real-world trials to answer real-world questions

Pharmacoeconomics 2005; 23 (8): 747-754PRACTICAL APPLICATION 1170-7690/05/0008-0747/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Real-World Trials to AnswerReal-World QuestionsNick Freemantle,1 Lawrence Blonde,2 Bjorn Bolinder,3 Robert A. Gerber,4

F.D. Richard Hobbs,1 Luc Martinez5 and Stuart Ross6

1 University of Birmingham, Birmingham, UK2 Ochsner Clinic Foundation, New Orleans, Louisiana, USA3 sanofi-aventis Group, Bridgewater, New Jersey, USA4 Pfizer Inc, Groton, Connecticut, USA5 Societe Francaise de Medecine Generale, Issy les Moulineaux, France6 Departments of Medicine and Community Health Sciences, Calgary, Alberta, Canada

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7471. Questions Faced from Regulatory Authorities in Drug Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7482. What Methods are Required for Health Technology Evaluations? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7493. Designing Real-World Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7514. Real-World Trial of Inhaled Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7515. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753

Currently, there is a discrepancy between clinical trials designed to assess theAbstractefficacy and safety of a new medication under investigation and the real-lifequestions that need to be addressed regarding the clinical use of the medication bypatients, healthcare professionals and society. The data necessary to obtainregulatory approval may be of limited relevance to policy makers when calculat-ing economic parameters such as value for money or cost effectiveness.‘Real-world’ studies examine questions relevant to health policy and reimburse-ment. There are many different forms of clinical trials, but in designing trialsincorporating realistic budget impact estimates the important issue is to ensure weare asking a sensible question and attempting to answer it with an appropriateexperimental design. As an example, a real-world trial currently underway thatexamines scenarios of introducing inhaled insulin into clinical practice isdescribed.

Randomised, controlled, double-blind clinical safety and efficacy of a medication under investiga-trials are the ‘gold standard’ for determining the tion. Results from these studies are necessary in

748 Freemantle et al.

order to obtain the required regulatory approval that 1. Questions Faced from RegulatoryAuthorities in Drug Evaluationallows a new medication to be used and marketed.

Randomised trials form the mainstay of the regula-Regulatory processes addressing the licensing of

tory evaluation of the efficacy of health technologiespharmaceutical products require evidence on effica-

and are regarded as providing the most reliablecy, safety and quality.[1] Issues of efficacy are usual-

evidence available, superior to observational studiesly assessed through at least two independent, confir-

and other prospective but non-randomised designs. matory, randomised trials undertaken in phase IIIaHowever, the hypotheses addressed in trials re- of the regulatory stage of drug evaluation.[3] Safetyquired for regulatory (licensing) purposes may often questions are refined during the exploratory andnot answer some of the important clinical and eco- confirmatory trial phases and tend to be addressednomic questions on how a new treatment should best using data from across the entire trial programme.be applied for the benefit of patients and society. As investigations of the safety of pharmaceuticals

require the consideration of potentially rare unto-Thus, the limited generalisability from randomisedward events, initial assessment of safety must beclinical trials-based economic analyses may, inupdated systematically through increased experi-some cases, restrict their relevance for policy mak-ence with new products after licensing has beeners.achieved. Indeed, it is inevitable that the data pro-

Treatment efficacy measures in a defined popula-vided by the licensing process are partial and incom-

tion under controlled study conditions may not re-plete as the data are derived before licensing and the

flect those observed in actual clinical practice. general availability of the product for clinical use.Therefore, there are an increasing number of or- The focus is therefore on a limited number of ques-ganisations that have been developed to assess the tions to achieve a licence. As described in the Inter-value for money, or cost effectiveness, of different national Conference on Harmonisation of Technicaltreatments in actual practice.[1,2] These organisations Requirements for Registration of Pharmaceuticalsrequire evidence to make efficient decisions (i.e. to for Human Use (ICH) E9: Statistical Principles forvalue correctly the benefits of different treatments) Clinical Trials:[3] “A confirmatory trial is an ade-

quately controlled trial in which the hypotheses areand so there is an increasing obligation for thestated in advance and evaluated. As a rule, confir-developers of new treatments to provide evidence onmatory trials are necessary to provide firm evidencea broader range of questions and outcomes in addi-of efficacy or safety. In such trials, the key hypothe-tion to the efficacy and safety data required bysis of interest follows directly from the trial’s prima-licensing authorities.ry objective, is always pre-defined, and is the hy-

