DISCUSSION PAPER

Real-World Evidence to Guide the Approval and Use of New Treatments Steven Galson, Amgen, and Gregory Simon, Group Research Institute

October 18, 2016

Current State Effectiveness The Focus of Traditional Evidence Generation on Traditional efficacy trials typically aim to evaluate a Narrow Questions Regarding Efficacy and Safety single treatment rigorously. In contrast, patients, pro- viders, and health systems choose among alternative Research regarding new treatments (drugs, biologi- treatments on the basis of net benefit in real-world cal products, and high-risk devices) often begins with practice. Real-world effectiveness may differ substan- a broad assessment of epidemiology, disease tially from efficacy detected in the traditional clinical burden, and shortcomings of existing treatments. That trial setting. Factors contributing to that efficacy–effec- research may draw from diverse data sources, includ- tiveness gap include variation in practice settings, pro- ing real-world data generated by health system opera- vider decision making, patient adherence, co-occurring tions (see Figure 1). conditions, and concomitant treatments. In a clinical The phase of treatment develop- trial designed to assess efficacy, these factors would ment typically follows a well-established pathway from be considered sources of noise or error, and trial de- initial evaluation of safety to preliminary evaluation of sign would attempt to minimize variation. In everyday therapeutic efficacy to pivotal trials intended - tosup clinical practice, these sources of variation are directly port regulatory approval for marketing. Those pivotal relevant to practical decisions by patients and provid- trials focus on key questions of efficacy (typically in ers and are central to the information stakeholders comparison to placebo or some analogous control need to inform practical decisions. Many treatments condition) and safety (especially serious or previously would be expected to show some slippage or loss of unrecognized adverse effects). This focus is consistent benefit between efficacy trials and real-world practice. with the responsibility of the U.S. Food and Drug Ad- But we cannot presume that slippage is consistent ministration (FDA) for assuring the safety and efficacy across treatments, patient populations, or practice of drugs, biological products, and medical devices at settings. Consequently, findings from efficacy trials re- the time of approval. garding differences (or lack of differences) in efficacy Regulatory approval is sometimes followed by sys- do not necessarily translate to the same differences in tematic postmarketing evaluation to address a wider real-world performance. range of practical or real-world questions. This more pragmatic research again draws from more varied Tolerability sources of data drawn from diverse clinical settings. While patients and are certainly concerned about less common and more serious adverse effects A Lack of Information for Stakeholders (Patients, of new treatments, they are equally concerned about Providers, and Health Systems) to Guide Real- more common adverse effects—such as nausea, trem- World Decisions or, fatigue, weight gain, or interference with sexual Evidence generated by traditional clinical research of- function. Even when traditional efficacy trials evaluate ten fails to address key questions of patients, physi- these effects, the resulting evidence is rarely adequate cians, and health systems regarding the appropriate to guide patients’ and physicians’ decisions regarding role of new treatments. Those unaddressed concerns alternative treatments—especially if those treatments include the following: are to be continued for months or years.

Perspectives | Expert Voices in Health & Health Care DISCUSSION PAPER

Figure 1 | Real-world evidence is derived from curating, standardizing, and analyzing real-world data to ob- tain high-quality and reliable information from diverse and complex sources. Real-world evidence could inform all phases of treatment discovery and development, although thus far has been more commonly used to inform the questions and data in early development decisions and in postmarketing safety surveillance or comparative effectiveness studies. In contrast, clinical development and review has tended to more use idealized and tightly controlled data sources for efficacy trials.

Value in the early phases, heterogeneity of effects is more Health care payers base coverage and reimbursement often a source of error to be minimized rather than an decisions regarding new treatments on the balance of important signal to be detected. net cost and benefit, although payers may not consider Current Incentives Do Not Promote Necessary long-term factors, such as the benefits of prevention, Innovation over a typical lifespan. Given the increasing of high insurance deductibles and coinsurance ar- Our current evidence-generating process has evolved rangements, patients and families must also consider to fit our traditional regulatory and business environ- the value of alternative treatments. True net cost of a ment. Business imperatives of new treatment develop- new treatment depends not only on its price but also ment drive research toward a relatively narrow focus: on the net impact on overall cost of care. Traditional producing the data essential for regulatory approval. clinical trials, in which treatment protocols are highly Traditional clinical trials are optimized to efficiently -ad controlled, usually offer little information on how new dress key questions in the regulatory process: Is a new treatments affect overall or downstream use of health treatment superior to a placebo or other appropriate services. control treatment with respect to a specific clinical out- come? Is there evidence of a specific danger or harm— Heterogeneity of Treatment Effects especially a harm not previously recognized? An individual patient and his or her are natu- Bringing a new treatment to market involves sig- rally most interested in person-specific effects (“What nificant time and expense. For developers of new are the expected benefits and harms of this treatment treatments, broadening research to address real- for someone like me?”). Traditional clinical trials focus world questions may introduce additional uncertain- instead on assessment of average effects. Particularly ty or delay and, in addition, require data not readily

