Case and Lack of PCORI Endorsement

In the October issue of Health Affairs, the journal’s editorial team created a fictional set of clinical trials and observational studies to see what various stakeholders would say about comparative effectiveness evidence of two migraine drugs.[1]

The hypothetical set-up is this:

The newest drug, Hemikrane, is an FDA-approved drug that has recently come on the market. It was reported in clinical trials to reduce both the frequency and the severity of migraine headaches. Hemikrane is taken once a week. The FDA approved Hemikrane based on two randomized, double-blind, controlled clinical trials, each of which had three arms.

  • In one arm, patients who experienced multiple migraine episodes each month took Hemikrane weekly.
  • In another arm, a comparable group of patients received a different migraine drug, Cephalal, a drug which was reported to be effective in earlier, valid studies. It is taken daily.
  • In a third arm, another equivalent group of patients received placebos.

The study was powered to find a difference between Hemikrane and placebo if there was one and if it were at least as effective as Cephalal. Each of the two randomized studies enrolled approximately 2,000 patients and lasted six months. They excluded patients with uncontrolled high blood pressure, diabetes, heart disease, or kidney dysfunction. The patients received their care in a number of academic centers and clinical trial sites. All patients submitted daily diaries, recording their migraine symptoms and any side effects.

Hypothetical Case Study Findings: The trials reported that the patients who took Hemikrane had a clinically significant reduction in the frequency, severity, and duration of headaches compared to placebo, but not to Cephalal.

The trials were not designed to evaluate the comparative safety of the drugs, but there were no safety signals from the Hemikrane patients, although a small number of patients on the drug experienced nausea.

Although the above studies reported efficacy of Hemikrane in a controlled environment with highly selected patients, they did not assess patient experience in a real-world setting. Does once weekly dosing improve adherence in the real world? The monthly cost of Hemikrane to insurers is $200, whereas Cephalal costs insurers $150 per month. (In this hypothetical example, the authors assume that copayments paid by patients are the same for all of these drugs.)

A major philanthropic organization with an interest in advancing treatments for migraine sufferers funded a collaboration among researchers at Harvard; a regional health insurance company, Trident Health; and, Hemikrane’s manufacturer, Aesculapion. The insurance company, Trident Health, provided access to a database of five million people, which included information on medication use, doctor visits, emergency department evaluations and hospitalizations. Using these records, the study identified a cohort of patients with migraine who made frequent visits to doctors or hospital emergency departments. The study compared information about patients receiving Hemikrane with two comparison groups: a group of patients who received the daily prophylactic regimen with Cephalal, and a group of patients receiving no prophylactic therapy.

The investigators attempted to confirm the original randomized trial results by assessing the frequency with which all patients in the study had migraine headaches. Because the database did not contain a diary of daily symptoms, which had been collected in the trials, the researchers substituted as a proxy the amount of medications such as codeine and sumatriptan (Imitrex) that patients had used each month for treatment of acute migraines. The group receiving Hemikrane had lower use of these symptom-oriented medications than those on Cephalal or on no prophylaxis and had fewer emergency department visits than those taking Cephalal or on no prophylaxis.

Although the medication costs were higher for patients taking Hemikrane because of its higher monthly drug cost, the overall episode-of-care costs were lower than for the comparison group taking Cephalal. As hypothesized, the medication adherence was higher in the once-weekly Hemikrane patients than in the daily Cephalal patients (80 percent and 50 percent, respectively, using the metric of medication possession ratio, which is the number of days of medication dispensed as a percentage of 365 days).

The investigators were concerned that the above findings might be due to the unique characteristics of Trident Health’s population of covered patients, regional practice patterns, copayment designs for medications, and/or the study’s analytic approach. They also worried that the results could be confounded by differences in the patients receiving Hemikrane, Cephalal, or no prophylaxis. One possibility, for example, was that patients who experienced the worst migraines might be more inclined to take or be encouraged by their doctors to take the new drug, Hemikrane, since they had failed all previously available therapies. In that case, the results for a truly matched group of patients might have shown even more pronounced benefit for Hemikrane.