We consider ‘real-world’ studies to be those thatpothesis that is subsequently tested when the trial is

examine questions of relevance for health policy and complete… Each trial should address only a limitedreimbursement. In this paper, we consider the number of questions. Firm evidence in support ofreal-world studies that may be undertaken to support claims requires that the results of the confirmatorythe evaluation of health technologies (e.g. drugs, trials demonstrate that the investigational productdevices and diagnostics) and illustrate our paper under test has clinical benefits.”[3]

with an example from a study that is currently One of the key concepts described in the excerptunderway with an innovative treatment for diabetes above is encapsulated in the words “test” and “hy-mellitus: inhaled insulin (INH). potheses”. Drug regulation for licensing is refined

© 2005 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2005; 23 (8)

Real-World Trials to Answer Real-World Questions 749

by process to a relatively simple “yes/no” question, uses of available resources and whether (regardlesswhere sponsors of new pharmaceuticals are required of an efficiency criterion) a technology is affordableto demonstrate benefits with sufficient statistical to a health system.precision on conventional pre-agreed primary out-comes or markers of efficacy.[4] In the standard 2. What Methods are Required for Health(abstract) case, this requires two confirmatory trials Technology Evaluations?to each achieve p-values on the primary outcome

Many healthcare technologies have the potentialvariable of p < 0.025 (one sided). In other words, theto provide only modest health benefits for patients,minimum treatment benefits required to license aand these benefits may vary considerably betweendrug from two confirmatory trials would occur byindividuals. In addition, the course of a disease inchance alone less than one time in 1600.any individual may be uncertain. Some patients may

Of course, the licensing process is complicatedadvance slowly through a progressive condition,

by reality,[4] and exceptions are made under a varietywhereas others will experience a more rapid decline;

of circumstances, but the underlying principle re-crucially, this is usually only partly predictable in

mains that a pharmaceutical will be licensed only ifadvance. The key advantage of randomisation is that

it achieves an effect that is highly unlikely to haveit deals with these biases neatly and efficiently.

occurred by chance. This requirement makes noIn a properly randomised trial, patients allocated

judgement on the value of any effect found, butto alternative treatments may be considered to differ

simply that the effect is highly likely to be attributa-on only two criteria: treatment allocation (i.e. which

ble to the intervention and observed on an outcomegroup they are in); and the play of chance (i.e. the

understood to be related to the underlying diseaserandom process by which they were allocated to the

process that was specified in advance.treatment group). In other words, between-patient

The licensing process has, arguably, provided variation in a randomised trial differs by group onlyconsiderable protection for society in avoiding the by chance. Unless it is of infinite size, the groups inavailability of pharmaceuticals that provide no ben- a randomised trial will not be the same, although weefits, or even represent risks, to those that take them. frequently go to some lengths to minimise differ-However, inevitably, risks, especially those associ- ences between them (perhaps by stratification on anated with relatively rare adverse effects, remain until important clinical classification such as severity ofthe product achieves large-scale use within subse- disease). Statistics can help us, as statistical methodsquent clinical trials and longer-term use in clinical provide a probabilistic estimate of the extent topractice. which differences of the magnitude observed be-