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available to industry. Expanding the evidence-generat- Leveraging the full potential of these data sources ing process to address real-world effectiveness, value, will depend on data integration capabilities. Analytic tolerability, and heterogeneity of treatment effects processes enabling patient-level linking of disparate would almost always require more flexible treatment clinical data sources are helping to address data qual- protocols and more heterogeneous clinical popula- ity issues (e.g., filling in missing data and vetting data tions. The “noise” introduced by that flexibility and het- by searching for inconsistencies across data sources). erogeneity could certainly interfere with the detection Networked systems (e.g., the Observational Health of primary “signals” regarding efficacy and safety. Data Sciences and Informatics [OHDSI] Collaboration) Ideally, developers of new treatments would be re- are enabling data aggregation on a scale not previ- warded for generating evidence more relevant to real- ously possible and are yielding information on patient world decisions. Those rewards might include approval population characteristics and health care utilization for labeling regarding improved effectiveness, toler- that may significantly impact future trial design and ability, or value. Some European regulators may con- improve the generalizability of results (Hripcsak et al., sider evidence regarding cost-effectiveness or value 2016). in regulatory or pricing decisions. In the United States, A key challenge of leveraging clinical data to support research to support those claims has been impeded by the evaluation of medical products resides in the fact uncertainty regarding the types of evidence that will be that providers and health systems are not systemati- acceptable to support approval of novel and cally assessing the impact of treatment. The routine new indications (Bipartisan Policy Center, 2016). collection of standard outcome measures is an impor- tant but tractable barrier. Enabling Developments The Increasing Use of Electronic Health Records The Increasing Use of Standard Patient-Reported and Development of Linked Data Resources Outcome Measures Data generated from research and practice have his- In addition to traditional clinical data, patient experi- torically been siloed. However, as the concept of a ences and perspectives are increasingly being incor- learning health system continues to take hold, such porated as essential aspects of the medical product distinctions are increasingly being reexamined. The evaluation process. Patient-reported outcomes may nation’s electronic health information infrastructure include symptoms, quality of life, and functional status. has continued to mature over the past decades, and, Patient-centered outcomes research is a primary focus as a result, a wealth of clinical data—residing in elec- of the Patient-Centered Outcomes Research Institute tronic health records, patient registries, and adminis- (PCORI), which has initiated the development of mini- trative claims databases—now provides an opportuni- mum standards for patient-reported outcomes data. ty to generate evidence on the effectiveness of medical PCORI has also established PCORnet, a centrally coor- products directly from clinical experience, comple- dinated network of research networks, to improve the menting the data generated through traditional ran- speed and efficiency of clinical research by leveraging domized controlled trials. Electronic records systems existing large data sources, including patient-powered can certainly facilitate the traditional clinical trials, ex- research networks. panding the scale and lowering the cost of participant The Use of E-Health and M-Health Tools to Collect recruitment and recording of clinical outcomes. In ad- Real-World Data dition, the “data exhaust” of ordinary (nonresearch) health care has the potential to inform regulatory and The increasing popularity of wearable and other mo- reimbursement decisions. However, ensuring that the bile devices that collect health-related data from indi- data are fit for the purpose of research will require viduals has opened new avenues for consumer and thoughtful consideration. Most real-world data, includ- patient engagement and the collection of real-world ing those from electronic health records and claims da- data. Of course, such data only have value if they are tabases, are not currently generated for the purpose meaningful. Mobile devices such as medical wear- of research. ables that can passively and accurately collect data on

