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When is evidence sufficient for decision-making? A framework for understanding the pace of evidence adoption Translation of medical evidence into practice has not kept pace with the growth of medical technology and knowledge. We present three case studies  –  statins, drug eluting stents and bone marrow transplantation for breast cancer – to propose a framework for describing five factors that may influence the rate of adoption. The factors are: validity, reliability and maturity of the science available before widespread adoption; communication of the science; economic drivers; patients’ and physicians’ ability to apply published scientific findings to their specific clinical needs; and incorporation into practice guidelines.

Robert W Dubois*1, Michael Lauer2 & Eleanor Perfetto3 National Pharmaceutical Council, 1717 Pennsylvania Avenue, NW, Suite 800, Washington, DC 20006, USA 2 National Heart, Lung, & Blood Institute, Bethesda, MD, USA 3 Pfizer, Washington, DC, USA *Author for correspondence: Tel.: +1 202 827 2079 [email protected] 1

KEYWORDS: adoption n evidence n evidence-based medicine n technology diffusion

Enthusiasm about comparative effectiveness research (CER) and funding to perform it will only benefit patients if they and their providers incorporate the resulting evidence into routine practice. In 2001, the Institute of Medicine issued a highly cited report on the “quality chasm” between scientific evidence and routine medical practice [101]. The Institute of Medicine noted that it takes “an average of 17 years for new knowledge generated by randomized controlled trials to be incorporated into practice, and even then application is highly uneven.” However, the 17-year delay does not always occur, and in some cases the opposite does: medical technologies are adopted in an absence of sufficient evidence of benefit and safety. In 1974, Aday and Andersen proposed a framework for the study of healthcare access [1]; it has been widely used by health services researchers when considering the drivers of healthcare utilization. The framework is based upon the assumption that healthcare utilization is a function of individual, societal and health system determinants. The model has four factors that directly and indirectly influence use: ■■ Health policy ■■

Characteristics of the healthcare system

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Characteristics of the population

Consumer satisfaction However, this basic model of access and utilization does not capture influences from communication vehicles such as the media and ignores the attributes of the service that is being used, such as its innovation or the strength of the evidence behind it. As an extension to the Aday and Andersen access model, the Rogers’ model of diffusion of innovation [102] also provides insights. Rogers describes four diffusion elements: an innovation, which is communicated through certain channels, over time, among members of a social system. Rogers recognized the role of key opinion leaders, social networks, the media, and other communication forms in innovation diffusion. ■■

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Given that multiple stakeholders influence evidence adoption, we thought it worthwhile as a preliminary thought exercise to build upon this previous work by bringing together representatives of different sectors. Therefore the authors, representing public, private and academic backgrounds engaged in dialog to combine an approach that considers healthcare access and utilization with an approach that considers diffusion of innovation. We then explored whether the resulting conceptual framework might elucidate why adoption occurs slowly in some instances and more rapidly in others. The framework includes five domains: ■■

Validity, reliability and maturity of the science: whether the current understanding of the pathophysiology of the disease, the mechanism of the therapeutic intervention, and the measured effectiveness in improving clinical outcomes are sufficiently mature to i­ncorporate the newly released evidence;

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Communication of the science: whether the study results are amplified through the media or other communication vehicles;

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Applicability: patients’ or providers’ ability to apply published scientific evidence to specific clinical needs;

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Economic drivers that might influence adoption (who gets paid? Was it reimbursed? What marketing or detailing efforts were i­nfluential?);

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Rapid (or slow) incorporation into practice guidelines, which on the one hand might result from other factors like maturity of the science, while on the other hand has the p­otential to influence clinical behavior.

We apply this framework to three specific adoption scenarios (statins, drug eluting stents [DES], and bone marrow transplantation [BMT] for breast cancer), which we chose because they:

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Are well documented (both the published clinical evidence and the utilization changes that resulted);

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Exemplify how the pace of adoption into routine practice ranges from ‘slow’ (more than 17 years) to ‘rapid’ (less than a year). Pace refers to the time interval between evidence availability and its adoption into routine clinical practice;

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Encompass drugs, devices and procedures;

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Address evidence that supported increased use in some circumstances and decreased use in others;

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Reflected high quality evidence (e.g., each case consisted, at least in part, of multiple r­andomized control trials).