Given the practically unlimited range of health tween two groups in a randomised trial may havetechnologies available, and the finite resources occurred simply through chance alone. If we canavailable for their purchase, some additional criteria reasonably reject the possibility that changes oc-are required to inform decision making for health curred due to chance, the only alternative is that thepolicy and clinical practice. The licensing process observed benefits occurred due to the impact of theessentially deals with questions of safety, efficacy treatment. Although the logic may seem obscure (toand quality (although uncertainty on safety will fre- attribute a treatment effect on the basis of the im-quently remain). The remaining questions tend to plausibility of the alternative: the play of chance),address whether new technologies represent good randomisation has served us very well, and quitevalue for money in contrast with the other potential correctly there remains no generally accepted alter-



native to the level of evidence that randomised consider the cost effectiveness of a new treatment.clinical trials provide. For example, in double-blind trials that compare

treatments that have to be taken several times a dayThe main objection to interpretation of the resultswith those that require once-only dosing, all patientsof confirmatory trials in the licensing process tendstake all dosages (either as active treatment or identi-to be that the patient population included may notcal placebos). This ‘double dummy’ technique ef-represent the target population for treatment in soci-fectively designs out the potential benefits of theety. Inevitably, investigators undertaking confirma-once-only preparation as all subjects experience thetory trials will exclude patients with serious co-inconvenience of both regimens.[7] Such confirmato-morbidities if they can, otherwise it may be difficultry trials may also serve to undermine the appropri-to determine whether serious adverse events exper-ateness of undertaking within-trial health economicienced in the trial are attributable to the investiga-analyses, where the resources consumed by bothtional treatment or to the patient’s condition. Simi-groups are made artificially similar because all pa-larly, the investigators may well exclude patientstients are required to receive all healthcare interven-who are considered unlikely to adhere consistentlytions even if they apply in different measures toto treatment recommendations.different groups.

Patient follow-up may also be foreshortened inWhile the list of objections to interpretation fromconfirmatory trials. With the pressure on pharma-

confirmatory trials is long, and the discussion in thisceutical companies to minimise the time betweenarticle is necessarily rather incomplete, it is of notedrug development and licensing, the temptation willthat all the problems described apply to confirmato-always be to follow patients up for the minimumry trials rather than to randomised trials per se.acceptable time rather than for a period that providesIndeed, it is quite possible to conduct randomisedinsights into the full clinical course of the condition.trials of treatments in which none of the challengesThis temptation may be addressed through the re-of confirmatory trials are present. Thus, trials maycruitment of large numbers of patients, such as in theinclude a representative range of patients. Indeed, inMERIT-HF (Metoprolol Randomized Interventionthe recently published Heart Protection Study,[8]

Trial in Congestive Heart Failure) study[5] that had aover 20 000 patients with coronary disease, otherrelatively short period of follow-up (mean 1 year).[5]

occlusive heart disease or diabetes were included.Of course, an advantage of a randomised trial is thatRecruitment was said to be straightforward as, in thepatients can differ in severity at the beginning of thewords of one investigator, “patients who met thetrial (i.e. both more and less severe patients may beinclusion criteria were the patients I see in largeincluded) so it may simultaneously provide insightsnumbers in my clinic…” Similarly, it is possible foron a range of patient characteristics. However, thistrials conducted with health technologies that haveis less adequate than following patients through thealready been granted a licence to include a broaderfull course of the condition. In addition, the out-range of patients than those necessarily included incomes measured may not be those of most clinicalthe licensing trials, as issues of safety have alreadyinterest. For example, the measurement of en-been addressed sufficiently for the licensing pro-doscopically detected lesions in trials of newercess.NSAIDs would not be an endpoint of interest for

routine clinical practice.[6] Finally, the protocols for Follow-up may be extended to enable assessmentconfirmatory trials may be so demanding and re- of rarer but more relevant clinical endpoints over thestrictive that there may be little or no opportunity to course of a disease, although an alternative or sup-



portive approach may be to undertake individual nal validity to ensure that the findings are due to thepatient meta-analysis over the entire trial pro- intervention being studied and are generalisable be-gramme addressing a similar question, as conduct- yond the specific parameters of the study. Rathered, for example, on one of the newer NSAIDs.[9] than considering a dichotomy in trial design, moreHowever, characteristics of the trial programme appropriately, we are considering a continuum insuch as length of follow-up and overall patient num- which different aspects are addressed on the basis ofbers will still constrain this approach. the requirement for specific information and the

