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Acorns and inhalers: The Asthma ClinicalResearch Network

Jeffrey M. Drazen, MD,a Claude Lenfant, MD,b and Suzanne S. Hurd, PhDb Boston,

Mass, and Gaithersburg, Md

Key words: Beta-agonists, albuterol, pharmacogenetics

In the early 1970s, the medicine chest for an asthmaphysician in the United States was quite bare. A fewnonspecific inhaled bronchodilators were available, alongwith theophylline and systemic steroids. Treatment withinhaled steroids was just coming into common use, butmany physicians and most patients were either wary oftheir use or not convinced of their effectiveness. In 1989,when the National Asthma Education and PreventionProgram promulgated the first set of treatment guidelines,the good news was that there were many more therapeuticoptions. The bad news was that the evidence base on howto use these treatments was small and strongly biasedbecause the majority of the clinical data came from studiesconducted by manufacturers. The National Asthma Educa-tion and Prevention Program guidelines were based mostlyon ‘‘expert opinion’’; what was needed was to expand theevidence base for asthma treatment through rigorousclinical trials.

The only entity that had the resources and the will to dothis was the National Institutes of Health, and thus a groupof clinical and basic investigators backed by the leadershipof the American Academy of Allergy, Asthma and Immu-nology approached the National Heart, Lung, and BloodInstitute (NHLBI) to explore the possibility of initiatinga clinical network to test the effectiveness and safety ofinterventions, which could then be quickly transportedinto practice.

The reaction of the NHLBI was at first mixed. Althoughthere were concerns, there was also strong enthusiasmabout the potential of rapid and practical outcomes fromwhich patients would surely benefit. The concerns focusedon whether investigators located in several institutionswould really agree to work together for the 5-year durationof the proposed network, whether they would truly be

From athe Respiratory Disease Division, Brigham and Women’s Hospital,

Boston, and bGlobal Initiative for Asthma, Gaithersburg.

Disclosure of potential conflict of interest: C. Lenfant has consultant arrange-

ments with Altana. The rest of the authors have declared that they have no

conflict of interest.

Received for publication June 9, 2006; accepted for publication June 14, 2006.

Available online July 28, 2006.

Reprint requests: Jeffrey M. Drazen, MD, New England Journal of Medicine,

10 Shattuck St, Boston, MA 02115. E-mail: jdrazen@nejm.org.

J Allergy Clin Immunol 2007;119:28-9.

0091-6749/$32.00

� 2007 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2006.06.011

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interested in designing short protocols with the goal ofproducing outcomes readily applicable in practice, and thecost of such a venture.

Because of the novel concept under consideration, itwas decided that if such a program was to be implemented,it should be subjected to the usual rigorous NationalInstitutes of Health peer review and should be supportedby set-aside funds. After much deliberation and conceptreview, the NHLBI decided to proceed with fundingthrough a cooperative agreement. A request for applica-tions was issued that required the applicants to propose2 important clinical questions related to asthma treatmentthat required multicenter investigation. More than 30applications were submitted, and the applications thatreceived the top 5 ranking in the peer review process(based on the scientific merit of the proposed clinicalquestions) were selected. A separate request for applica-tions resulted in an award for a data-coordinating center.The NHLBI selected the chair of the steering committee,Reuben Cherniack, a well-known expert who was not oneof the principal investigators. Funding for the networkincluded ‘‘core support’’ for the investigators to developthe protocols, but the majority of the funding was‘‘restricted’’ for use during the conduct of the clinicaltrials; funds were made available on a cost-per-patientbasis. The Asthma Clinical Research Network (ACRN;often referred to as the ACoRN) was established, and therest of the work was up to the investigators!

At the first meeting of the newly constituted ACRN,it was clear the NHLBI expected the network to tackleimportant problems in asthma treatment. There were 2problems that had not been solved in such a setting before:(1) how to set up a network capable of doing multiplestudies spread across the country with uniform protocols,data entry procedures, and quality control measures and (2)how to identify the right important question and then write,review, and implement an asthma treatment protocol.

The problem of organizing a disaggregated networkwas solved by using a novel idea at the time: the Internet.Even though this information-sharing network was justgetting organized, the ACRN took full advantage of it.