For each scenario we use our framework to describe, as much as possible, the impact of our factors on the speeds of evidence adoption. We also explore how the framework elements may explain future adoption. We acknowledge that these three scenarios are too small a sample size to pinpoint, in a definitive manner critical, factors impacting adoption but are a starting point for further work. Cholesterol-lowering therapy & the course of statin treatment ■■ Clinical background

The cholesterol-lowering scenario exemplifies an evidence base that developed gradually and that slowly became incorporated into clinical care. In 1961, Framingham Heart Study investigators reported a strong relationship between blood cholesterol levels and risk of coronary artery disease [2]. However, it was not until the early 1980s that a NIH panel concluded that reduction of cholesterol levels lowers risk [3]. Lovastatin, introduced in 1987, was the first in the new statin class that inhibits the primary enzyme involved in cholesterol formation and was easier to administer than existing drugs. Guidelines at the time noted an absence of evidence regarding long-term safety and impact on coronary disease risk, and therefore only recommended lovastatin as second-line therapy [4]. The subsequent introduction of pravastatin and simvastatin was followed by publication of three secondary and two primary large-scale prevention trials [5–9]. These randomized trials provided evidence that statins: ■■

Improve survival in patients with existing coronary artery disease, with no increase in noncardiac mortality;

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Reduce the risk of recurrent coronary events, including death, even in patients with modest elevations of cholesterol levels;

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Reduce the risk of coronary events in men with no primary history of coronary disease and with moderate hypercholesterolemia;

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Reduce first major coronary events in men and women with average overall cholesterol levels and below average high-density lipoprotein levels.

A 1999 meta-analysis concluded that statin therapy decreased all-cause mortality, and risk reduction was similar for men and women as well as for middle-aged individuals and elderly patients [10]. Despite these encouraging data, there were safety concerns. Cerivastatin was withdrawn from the market in 2001 after reports of fatal rhabdomyolysis, an extreme form of muscle damaging myopathy. The 2002 Adult Treatment Panel III guidelines nevertheless asserted that statins were generally safe, with only rare incidence of myopathy [11]. Additional concerns arose and the US FDA issued a warning in 2011 that patients undergoing statin therapy may ­experience m ­ emory loss or develop diabetes [103]. In 2005 and 2010, meta-analyses involving hundreds of thousands of patients were published, reporting that prolonged statin treatment should be considered in all patients at high risk of any type of major vascular event [12], and that intensive lowering of cholesterol beyond current target levels may provide additional benefits [13]. ■■ What happened: trends in use of statins

In 1992, 5 years after the introduction of lovastatin, drug therapy was recommended in only 20% of ambulatory visits involving a diagnosis of hyperlipidemia. By 2000, more than 50% of such visits involved drug therapy, with statins accounting for more than 90%. Nevertheless, treatment gaps remained. In 2002, more than 50% of outpatient visits for moderate- and highrisk hyperlipidemic patients did not record use of a statin [14]. An analysis for 1999–2006 also indicated that opportunities for improvement remained. Among adults who had been told they had high cholesterol, those who reported using cholesterol-lowering medications rose from 39.1% to just 54.4% [15]. Between 1988 and 2010, the proportion of all American adults using cholesterollowering medications rose from 3 to 16%, with proportions of 30–40% among women and men over the age of 60 [16]. ■■ Explaining the trends

Lack of maturity in the science was probably the most important factor for the delay in acceptance