possibility to address different questions. It maySince health policy questions relate to the bene-simply not be possible to avoid extensive data col-fits of a health technology in practice, rather than,lection on safety issues if a trial is conducted whenfor instance, the pharmacological action of a specif-an intervention is not yet licensed, while other ques-ic drug, blinding (and thus the designing out oftions (such as the benefits of a more acceptable‘convenience factors’) is not necessary or desira-mode or route of delivery) may be examined.ble.[7] Thus, in an unblinded trial, the benefits of

different routes or dosages of delivery may be esti- Indeed, it could be argued that what we aremated. suggesting is to design trials to address the specific

questions of interest and, as the questions change,3. Designing Real-World Trials inevitably the design changes in tandem. Each pa-

tient in the trials should be able to achieve his or herWe suggest that, in addition to the important best possible health state given the disease severity

confirmatory trials required to license a new health and treatment options. The physicians should betechnology, additional real-world trials could be able to identify medications and, after discussionconducted (or aspects of the confirmatory trials with the patients, prescribe an appropriate dosagechanged when this is possible to accommodate the and change medications or dosages throughout theneeds addressed by these trials). In many cases, trial based on patients’ needs and responses. Thus,these trials should be conducted prior to registration. the clinical and economic results should mirror asSuch real-world trials would attempt to answer the closely as possible the way in which patients arehealth policy questions that remain, providing evi- treated in actual practice. In section 4, we illustratedence on the effectiveness and cost effectiveness of our suggestions with a specific example, a real-the health technology in practice. Previously, it has world trial of INH in type 2 diabetes that we arebeen suggested that this would represent a dichoto- currently developing.my.[7]

In contrast to this view, we argue that the aspects 4. Real-World Trial of Inhaled Insulinof trial design that we have discussed may or maynot be implemented in any specific trial. Although a Exubera®,1 an inhaled dry powder, pulmonaryprospective, randomised trial designed primarily to insulin, with aerosol delivery that permits non-inva-obtain cost-effectiveness information and assist sive administration of rapid-acting insulin, is beingtreatment decisions under actual practice is ideal, developed by Pfizer Inc, sanofi-aventis Group andthere is no consensus on specific design features of Nektar Therapeutics. The pulmonary route exploitssuch a trial. The fundamental design challenge with the large vascular bed and permeability of the alveo-real-world studies is to maximise internal and exter- li to deliver insulin directly into the bloodstream.[10]

1 The use of trade names is for product identification purposes only and does not imply endorsement.



INH is being developed for postprandial glycaemic rently not achieving targets for the control of bloodcontrol in patients with type 1 or type 2 diabetes, and sugars with oral medication are invited to participatetrials have shown that INH provides reproducible in a trial where they consent to be managed in one ofand effective control of meal-related gly- two clinics. These two clinics contrast two differentcaemia.[11-15] INH enables the delivery of insulin ‘states of the world’: one in which all currentlywithout the need for an injection, which is often available interventions may be used; the other inconsidered to be a powerful deterrent to those pa- which all currently available interventions may betients for whom insulin therapy may be beneficial. used along with INH. While the clinician and patient

are under no obligation to use INH in the interven-Interestingly, the licensing requirements, whilemeant to demonstrate safety and efficacy, mean that tion group, it will be available as one of the treat-any advantages of improved acceptability as a result ment options. Patients are randomised between theof advances in the method of delivery associated two ‘states of the world’; thus, the trial will providewith INH are relegated to a convenience factor; the an estimate of the effect of introducing INH intomajor requirement for licensing has been to estab- practice on the rates of uptake and on any clinicallish equivalence with injectable insulin in patients benefits accrued, as measured by relative improve-who have consented to be randomised to INH or ments in glycosylated haemoglobin (HbA1c). Inter-continued injections. While the clinical trial pro- action between the patient and his or her clinician isgramme has provided some experience in patients a necessary step in the real-world trial, in starkwith type 2 diabetes,[15,16] this again has been gained contrast with confirmatory trials where this issue hasonly in patients prepared to be randomised to INH or been addressed ‘upfront’ at the time of consenting.an alternative comparator therapy.