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primary clinical endpoints can help to demonstrate the require minimal data transfer from data sources that benefit of a particular intervention—a capability that would remain under the control and maintenance of is of great interest to not only patients and providers their owners (Kuehn, 2016). Beginning in late 2014, but also health systems and manufacturers of medical FDA has been transitioning from the Mini-Sentinel sys- products. Online patient communities and consumer tem to the full Sentinel initiative. Along with the Har- search behavior, too, may be sources of data on ef- vard Pilgrim Health Care Institute, which was chosen as fectiveness, safety, use, and compliance. However, in a data analytics partner to the program, the initiative addition to technical barriers related to data capture has established relationships with 19 data partners and integration, a number of legal and regulatory chal- that cover a combined 178 million lives. lenges must be addressed prior to routine integration of these real-world data sources with more traditional Example: Observational Health Data Sciences and structured clinical datasets. Informatics Program The OHDSI program was created with the aim of facili- Promising Practices tating better health decisions by using collaboratively Population-Based Surveillance Using Health generated evidence (1). OHDSI builds on the 5-year System Data Observational Medical Outcomes Partnership (OMOP), The linkage of health system records has enabled a public–private partnership that focused on the use large-scale observational research including represen- of observational datasets for investigating medical tative samples of patients treated in under real-world products. The program was relocated to the Reagan- conditions. Research to date has focused primarily on Udall Foundation for the FDA and is the basis of the outcomes detectable through traditional insurance Innovation in Medical Evidence Development and Sur- claims data, including billing diagnoses and proce- veillance (IMEDS) program, in which the OHDSI infor- dures. The increasing availability of rich clinical data mation model was developed (Hripcsak et al., 2015). from electronic health records should enable research OHDSI now operates as an international collaborative regarding a broader range of effectiveness outcomes, that utilizes open-source data analytic tools applied including laboratory results, vital signs, and standard- to a network of databases contributed to by 90 par- ized patient-reported outcomes. ticipants for population- and patient-level analyses. In a recent demonstration of the potential for using the Example: FDA Sentinel Initiative OHDSI system in large-scale, international observa- tional research, the disease treatment pathways for The FDA Sentinel initiative was created with the goal of type 2 diabetes mellitus, hypertension, and depres- establishing an integrated, national, electronic system sion were investigated using data aggregated from that monitors the safety of medical products, includ- 11 sources providing electronic health records of 250 ing small molecule drugs and biologics. The initiative million patients across four countries (Hripcsak et al., was taken in response to recommendations of the In- 2016). stitute of (IOM) (IOM, 2006) and the 2007 FDA Amendments Act that mandated FDA to have a system Research Embedded in New Product Registries in place for active postmarket risk identification and analysis (Food and Drug Administration Amendments Systematic registries of patients exposed to new treat- Act of 2007). The Sentinel initiative for medical product ments are more common for the postmarketing evalu- safety surveillance was launched in 2008. In 2009, the ation of medical devices than for drugs or biological Mini-Sentinel program was established as a pilot effort products. These registries can support both observa- to test the core function of the future system—mainly tional research and randomized trials to evaluate the the analysis of health care information obtained from effectiveness and tolerability of new products. multiple and varied data sources and the utilization Example: Transcatheter Valve Registry of the data to inform FDA decision making (Sentinel Program Interim Assessment—FY15, 2015). A main The Society for Thoracic Surgeons and the American goal for the program was to enable real-time queries College of collaborated with FDA and the while maintaining the privacy of patients and to build Centers for Medicare & Medicaid Services to create a system that would rely on existing infrastructure and the Transcatheter Valve Therapy (TVT) Registry (2) of