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and adoption. Although epidemiological investigations had established the relationship between elevated levels of cholesterol and coronary events, numerous questions remained: did statins impact coronary mortality and all-cause mortality? Would evidence generalize to women and the elderly? And, what was the long-term safety of these drugs? It was not until the end of the 1990s that large-scale, double-blind, randomized controlled studies had addressed these issues. Statin use temporarily trended downward in 2001 and 2002 with the withdrawal of c­erivastatin but continued upwards thereafter. Other factors probably had less of an impact. Given the limited evidence on effectiveness in long-term use, statins remained the second choice drug therapy in the Adult Treatment Panel guidelines throughout the 1990s. The media primarily focused on the potential for statin-induced myopathy, but the effect was neither severe nor enduring. Patients and physicians may not have felt comfortable applying scientific evidence to their specific circumstances until after publication of huge individual-level meta-analyses in the early 2000s. Multiple drug companies focused resources on appropriate statin use through advertising, samples and sales efforts. It is quite surprising that in spite of these efforts, slow adoption occurred. Use of drug-eluting stents in coronary artery disease ■■ Clinical background

The scenario of drug-eluting stents (DES) represents a rate of evidence adoption that greatly exceeded those of statins and it primarily occurred within 2–3 years, although subsequent utilization rates fluctuated markedly [17]. Coronary bypass surgery was demonstrated in the 1970s to improve survival with severe coronary disease [18]. Percutaneous options emerged in the late 1970s, with the advent of balloon angioplasty, followed in the 1990s by bare-metal stents (BMS). Sometimes the coronary arteries narrowed again (restenosis), limiting the value of these technologies. DES were designed with the hope of reducing risk the risk of restenosis. In 2002, a European multicenter trial found that compared with BMS, DES led to fewer major cardiac events, largely because of reduced rates of restenosis [19]. These positive findings were confirmed in 2004 in a similar American study [20]. However, later trials stimulated debate about the use of stents at all, as compared with medical

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therapy among patients with stable disease [21] (in other words, not in the setting of acute heart attacks), and as compared to bypass surgery in patients with extensive blockages in multiple coronary arteries [22]. ■■ What happened: trends in use of DES

Within 1 year of approval by the FDA in 2003, more than 50% of all percutaneous coronary interventions involved implantation of at least one DES; by the beginning of 2005 this rate had increased to approximately 90% [17]. Soon thereafter, a series of highly publicized events dampened this trend [23,24]. In 2006, reports emerged regarding a late risk of lifethreatening thrombosis [25,26]. In December, 2006, the FDA hosted a contentious debate[27], followed by publication in January 2007 of a landmark observational analysis that supported extended use of clopidogrel to reduce long-term risk of thrombosis [28]. Several similar studies corroborated these findings [29,30]. Within months, use of DES fell, from 90 to 60% of all stents [17,24], especially for ST-elevation myocardial infarction, de novo lesions and uninsured patients [24]. Usage later increased after reports showed that antiplatelet therapy reduced long-term re-stenosis rates [17,28,31] along improvements in matrix, strut thickness, stent structure, eluting surface and drugs available for elution [32]. ■■ Explaining the trends

When the FDA approved DES, experts felt comfortable advocating rapid adoption [19,20,33], as many cardiologists were convinced that they had ‘solved’ the restenosis problem. In retrospect, neither the science nor the economic forecasts were mature, as over time, a complex and confusing picture emerged [33]. Post-approval science not only revealed thrombosis problems, but suggested that the results of early trials overstated benefits [20,23]. A recent analysis of over 1.5 million procedures suggest that DES are overused relative to their primary benefit of reducing the risk of restenosis [34]. The DES market has been characterized as extraordinarily complex and competitive. One company, Johnson & Johnson/Cordis (NJ, USA), took the early lead to convince CMS to establish a new DRG and thereby increase stent reimbursements; the combination of assured reimbursement, positive clinical trials and an aggressive direct-to-consumer advertising

