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Keywords:

  • best practice;
  • critical appraisal;
  • evidence-based;
  • formulary;
  • transparency

Introduction

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

The Regence Group is a Blue Cross, Blue Shield plan in the Pacific Northwest that covers approximately two and a half million people resident in the states of Washington, Oregon, Idaho, and Utah. The Pharmacy Department at Regence is responsible for reviewing all drugs that are ultimately placed on their formulary and also for drug policy. The evolution of the use of medication reviews in managed care plans, how evidence is used to make formulary decisions, and the role of the Pharmacy and Therapeutics Committee in the decision-making process, are discussed.

Evolution of Medication Reviews

Medication reviews of evidence that inform formulary decision-making have been utilized by health insurance organizations in the United States for many years. Approaches to conducting these types of reviews have evolved over time from manual methods of assessing formulary kits and abstracts of some published literature, to the application of sophisticated electronic processes that facilitate the processing of huge amounts of information and lead to a much more comprehensive assessment of pertinent information (Fig. 1). Notably, The Regence Group was instrumental in the early development of the Academy of Managed Care Pharmacy dossier, a medical data source that is currently widely used in the United States. Other tools and sources of information include evidence tables, pharmacoeconomic modeling, Food and Drug Administration (FDA) docket material, primary and secondary literature, and practice guidelines from nationally recognized agencies. At The Regence Group, we are now at the stage where best practice is not only having evidence, but is also being consistent with how that evidence is used. As such, the approach we take is to formulate the key research questions in the context of the goals of a particular analysis and then apply a reproducible, systematic method comprising a critical appraisal framework that is transparent to the general public. Indeed, with due regard to transparency, all of the information that we evaluate for formulary decisions is readily available on RegenceRx.com [1].

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Figure 1. Evolution of medication reviews.

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Although drug and technology assessments are continually being undertaken by multiple well-funded and high-quality agencies that provide access directly to relevant information; such as the Cochrane Library [2], National Institute for Health and Clinical Excellence [3], Clinical Evidence [4], Agency for Healthcare Research and Quality [5], The Canadian Agency for Drug's and Technologies in Health [6] and the FDA [7], our assessment process agenda is not necessarily aligned with the timing of publication. This is partly because of the way information is used in our appraisal process and partly because of time pressures for producing formulary decisions within the US health-care environment.

Evidence-Based Medicine Decision-Making

At The Regence Group, our best practice framework for evidence-based medicine decision-making comprises systematic evaluation, study data audit, critically appraising the evidence, and compilation of best information for informing formulary decisions in the form of a drug monograph. The systematic evaluation starts with a predefined search strategy that comprehensively gathers information in the form of randomized controlled trials, meta-analyses, systematic reviews, and observational studies about relevant end points and populations. As mentioned previously, the sources for this are myriad and can lead to collections of hundreds of publications (Fig. 2). Critical appraisal of the studies is done using a modification of the Delfini Group's process (http://www.delfini.org/—March 21, 2010) which typically reduces the number of publications that are deemed reliable to, on average, about 15%, and upon which the formulary considerations are made.

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Figure 2. Systematic evaluation for evidence-based decision-making in medicine.

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As is the case with many other managed care plans, we simplify the information selected by the critical appraisal of the evidence into categories of “inferior value,”“equivalent value,” and “superior value.” Inferior value typically means that a product may have a lesser clinical benefit than existing options, or there is some sort of a safety issue that suggests the product may not bring any clinical benefit and, in fact, may bring harms to the patient population. Equivalent value, which comprises about 85% of the evidence, refers to drugs that, unless there are significantly different clinical properties, are considered to be not very different from existing therapies; i.e., there are already multiple similar drugs of the same class with a similar mechanism of action. The last category, superior value, is reserved for products that may indeed bring additional clinical benefit to the armamentarium of existing products.

Establishing a Systematic Review Process

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

The Consolidated Standards of Reporting Trials statement [8] details 22 descriptions of informational elements that are important in determining whether a study provides value to your assessment. Using this as a template, we create a checklist for each study that is identified by our search strategy. We then apply a validity and usability grading scale based on that of the Delfini Group [9] (Fig. 3). According to this scale, Grade A is a straightforward designation of utility; Grade B encompasses a high and a low category accommodating the fact that the evidence may be potentially strong and therefore might be sufficient in making useful health-care decisions. Then there are Grades U and Grade X that encompass uncertainty and lack of utility; information in these grades is typically not considered by the Pharmacy and Therapeutics Committee. In addition to assigning a grade to the evidence, for added transparency, we also prepare a critique that summarizes our findings based on the critical literature review for each of the studies. This will have the salient points for the physicians on the committee to use to decide whether or not they will consider the evidence in making the ultimate formulary decision.

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Figure 3. Grading of evidence: Modified Delfini Validity & Usability Grading Scale [9].

