Pragmatic trials

To illustrate how explanatory and pragmatic trials differ from one another we look in turn at subjects, treatments and delivery, outcome measures, conduct and analysis. 

In explanatory trials, endpoints are likely to be objective, possiblly surrogate, and may be chosen to maximise the sensitivity to detect treatment differences. In contrast, endpoints in pragmatic trials will tend to be more patient-centred including, for example, survival and quality of life. 

The conduct of explanatory trials will include close monitoring of the study in an attempt to ensure strict adherence to the protocol. There is likely to be exhaustive recording of data. In contrast, the conduct of pragmatic trials will tend to mirror real life. There will be attempts to minimise data recording, but there is hkely to be exhaustive follow-up of all patients. 

In explanatory trials, we are hkely to exclude both protocol violators and treatment non-compliers. The objective behind these exclusions is to increase the efficiency. However the exclusions may give rise to bias and hence to compromise the results if too many patients are excluded. Such an analysis population is termed as completers, or per protocol, population. In pragmatic trials, we generally include all patients using the intention-to-treat (ITT) principle. 

The CIP system evolved in four steps by a combination of logical reasoning and a pragmatic trial and error approach. The evolution was driven by the practical necessity to describe the vast number of known molecules and an impressive array of brain-teasers proposed by clever chemists. 

In these real life, or naturalistic, conditions the drug may not perform so well, e.g. minor adverse effects may now cause patient noncompliance, which had been avoided by supervision and enthusiasm in the early trials. These naturalistic studies are sometimes called pragmatic trials. 

I There is increasing interest in desigrting valid rraturahstic or pragmatic trials to determine effectiveness in usual clirtical practice. 

Pragmatic trials are increasingly being applied in psychiatry. 

Nevertheless, where we are interested in the pharmacological consequence of treatments it seems intuitively reasonable that some sort of adjustment for compliance is relevant. In this connection, an interesting distinction between explanatory (or scientific) trials and pragmatic trials was introduced by Schwartz, and colleagues (Schwartz et al., 1980 Schwartz and Lellouch, 1967). For the former, a per-protocol analysis would be more relevant, whereas the latter might require intention to treat. 

This is related to the famous distinction between explanatory and pragmatic trials made by Schwartz and Lellouch (1967). Here we are faced with the pragmatic task of choosing between the hypothesis that the drug is useless or worse than useless and the... 

Uijl SG, Uiterwaal CS, Aldenkamp AP, Carpay JA, Doelman JC, Keizer K, Vecht CJ, de Krom MC, van Donselaar CA. Adjustment of treatment increases quality of life in patients with epilepsy a randomized controlled pragmatic trial. Eur J Neurol 2009 16(11) 1173-7. 

Although one cannot readily identify any comprehensive, official pronouncement on the topic of development bioequivalency, it is apparent that in many cases FDA officials have adopted a pragmatic and common-sense approach to problems of this type. Obviously, in development bioequivalency our fundamental objective should be, for example, to build an appropriate bridge between F3 and F3 and F2 and F3 such that it is legitimate to use data obtained in clinical trials with F3 and F2 to support a conclusion of safety and efficacy for F3. Depending on how substantial the differences are between Fi and F3 and F2 and F3, the required bridge can be very simple or possibly more elaborate. 

Helms, P. 2002. Real world pragmatic clinical trials what are they and what do they tell us Pediatric Allergy... 

A large proportion of the technology appraisals so far performed by NICE on pharmaceuticals have been on products recently introduced into the marketplace. This has created difficulties for manufacturers trying to answer the questions posed by the appraisal. For most compounds, at the time of launch it is very unlikely that outcome studies will have been completed that allow accurate cost effectiveness calculations to be performed. The emphasis in Phase III is on clinical efficacy and safety to satisfy the requirements of the regulatory authorities. In most cases, it is impossible (and probably imethical) to perform pragmatic studies on the general population imtil safety and efficacy have been satisfactorily demonstrated in a tightly defined trial population. 

Storosum JG, van Zwieten BJ, Vermeulen HDB, Wohlfarth T et al (2001) Relapse and recurrence in major depression a critical review of placebo-controUed efficacy studies with special emphasis on methodological issues European Psychiatry, 16, ill- i iS Stutchfield P, Whitaker R and Russell I, on behalf of the Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team (2005) Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section pragmatic randomised trial British Medical Journal, 331, 662-667... 

Beyond this initial theoretical drawing-board-and-slide-rule approach, of course, lies the critical need for experimental proof in actual process machinery and prototype field trials, which should be included as a 4th dimension in such a schematic diagram, and is the final pragmatic judgment to determine technical success of any plastic product. This is the direction in which applications research and product design must grow in the future, in order to convert plastics art into plastic science. 

From a pragmatic viewpoint, there is no need for a model of the photon. One may be content with a description of the particle based entirely on the equations that it obeys. This is a very respectable scientific stance. There is another equally respectable scientific position—try to understand the mathematical equations in relation to a physical model. In previous paragraph we mentioned the attempts of several investigators [30-33]. More recent trials are those of Warburton [34], Fox [35], Scully and Sargent [36], Hunter and Wadlinger [37,38], Evans and Vigier [39], Barbosa and Gonzalez [40], and Lehnert [41]. For additional contemporary models see Hunter et al. [42]. 

Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry 2004 185 63-9. 

Table 18.6. Examples where trials based ori surrogate outcomes proved to be misleading predictors of the effect of treatment on clinical outcomes in subsequent pragmatic clinical trials...

The more pragmatic Medical Research Council Asymptomatic Carotid Surgery Trial (ACST) has probably produced more widely generalizable results (Halliday et al. 2004). Between 1993 and 2003, ACST randomized 3120 patients with > 60% mainly asymptomatic carotid stenosis (12% had symptoms at least six months previously) to immediate endarterectomy plus medical treatment versus medical treatment alone or until the operation became necessary. Surgeons were required to provide evidence of an operative risk of 6%... 

Pragmatically, the companies are geared up for a steady flow of new products, which means a steady flow of clinical candidates to put into trial. Capacity at CROs helps to even the flow. If a company is not putting drugs into clinical trials, confidence from investors will drop, and they will adjust their portfolios accordingly. Stock price is as heavily affected by the prospects of a company s pipeline as by its current sales. 

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