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campaign [35] together led to rapid adoption. Ironically, in 2011 J&J/Cordis withdrew from the DES market because of sagging sales and diminishing market prospects [104]. Meanwhile, economic and policy concerns of hospitals and clinicians were not borne out: these concerns included a higher cost per procedure (US$2200); increased procedural complexity and duration; potential malpractice liability; and requirements for ancillary medications [36,37]. In fact, investigators at the Mayo Clinic (MN, USA) found that DES reduced procedural, hospital and physician costs, primarily due to lower rates of repeat procedures [38]. Cardiology societies released guidelines that followed published literature [19,20,39]. The 2005 percutaneous coronary intervention guidelines recommended simply that “DES be considered as an alternative to BMS in subsets of patients in whom trial data suggest efficacy.” In 2007, the guidelines were updated and included caution evident in research about risk of thrombosis and the need for antiplatelet therapy. Critics have noted a high prevalence of conflicts of interest among writers of cardiology guidelines [40]. Of the 26 writers of the 2005 percutaneous coronary intervention guidelines, 12 (46%) disclosed conflicts, including seven who received honoraria or served on speaker bureaus, four who received equity, and seven who served as consultants or members of advisory boards. The most commonly cited company was Medtronic (MN, USA), which manufactures the Endeavor ® DES. Given the multiplicity of events occurring during the time that DES were developed, studied and disseminated, it is uncertain what impact practice guidelines, or the possible conflicts that affected their writing, had on adoption. BMT for breast cancer ■■ Clinical background

High-dose chemotherapy with autologous BMT for breast cancer represents an example where newly available evidence from four simultaneously released randomized controlled trials led to an almost immediate and profound impact on clinical decision-making. Many have chronicled the rise in enthusiasm and use of this procedure. Here we focus on the rapid adoption of the subsequent evidence showing lack of efficacy and the precipitous decline in use. In the 1970s, patients with leukemia could be cured by receiving a combination of radiation

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and high-dose chemotherapy. Since treatment not only affected the cancer cells but also the patient’s own immune system, they could only survive by receiving a subsequent infusion of bone marrow cells. In the 1980s, this approach was attempted in patients with metastatic breast cancer. Early Phase II studies showed survival benefit compared with historical controls [41]. Throughout the 1980s and up through the middle of the 1990s, use of the procedure rose [42]. As others have written, growth in use related to enthusiasm by key opinion leaders, powerful lobbying efforts by breast cancer groups, legal challenges when insurance companies denied coverage, and legislative mandates to require coverage [42]. In 1999, the results of a series of prospective randomized trials became available. At the annual meeting of the American Society for Clinical Oncology (ASCO), the results of four studies were presented. Three of the studies showed no benefit for the procedure compared with conventional chemotherapy. One study showed benefit, but was later found to be based upon fraudulent data [42]. The New England Journal of Medicine published the results of the largest trial with an accompanying editorial stating: “We should now acknowledge that, to a reasonable degree of probability this form of treatment for women with metastatic breast cancer has been proved to be ineffective and should be abandoned in favor of well-justified alternative experimental approaches” [41]. ■■ What happened: trends in use

In the years leading up to the ASCO presentation, 2000–4000 women underwent the procedure each year at a unit cost of approximately $80,000 with a mortality rate between 2 and 6%. In the year following the ASCO presentations, use fell by over 75%. By 2002, only 118 women received the therapy, a 97% fall from its peak annual use [42]. ■■ Explaining the trends

In an unprecedented fashion, the field progressed from little high quality evidence to replicated results from both USA and International trials. This profound evidence was conveyed to approximately 20,000 attendees of the ASCO conference. The media also had great interest in the topic. In the month before the conference, the National Cancer Institute announced that

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results would be forthcoming and NBC Nightly News, The Wall Street Journal, and The New York Times had prominent stories. On the day of the ASCO presentations, an Op-Ed in The New York Times stated that the procedure “is not a miracle cure” and the results “do not show the leap in survival rates that had been predicted” [42]. Several other factors probably contributed to the rapid adoption of the findings. The base of scientific knowledge was ready to accommodate the new information. The risks of the procedure were clear but the benefits were not yet scientifically proven. The National Comprehensive Cancer Network had also recently concluded that the data were insufficient upon which to develop clinical practice guidelines. The procedure had high associated costs. Subsequent to the trial results, the insurer Aetna withdrew reimbursement [42]. Given that the BMT procedure utilized a variety of drugs sold by multiple companies and that the reduction in use occurred so rapidly, it is very unlikely that marketing changes by industry had substantial impact. Discussion