Abbreviations used

ACRN: Asthma Clinical Research Network

NHLBI: National Heart, Lung, and Blood Institute

J ALLERGY CLIN IMMUNOL

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Both clinical and lung function data were entered usingWeb-based protocols. A manual of procedures wasadopted that codified all aspects of trial performance.This resulted in minimal measurement variance andimproved the ability to detect small signals. In 1995, thefledgling Internet was taxed with large data downloads,but the technology proved robust and was essential tosolving the first problem.

The problem of identifying the right protocol wasmuch more difficult. The investigators needed to identifyimportant problems that could be solved with limitedresources, both human and fiscal. To complicate matters,they were just getting to know each other, and each ofthem had submitted a number of sample protocols forthe grant competition. Each of the 5 centers wanted theirprotocol to be the lead protocol, and all of them wanted theACRN to step to the plate and hit the first pitch out of thepark. Most of the first meetings were spent in debate aboutwhat was the most important question to which we couldexpect a clean answer. Multiple protocols were offered,some addressing treatment questions in patients withsevere asthma and others addressing treatment questionsin patients with mild asthma. A number of secret ballotswere held, but no single idea easily emerged.

In the end, we were lucky. In the early 1990s, a numberof articles were published that suggested that regularlyscheduled use of inhaled b2-selective agonists, when ad-ministered on a regular schedule, had adverse effects onasthma control. These inhaled asthma medications werethe most commonly used asthma medications in the world.If they had adverse effects, even in a small proportion ofpatients, the overall negative effect could be substantial.Thus we chose a protocol to answer the research questionof whether recurrent use of regularly scheduled albuterolwould be associated with adverse effects on asthma con-trol. The target population was patients with mild asthmain whom inhaled b2-agonists were most likely to be usedas the only asthma medication. Peak expiratory flow waschosen as the primary outcome indicator because to powera trial on asthma exacerbations in patients with such milddisease would require more time or money than the net-work had available. Expiratory flow, although a surrogatemarker, was robust, easy to measure, and linked to asthmacontrol.

The final trial design was straightforward. Patients withmild asthma were enrolled, and their baseline lung func-tion was monitored during a 6-week run-in period. Thiswas followed by a 16-week randomized treatment periodand a 6-week washout period. The study was powered todetect a 25 L/min difference between the 2 treatmentgroups. The trial design was improved by the protocolreview committee and approved by a data safety andmonitoring board (both committees had been established

by the NHLBI). Each center was successful in piloting theprotocol through their local institutional review boards.The key aspect of the protocol was that if the recruitmentgoal and time guidelines could be met and if the treatmentgroups were balanced, then the results would be of clinicalinterest, regardless of the ‘‘sign’’ of the outcome.

Timelines were met by identifying a single group to dothe majority of the work in a single area; every group had atask, and everyone agreed to abide by the solutions offeredto the group. The investigators soon learned that thebiggest problem was to obtain placebo inhalers. Again,the investigators were lucky when senior management atSchering-Plough agreed to provide active and placeboinhalers; they had little to gain from this protocol andprovided the medication as a public service. The ACRNinvestigators will always be grateful to these persons fortheir willingness to help in their first protocol, but obtain-ing matched drug and placebo continues to be a majorobstacle for the network.

The results of the first study, ‘‘Comparison of regularlyscheduled with as-needed use of albuterol in mildasthma,’’ were published in 19961 and have been widelyaccepted by the asthma treatment community. The studydemonstrated that in the population of patients with mildasthma, the regularly scheduled use of inhaled albuterolis not associated with adverse events, but it also doesnot provide clinical benefit. This is information that a cli-nician can use in daily decision making and is the hallmarkof ACRN studies. Since the network was constituted(1993), the ACRN has produced more than a dozen clini-cal trials that have provided the basic building blocks ofasthma treatment. The data have not only furthered theevidence base, they have also questioned our currentthinking and provided provocative results to serve as thefoundation for the next generation of asthma treatment.One of the most important questions with respect toasthma treatment has to do with the substantial among-patient variance in the treatment response and the potentialgenetic basis of this variance. The use of genetic informa-tion to first predict and then to tailor asthma treatment isthe next frontier. The ACRN has already begun to chipaway at this problem.2 They have the intellectual and pa-tient resource capital needed to make this dream a reality.We hope that they succeed.

REFERENCES

1. Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE, et al.

Comparison of regularly scheduled with as-needed use of albuterol in mild

asthma. N Engl J Med 1996;335:841-7.

2. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ,

et al. Use of regularly scheduled albuterol treatment in asthma: genotype-

stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;

364:1505-12.