The trial will be conducted without blinding ofFrom discussion with health policy makers, it is

the investigator or patient, and follow-up will be forevident that those potentially charged with the re-

12 months (ample time for the well establishedsponsibility for making reimbursement decisions on

outcome measure – HbA1c – to respond to changesthe availability of INH in different health systems

in management with insulin or another oral agent). Ifare interested both in the benefits of INH and the

the trial is undertaken before licensing of INH, thelikely level of uptake of the new technology within

technology should only be available for patientsthe stratum of patients potentially eligible to benefitallocated to the INH option group. Analysis will befrom its use. Thus, while demonstrating equivalentby intention to treat, as the overall question in theefficacy to injectable insulin and acceptable safetystudy addresses the benefits of treatment at thewill be sufficient to license INH, these data will nothealth policy level and not the physiological effectsprovide necessary information to judge the healthof an individual taking INH. Safety issues will alsobenefits and budgetary impact of the technology.be addressed during the trial, as it will provide

In developing a real-world trial for INH in type 2additional information to that otherwise available on

diabetes, we had to address a number of the issuesthe use of the product.

described in section 3 as the characteristics of con-The design of the real-world trial has been in-firmatory trials. An important criterion is the group

formed by a questionnaire-based, randomised, feasi-of patients included. In the real-world INH trial,bility trial that demonstrated substantial differencespatients are not consenting on the basis that they arein the theoretical acceptability of insulin as a treat-prepared to be randomised to an INH group orment option with the availability of INH.[17]alternative therapy. Instead, patients who are cur-



The real-world trial of INH is key to establishing The value of a cost-effectiveness analysis be-cost effectiveness in patients with type 2 diabetes. comes greater if the circumstances pertain approxi-The results of the trial will populate an economic mately to the settings in which the interventionmodel currently under development,[18] with an un- might be applied.[19] There are many similaritiesbiased estimate of the effects of the availability of between the real-world trial of INH and confirmato-INH on glycaemic control and resource use. The ry trials for the licensing process. All estimate thecost effectiveness of INH will be estimated in the effects of INH on HbA1c and all assess the safety ofreal-world trial by comparing two ‘states of the the intervention. However, in the real-world trial,world’; however, the differing pricing and reim- unlike in the confirmatory trials, the question ad-bursement structures in different countries compli- dressed includes behavioural and psychological ele-cate this. In the feasibility study for the real-world ments by allowing self-selection of treatment bystudy, patients from the US, Canada, Sweden, patients in consultation with their physicians. WillFrance, Spain, Germany and Italy were included. An physicians and patients choose INH if it is availa-advantage of undertaking such a trial in phase III is ble? Will the availability of INH lead to earlierthat the cost structures may be made artificially implementation of insulin therapy and, if so, willsimilar, providing estimates of cost effectiveness on that, in turn, lead to improved glycaemic control?a common reference base. After licensing, it is likely Will the ‘new world’ in which INH is available bethat different reimbursement structures will exist in more cost effective than the old? Finally, the expec-different health systems. Thus, we are asking the tation is that selection of the appropriate patientreal-world question about the effects of a decision to population will mean that results from the trialmake INH available, explicitly estimating the poten- should be generalisable to a substantial proportiontial benefits of additional ‘convenience’ of use, of patients with type 2 diabetes treated in real-worldtranslating to improved glycaemic control. practice.

Acknowledgements5. Conclusions

The authors sit on the steering committee of the ‘RealWith the increasing need for valid data on the World Trial of Inhaled Insulin’ sponsored by Pfizer Inc and

sanofi-aventis Group. Bjorn Bolinder and Robert A Gerbereffectiveness, cost effectiveness and realistic budgetare employees of sanofi-aventis Group and Pfizer Inc, respec-impact estimates of health technologies, there is antively. Nick Freemantle, Lawrence Blonde, Richard Hobbs,increasing need for a broader range of experimentalLuc Martinez and Stuart Ross have received fees and ex-

research. We have described the particular chal- penses from the sponsors of the Real World Trial.lenges of designing trials that ask real-world ques-tions of real-world patients and focused on the series

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