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patients undergoing valve repair or replacement sur- Example: Salford Lung Study gery. The registry was launched in 2011 to track patient Initiated in 2012, the Salford Lung Study was a safety and outcomes from transcatheter aortic valve 12-month, open-label, phase III pragmatic randomized replacement in real-world settings, enrolling nearly controlled trial (pRCT) sponsored by GlaxoSmithKline all patients receiving a device. One important reason and conducted in the Salford borough of the greater for establishing the registry was to support gaps both Manchester area in the United Kingdom (3). The study in premarket trials of medical devices, which are typi- represents the first time a pRCT was conducted- be cally held only in specialized centers and on a carefully fore the registration of the treatment being investi- selected patient samples, and in the postregulatory gated (New et al., 2014). The study included a series approval period. Postregulatory approval is aimed at of trials that evaluated a new once-daily-administered optimizing outcomes, patient selection criteria, device dry-powder inhaler containing both the corticoste- safety monitoring, and possible expansion of device roid fluticasone furate and the long-acting β2 agonist indications. While traditionally different stakeholder vilanterol (FF/VI). Previous studies demonstrated that a groups collected data to support such efforts in dispa- combined administration was more effective in treat- rate ways, a collaboration among professional societ- ing chronic obstructive pulmonary disease (COPD) ies, regulators, payers, the medical device industry, cli- than each of the components administered separately nicians, and patient groups enabled the selection and (Bakerly et al., 2015). The trials were specifically -de harmonization of the data elements comprising the signed to compare the real-world effectiveness of FF/VI TVT Registry as well as patient selection criteria (Carroll to existing treatments for asthma and COPD in a large et al., 2013; Carroll et al., 2015). segment of the population of patients during routine In 2011 the TVT Registry began a partnership with clinical care. The primary outcomes measured in the the Duke Clinical Research Institute for registry data trials were the rate of moderate and severe exacerba- analytics, and in 2013 the first results from the TVT tions and measured improvement in asthma control Registry were published, reporting on outcomes from for COPD and asthma, respectively. 7,710 patients. By 2015, more than 319 medical centers Patients were randomized and received the usual participated in the TVT Registry involving more than care for the duration of their study, including dispens- 18,500 cases of transcatheter aortic valve replacement ing of trial medication at local . The local (Rumsfeld et al., 2015). As an example of the TVT Reg- technological and clinical infrastructure in Salford fa- istry’s role as an infrastructure for conducting postap- cilitated the implementation of this pRCT. While more proval studies, in 2013 FDA approved expanded label- than 60 primary care clinics were involved in the trial, ing for a transcatheter heart valve (Edwards SAPIEN), patients in the study area are served by one regional allowing its use among a larger segment of patients hospital, and both primary and secondary health pro- with aortic stenosis; the decision was based partially viders share one integrated on data provided from the TVT Registry (Society of Tho- system. The Salford Integrated Record, originally cre- racic Surgeons, 2013). ated in 2001, is updated in real time and allowed the necessary safety monitoring required from a phase III Randomization Embedded in Real-World Practice trial. Additional data feeds into the system were cre- Despite common misperceptions, real-world evidence ated to capture information on mortality and access to need not be generated solely through retrospective health care services outside the region. Furthermore, analysis of existing data. Increasingly, clinical trials are all community pharmacies in the Salford area also being conducted in real-world settings to improve the participated in the study and provided information on generalizability of results and to reduce inefficiencies medication adherence and prescriptions delivered. related to separate research infrastructures. These Following the Salford Lung Study pRCT, the European pragmatic clinical trials use an existing clinical infra- Commission granted marketing authorization to FF/ structure to prospectively test interventions in every- VI treatment for asthma and COPD in November 2013 day situations and enable randomization at the point (Woodcock et al., 2015). of care (FOCR, 2016).