As funding for CER accelerates, it will be important to minimize delays in the availability of credible evidence to its use in routine care. To better understand why the speed of evidence adoption varies, we propose a framework and applied its factors to case studies where findings rapidly (e.g., BMT for breast cancer), moderately (e.g., DES), and slowly (e.g., statins) impacted care. Table 1 summarizes our findings. ■■ Validity, reliability & maturity of the science

For many years, there was clear recognition that statins had beneficial effects on cholesterol levels. However, proof of their effects on cardiovascular conditions and mortality, and for whom and under what circumstances such effects could be expected was slow to develop. There were many high-quality studies, but none (positive or negative), that resulted in dramatic changes in clinical understanding. As a result, statins remained second-line therapy until the science matured and proof emerged. By contrast, rapid reductions in use of BMT for breast cancer resulted from the availability of multiple, corroborating randomized controlled trial results. The science was mature, the risks were clear, but the benefits needed substantiation from reliable

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Table 1. Conceptual factors applied to case examples. Conceptual factor

Statins

Drug-eluting Bone marrow stents transplantation for breast cancer

Validity, reliability and maturity of the science

+

++

Communication of the science

+

+

+++

Ability to apply published findings

0

++

++

Economic drivers

-

++

++

Rapid (or slow) adoption into practice guidelines

-

NA

NA

+++

■■Ability to apply published scientific findings

-: Retarded evidence adoption; +: Modestly increased evidence adoption; ++: Strongly increased evidence adoption; +++: Very strongly increased evidence adoption; 0: No discernible relationship; NA: Not applicable.

and valid studies, which simultaneously became available at the ASCO Conference. By the time DES were introduced, BMS were already a large part of percutaneous coronary intervention procedures. Two randomized studies supported the benefits of the new drug device combination and provided the necessary evidence to shift the market away from BMS to the newer type, which occurred in a fairly rapid fashion. ■■ Communication of the science

The presentation of the BMT results at an international conference provided a communication forum where the opinion leaders and routine providers heard a compelling set of study results. Multiple reports in leading newspapers led up to the release and later communicated the trial findings. An editorial in a leading journal stated unequivocally that the procedure should be abandoned for this use. By contrast, there were no singular ‘landmark’ research results for statins, and thus there were no headline communications that immediately affected adoption. Communication about DES may have had some positive influence on use simply because it r­epresented an innovation in therapy. We also note that new findings about potential harms, as in BMT when it provided no benefit, unexpected vessel closures in DES, and muscle damage from statins, may receive more attention and become more rapidly incorporated into doctor–patient decisions than findings about potential benefit. Moving forward, if the level of confidence in the evidence is high, the findings can be properly interpreted, and the populations to which they apply are well understood, media outreach

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may provide an effective avenue to increase the speed of adoption. Articles in national and local papers, presence in social media, and segments on popular talk shows may lead to more rapid awareness of new evidence to drive change.

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For patients, adoption of a new therapy or test often requires several steps. They can and do search the web to learn about healthcare options. But, patients often need assistance from their provider to translate the evidence into routine care, especially when considering starting a new therapy. By contrast, discontinuing a therapy or choosing not to proceed with one, can be applied more readily and rapidly. For BMT, enthusiasm from patients and pressure from patient groups quickly abated when the new evidence became available. Since patients typically need referral to a BMT center, the new information they learned from the lay press could and likely did have a rapid impact on their discussions about BMT referral. It should be noted that stopping use of a therapy does not always occur quickly with new and unsupportive data. Experience with vertebroplasty for vertebral fractures shows that negative evidence may be disputed rather than incorporated into practice [43]. ■■ Economic drivers

Multiple studies have shown that financial incentives can impact evidence adoption [44– 46]. Although reimbursed at the time of the International meeting, the rapid cessation of BMT for breast cancer was likely accelerated by changes in insurers’ subsequent unwillingness to pay for the procedure. For DES, changes in reimbursement were also relevant. Hospital payment was increased when patients received DES, compensating for the increased cost of the new stent. In addition, multiple device manufacturers promoted these stents to cardiologists and ultimately to patients as well [37]. For statins, economic factors probably did not greatly i­nfluence the slow rate of adoption. ■■ Practice guidelines