To see if the findings could be replicated, the investigators contacted the pharmacy benefit management company, BestScripts, that worked withTrident Health, and asked for access to additional data. A research protocol was developed before any data were examined. Statistical adjustments were also made to balance the three groups of patients to be studied as well as possible—those taking Hemikrane, those taking Cephalal, and those not on prophylaxis—using a propensity score method (which included age, sex, number of previous migraine emergency department visits, type and extent of prior medication use and selected comorbidities to estimate the probability of a person’s being in one of the three groups) to balance the groups.

The pharmacy benefit manager, BestScripts, had access to data covering more than fifty million lives. The findings in this second, much larger, database corroborated the earlier assessment. The once-weekly prophylactic therapy with Hemikrane clearly reduced the use of medications such as codeine to relieve symptoms, as well as emergency department visits compared to the daily prophylaxis and no prophylaxis groups. Similarly, the Hemikrane group had significantly better medication adherence than the Cephalal group. In addition, BestScripts had data from a subset of employers that collected work loss information about their employees. These data showed that patients on Hemikrane were out of work for fewer days each month than patients taking Cephalal.

In a commentary, Joe Selby, executive director of the Patient-Centered Outcomes Research Institute (PCORI), and colleagues provided a list of problems with these real world studies including threats to validity. They conclude that these hypothetical studies would be unlikely to have been funded or communicated by PCORI.[2]

Below are several of the problems identified by Selby et al.

  • Selection Bias
    • Patients and clinicians may have tried the more familiar, less costly Cephalal first and switched to Hemikrane only if Cephalal failed to relieve symptoms, making the Hemikrane patients a group, who on average, would be more difficult to treat.
    • Those patients who continued using Cephalal may be a selected group who tolerate the treatment well and perceived a benefit.
    • Even if the investigators had conducted the study with only new users, it is plausible that patients prescribed Hemikrane could differ from those prescribed Cephalal. They may be of higher socioeconomic status, have better insurance coverage with lower copayments, have different physicians, or differ in other ways that could affect outcomes.
  • Performance Biases or Other Differences Between Groups is possible.
  • Details of any between-group differences found in these exploratory analyses should have been presented.

Delfini Comment

These two articles are worth reading if you are interested in the difficult area of evaluating observational studies and including them in comparative effectiveness research (CER). We would add that to know if drugs really work, valid RCTs are almost always needed. In this case we don’t know if the studies were valid, because we don’t have enough information about the risk of selection, performance, attrition and assessment bias and other potential methodological problems in the studies. Database studies and other observational studies are likely to have differences in populations, interventions, comparisons, time treated and clinical settings (e.g., prognostic variables of subjects, dosing, co-interventions, other patient choices, bias from lack of blinding) and adjusting for all of these variables and more requires many assumptions. Propensity scores do not reliably adjust for differences. Thus, the risk of bias in the evidence base is unclear.

This case illustrates the difficulty of making coverage decisions for new drugs with some potential advantages for some patients when several studies report benefit compared to placebo, but we already have established treatment agents with safety records. In addition new drugs frequently are found to cause adverse events over time.

Observational data is frequently very valuable. It can be useful in identifying populations for further study, evaluating the implementation of interventions, generating hypotheses, and identifying current condition scenarios (e.g., who, what, where in QI project work; variation, etc.). It is also useful in providing safety signals and for creating economic projections (e.g., balance sheets, models). In this hypothetical set of studies, however, we have only gray zone evidence about efficacy from both RCTs and observational studies and almost no information about safety.

Much of the October issue of Health Affairs is taken up with other readers’ comments. Those of you interested in the problems with real world data in CER activities will enjoy reading how others reacted to these hypothetical drug studies.


1. Dentzer S; the Editorial Team of Health Affairs. Communicating About Comparative Effectiveness Research: A Health Affairs Symposium On The Issues. Health Aff (Millwood). 2012 Oct;31(10):2183-2187. PubMed PMID: 23048094.

2. Selby JV, Fleurence R, Lauer M, Schneeweiss S. Reviewing Hypothetical Migraine Studies Using Funding Criteria From The Patient-Centered Outcomes Research Institute. Health Aff (Millwood). 2012 Oct;31(10):2193-2199. PubMed PMID: 23048096.

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