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Desired Future State More Flexible Boundaries between Premarket and Postmarket Research Evidence Generation Driven by the Needs of Real- World Stakeholders A new model for medical product development may see the blurring of current demarcations between Real-world evidence regarding new treatments premarket and postmarket evaluation. Continued as- should address the practical questions of various sessment for effectiveness, not just safety, in the post- stakeholders: market setting using real-world data will enable contin- • For patients and physicians: When is this new uous reevaluation of risk–benefit profiles and generate treatment preferred over existing alternatives? labeling changes and new indications. Premarket, re- Does effectiveness or tolerability vary in a predict- al-world evidence may augment evidence from tradi- able way among different groups of patients or tional RCTs, and increased use of pragmatic trials may different health care settings? improve external generalizability of results. Premarket • For payers: How does the value of this new treat- and postmarket evaluations can form a feedback loop, ment compare to existing alternatives? What enabling a rapid learning cycle. coverage or reimbursement policies will maxi- Improved through More Widely mize overall value to taxpayers or insurance plan Shared Real-World Data members? Data from industry-sponsored clinical trials are in- • For industry: Where and when is this treat- creasingly available for secondary analyses by a wide ment likely to deliver the greatest value to our range of users. Ironically, data from not-for-profit customers? health care systems are typically not as freely shared. • For regulators: How can labeling be more informa- Many real-world questions (especially those involving tive for patients and clinicians? cost and heterogeneity of treatment effects) require large samples only achievable with pooling of data Incentives Realigned to Promote Relevant and across institutions. Data sharing and more open data Efficient Research access will certainly require appropriate protections If developers of new treatments are expected to for patients’ privacy and health systems’ proprietary broaden clinical trials to address real-world questions, information. Open access will also require researchers they must be appropriately rewarded for bearing the to set aside proprietary interests in order to facilitate additional expense and not burdened by additional more efficient learning. delay in the approval process. Creating appropriate incentives for real-world evidence generation will re- True Integration between Research and Practice quire the following: Ultimately, the evidence necessary to guide policy deci- • Guidance regarding appropriate data sources, re- sions regarding new treatments overlaps substantially search methods, and analytic methods to support with the evidence necessary to guide everyday clinical labeling regarding effectiveness, tolerability, value, decisions for individual patients. If we are to use data and heterogeneity of treatment effects; and generated from everyday practice to create general- izable evidence, then we would need systematically • Consensus among payers regarding the role of recorded data regarding patients’ risk factors or prog- real-world evidence and more specific labeling in nostic characteristics, providers’ rationale for treat- decisions regarding coverage and reimbursement. ment choices, patients’ actual treatment exposures, Guidance on the use of real-world data from regu- and a range of clinically relevant outcomes. More sys- latory agencies—such as that recently released for tematic collection and recording of those data would medical devices (FDA, 2016)—can help to define a new not only facilitate practice-based research but also paradigm for evidence generation that improves the significantly improve the quality and effectiveness of impact of research efforts. everyday health care.

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Realizing this promise will necessitate an evolution to a FDA (Food and Drug Administration). 2016. Use of true learning health system approach, as described by real-world evidence to support regulatory decision- the IOM (IOM, 2013), where the traditional boundaries making for medical devices: Draft guidance for industry between clinical research and practice are blurred and and Food and Drug Administration staff. http://www. where knowledge is generated as a by-product of each fda.gov/downloads/medicaldevices/deviceregula- care experience. tionandguidance/guidancedocuments/ucm513027. pdf (accessed October 12, 2016). FOCR (Friends of Cancer Research). 2016. A blueprint Notes for breakthrough: Exploring the utility of real world evidence (RWE). Paper presented at the 5th Annual 1. For more information on the OHDSI program, see Alexandria Summit and Friends of Cancer Research http://www.ohdsi.org (accessed September 23, Blueprint for Breakthrough Forum, June 16, Wash- 2016). ington, DC. 2. See https://www.ncdr.com/WebNCDR/tvt/home Food and Drug Administration Amendments Act of 2007, (accessed September 23, 2016). Public Law 110-85, 110th Cong., 1st sess. (Septem- 3. For more information, see https://clinicaltrials. ber 27, 2007), §905, https://www.gpo.gov/fdsys/ gov/ct2/show/NCT01551758 (accessed September pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf (ac- 23, 2016). cessed September 23, 2016). References Hripcsak, G., J. D. Duke, N. H. Shah, C. G. Reich, V. Huser, M. J. Schuemie, M. A. Suchard, R. W. Park, I. Bakerly, N. D., A. Woodcock, J. P. New, J. M. Gibson, W. C. Wong, P. R. Rijnbeek, J. van der Lei, N. Pratt, G. Wu, D. Leather, and J. Vestbo. 2015. The Salford Lung N. Noren, Y. C. Li, P. E. Stang, D. Madigan, and P. B. Study : A pragmatic, randomised phase III Ryan. 2015. Observational Health Data Sciences and real-world effectiveness trial in chronic obstructive Informatics (OHDSI): Opportunities for observational pulmonary disease. Respiratory Research 16:101. researchers. Studies in Health Technology and Infor- Bipartisan Policy Center. 2016. Using real-world evi- matics 216:574–578. dence to accelerate safe and effective cures. Washing- Hripcsak, G., P. B. Ryan, J. D. Duke, N. H. Shah, R. W. ton, DC: Bipartisan Policy Center. Park, V. Huser, M. A. Suchard, M. J. Schuemie, F. J. Carroll, J. D., F. H. Edwards, D. Marinac-Dabic, R. G. DeFalco, A. Perotte, J. M. Banda, C. G. Reich, L. M. Brindis, F. L. Grover, E. D. Peterson, E. M. Tuzcu, D. Schilling, M. E. Matheny, D. Meeker, N. Pratt, and D. M. Shahian, J. S. Rumsfeld, C. M. Shewan, K. Hewitt, Madigan. 2016. Characterizing treatment pathways D. R. Holmes, Jr., and M. J. Mack. 2013. The STS-ACC at scale using the OHDSI network. Proceedings of the transcatheter valve therapy national registry: A new National Academy of Sciences 113(27):7329–7336. partnership and infrastructure for the introduc- IOM (Institute of Medicine). 2006. The future of drug tion and surveillance of medical devices and thera- safety: Promoting and protecting the health of the pub- pies. Journal of the American College of Cardiology lic, edited by A. Baciu, K. Stratton, and S. P. Burke. 62(11):1026–1034. Washington, DC: The National Academies Press. Carroll, J. D., J. Shuren, T. S. Jensen, J. Hernandez, D. IOM (Institute of Medicine). 2013. Best care at lower Holmes, D. Marinac-Dabic, F. H. Edwards, B. D. Zuck- cost: The path to continuously learning health care in erman, L. L. Wood, R. E. Kuntz, and M. J. Mack. 2015. America, edited by M. Smith, R. Saunders, L. Stuck- Transcatheter valve therapy registry is a model for hardt, and J. M. McGinnis. Washington, DC: The Na- medical device innovation and surveillance. Health tional Academies Press. Affairs (Millwood) 34(2):328–334. Kuehn, B. M. 2016. FDA’s foray into big data still ma- turing. Journal of the American Medical Association 315(18):1934–1936.