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Reasons for Excluding Data

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

There are many reasons why studies end up being considered unreliable sources of evidence:

  • • 
    lack of transparency of methodologies including randomization, allocation, and blinding methods;
  • • 
    large numbers lost to follow-up;
  • • 
    problematic choices of outcomes rendering the data meaningless to the population of a managed care organization;
  • • 
    lack of intent to treat analysis;
  • • 
    nonsignificant findings from underpowered studies;
  • • 
    post hoc analyses

By way of example, if we consider 24 randomized controlled trials, including a total of approximately 8000 patients, that examined the efficacy of a new medication for the treatment of seizures, nerve pain, fibromyalgia and anxiety, we find that the reported study conclusions are that the drug is effective for treating these conditions compared to placebo. Nevertheless, when we subject these trials to our critical appraisal process, we produce somewhat different conclusions (Fig. 4). Indeed, on assessing the quality of the data it appears there is only potentially useful information for this particular drug from one trial. So, our conclusions are somewhat different from the study authors in that although we did find evidence of treatment value over placebo for seizures, there was uncertainty in the evidence about its value in the treatment of the other conditions. Furthermore, it remains unknown whether or not this drug is any better than existing drugs for this indication.

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Figure 4. Critical appraisal of scientific evidence.

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Taking the treatment of fibromyalgia as a specific example, there are multiple trials of four existing drugs used to treat this condition (milnacipran, duloxetine, pregabalin, gabapentin), with the number of patients ever randomized to these treatments ranging from 150 to more than 2500. Using our critical appraisal criteria, we found none of the available evidence from these trials to be even possibly useful; indeed, there was uncertainty in all cases, with no data really demonstrating superiority of one over another and modest benefit, at most, among medications for reducing fibromyalgia pain symptoms.

Although we now apply equal rigor to all drug evaluations in all disease areas, it is worth noting that historically, the same rigor of appraisal was not usually applied to cancer drugs, which were generally automatically added to the drug formulary. Taking sorafenib as a current example, we were able to find reliable evidence of efficacy in the treatment of unresectable hepatocellular carcinoma in that it improved survival for about 3 months, compared to placebo. In this case, this was considered sufficient to have the drug placed on our formulary.

Pharmacoeconomic Data

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

From a practical standpoint, we would like to use pharmacoeconomic data in the review process; however, if there is no useful clinical evidence to guide a decision, then we will typically not use these data at all. This is based on the philosophy that before you can use a pharmacoeconomic model to support outcomes and/or cost savings, the model itself needs to be based on sound, reliable scientific data as its foundation. Areas where we have been able to utilize pharmacoeconomic data, such as that for different osteoporosis agents and ACE inhibitors, have contributed to our making of sound formulary decisions, because we acknowledge that there is reliable evidence that these medications provide positive outcomes (i.e., reduced fractures, decreased heart attacks).

Observational Studies and Real-World Data

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

Postmarketing observational studies are very important for us, as they help identify potential safety concerns within the local patient population of interest. A frequent limitation of these studies, however, is their inability to draw reliable cause and effect conclusions. These studies would generally not hold up to the rigors of critical appraisal, but allow insight as to where further clinical study may be needed to prove a medication's value.

We have real-world pharmacy and medical data available within our organization, and these data represent the entirety of the real-world information that we access. This source provides us with information about patient adherence to medication regimens, expected outcomes, and appropriate medication use. In the latter case, we can set our medication use policy and then monitor it to establish if the medications are being used within the bounds of our practice standards and within the bounds of conditions where there is reliable evidence for their value to the medical plan. Other questions we can address with these data include whether or not medications provide medical cost offsets, and/or quality of life and productivity benefits.

Closing Remarks

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References

The Pharmacy and Therapeutics Committee members are the stewards of the health-care dollar and they need to have an evidence-based philosophy in conducting their meetings and making decisions; clearly, it is important that the committee aligns in this way within the organization. Toward achieving this, all of the committee members are trained in evidence-based evaluation, so that when they receive the drug monographs, they are well able to understand the information as it is presented. Although 85% of the time the decisions are evidence-based, it is worth noting that the physicians in this committee will at times make decisions based on judgment rather than evidence. Interestingly, over the past 5 years, 8 out of 10 of the evidence-based decisions were to reject adding the drug to the formulary, whereas in instances where the decisions were based on judgment, the drugs were added to the formulary 9 times out of 10. An indicator of the robustness of our system is seen when we look at drugs that were withdrawn from the market in the United States, in the last decade, because of safety problems (rofecoxib, alosetron, valdecoxib, gefitinib, hydromorphine ER, inhaled insulin, tegaserod, efalizumab) and find that none of these drugs was added to our formulary before withdrawal. This further emphasizes the important role of the use of evidence in the decision-making process and the importance of transparency of decisions.

Source of financial support: Oxford Outcomes, the National Pharmaceutical Council, and Shire Pharmaceuticals.

References

  1. Top of page
  2. Introduction
  3. Establishing a Systematic Review Process
  4. Reasons for Excluding Data
  5. Pharmacoeconomic Data
  6. Observational Studies and Real-World Data
  7. Closing Remarks
  8. References