Practice guidelines likely were a retarding influence on statin uptake. The unresolved questions about statin efficacy and who might benefit probably slowed the adoption of statins as firstline therapy in practice guidelines. The benefits of DES resulted in a significant shift to this

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therapy well in advance of changes in practice guidelines. Similarly for BMT, the precipitous fall in use was not temporally related to changes in guidelines. Our framework combines elements from prior work on healthcare access and diffusion of innovation. We have augmented that work by considering characteristics of the evidence, incorporation into clinical practice guidelines, and financial drivers. It should be noted that our case studies, which represent three different types of therapy (medications, devices and surgery) were purposefully selected as a convenience sample to illustrate the potential usefulness of the framework. Given the single case study for each therapeutic type, we cannot determine whether there are distinct differences in ­adoption patterns among them. A more objective application of the framework to a broader and randomly selected set of situations is needed. As an example, we may have missed the opportunity to examine the role of interpersonal communication with peers and social networks that is necessary to persuade clinicians to change their practice. With our limited sample, we could not explore whether the number of publications, commentaries, or conference presentations at specialty meetings (with the exception of the BMT case study) relate to speed of adoption. Other factors, like focus on surrogate end points (e.g., cholesterol levels rather than patient-centered ­outcomes) and scientific complexity may play a role.

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Conclusion

There is substantial funding towards and enth­ usiasm about CER. To achieve the desired improvements in patient care, appropriate adoption of well-substantiated evidence needs to occur. Our framework may assist in e­ncouraging that to happen in a timely fashion. Future perspective

Over the next 6 years, CER entities funded through the Patient-Centered Outcomes Research Trust Fund, expect to receive approximately $4 billion [105]. It will be crucial that the potential care improvements identified by this research are adopted expeditiously to ensure that patients not only receive the most up-todate evidence-based care, but also see a return on their tax dollars used to fund this cutting edge research. With significant funding aimed at dissemination and translation, the authors hope that these federal efforts will meet these goals. Financial & competing interests disclosure RW Dubois is employed by the National Pharmaceutical Council, a policy research organization supported by the US’s major research-based pharmaceutical companies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Executive summary A proposed framework for understanding the pace of evidence adoption and application was applied to three case studies: statins, drug-eluting stents and bone marrow transplantation for breast cancer. These case studies ranged from slow to rapid adoption to illustrate the effects of each factor of the framework. ■■ Five factors in the conceptual framework were identified as influential: maturity of the science; communication of the science; economic drivers; patients’ and physicians’ ability to apply published scientific findings; and incorporation into practice guidelines. ■■ A more objective application of the framework to a broader and randomly selected set of situations is needed to further validate the findings from the three case studies. ■■ The overall goal of the framework is to encourage consideration of the critical factors that affect adoption and help to optimize the pace with which new treatments and new findings about treatments are brought into routine clinical practice. ■■

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future science group

When is evidence sufficient for decision-making? 

after widespread adoption of the procedure. The trial evidence did not support the use, yet clinical practice did not change. The authors discuss the issues related to the lack of evidence adoption.

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Uses vertebroplasty as an example where randomized trial evidence became available

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n

Recent analysis of adoption patterns for a series of case examples. The authors interviewed key stakeholders and identified five important reasons that adoption may not have occurred.

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medical services and health. J. Med. Pract. Manag. 8, 317–321 (1992). 46 Chernew M, Gibson TB, Yu-Isenberg K,

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Special report

http://iom.edu/reports/2001/crossing-thequality-chasm-a-new-health-system-for-the21st-century.aspx (Accessed 4 January 2012) n

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102 Rogers E. Diffusion of innovations (5th

Edition). The Free Press, NY, USA (2003). http://books.google.com/books?id= 9U1K5LjUOwEC&pg=PR2&lpg=PP1&dq= rogers+diffusion+of+innovation+5th+edition (Accessed 16 April 2013) 103 US FDA. FDA expands advice on statin risks.

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