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New, J. P., N. D. Bakerly, D. Leather, and A. Woodcock. Suggested Citation 2014. Obtaining real-world evidence: The Salford Galson, S., and G. Simon. 2016. Real-world evidence to Lung Study. Thorax 69(12):1152–1154. guide approval and use of new treatments. Discussion Rumsfeld, J. S., D. R. Holmes, Jr., W. G. Stough, F. H. Paper, National Academy of Medicine, Washington, Edwards, L. B. Jacques, and M. J. Mack. 2015. Insights DC: https://nam.edu/wp-content/uploads/2016/10/ from the early experience of the Society of Thoracic Real-World-Evidence-to-Guide-the-Approval-and- Surgeons/American College of Cardiology Transcath- Use-of-New-Treatments.pdf. eter Valve Therapy Registry. Journal of the American College of Cardiology Cardiovascular Interventions Author Information 8(3):377–381. Steven Galson is Senior Vice President, Global Regu- Sentinel Program Interim Assessment—FY15. 2015. latory Affairs and Safety, Amgen. Gregory Simon is http://www.fda.gov/downloads/ForIndustry/User- Senior Investigator and Psychiatrist at Group Fees/PrescriptionDrugUserFee/UCM464043.pdf (ac- Health Research Institute. cessed October 12, 2016). Society of Thoracic Surgeons. 2013. FDA approval of Disclaimer device labeling highlights growing use of clinical registry The views expressed in this Perspective are those of data for post-market device surveillance: STS/ACC TVT the authors and not necessarily of the authors’ orga- Registry™ data cited as part of FDA decision process. nizations, the National Academy of Medicine (NAM), or Press release, https://www.sts.org/sites/default/ the National Academies of Sciences, Engineering, and files/documents/pdf/pressreleases/STS_ACC%20 Medicine (The Academies). The Perspective is intend- TVT%20Registry_final.pdf (accessed September 23, ed to help inform and stimulate discussion. It has not 2016). been subjected to the review procedures of, nor is it a Woodcock, A., N. D. Bakerly, J. P. New, J. M. Gibson, W. report of, the NAM or the Academies. Copyright by the Wu, J. Vestbo, and D. Leather. 2015. The Salford Lung National Academy of Sciences. All rights reserved. Study protocol: A pragmatic, randomised phase III real-world effectiveness trial in asthma. BMC Pulmo- nary Medicine 15:160.

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