Clinical drug trials in general practice: a 10-year overview of protocols

About 90% of all drug prescriptions for outpatients are issued in general practice [1]. Patients in general practice are more likely to have less severe disease, and more undifferentiated symptoms than selected patients in secondary or tertiary health care, however, multimorbidity is common [2]. If a study population in a drug trial differs significantly from the population where the drug is most likely to be prescribed, the external validity of the trial may be impaired [3]. To avoid this uncertainty, many have argued that more clinical drug trials should be conducted in primary care settings to ensure that the benefits are proportionate to the risks and costs of the treatment for patients in general practice [4, 5]. Clinical drug trials may serve different purposes, from research of effectiveness, to marketing [6]. Trials with the main purpose of introducing new drugs to prescribers are often referred to as ‘seeding trials’. Various criteria for seeding trials have been proposed (Table 1) [7‐9], and it is characteristic that the trials are designed to make many clinicians familiar with a new drug. Being frequent prescribers, general practitioners (GPs) are probably of particular interest for designers of seeding trials; this is also because GPs are relatively independent in their decision-making processes.

In the UK between 1984 and 1989, general practice trials initiated by pharmaceutical companies were judged to have a low output of clinically relevant results [10]. The concerns addressed in that audit were mainly payments to GPs, information and safety issues, shortfall of investigators and patients, leading to inconclusive results, and low publication rates [10]. Among general practice studies published 1991 to 1996 in the BMJ, the British Journal of General Practice, and Family Practice, only 6% were randomized controlled trials, which was pointed out as a major challenge for the general practice research community [11]. Some Norwegian data regarding clinical drug trials have previously been reported, based on research applications submitted to the Research Ethical Committees (REC) [12‐14] and the Norwegian Medicines Agency (NoMA) [15, 16]. Between 68% and 85% of the trials were initiated by pharmaceutical industry [13‐15], however, neither of these reports highlighted studies in general practice.

From the 1970s, a subcommittee of the Norwegian College of General Practitioners had a voluntary agreement with the pharmaceutical industry to assess protocols for studies to be performed in general practice [17, 18]. If the committee judged the trial to be clinically relevant and of sound scientific quality, GPs were recommended to participate in the trial. However, by the turn of the millennium, the committee voiced critical comments regarding some trials judged to be marketing (due to features of seeding trials) rather than research [17]. Since then, this voluntary quality and relevance check has been largely bypassed by the industry [19], and information regarding industry initiated research in Norwegian general practice has thus become an almost hidden reality except for the investigators themselves. This prompted the Norwegian College of General Practitioners in 2008 to fund research to gain systematic knowledge of the drug research carried out by GPs. This included establishing an overview of all trials conducted, exploring whether GPs were subject for marketing trials, and assessing the relevance of the research questions addressed, as well as the studies’ validity and publication output. The College requested this knowledge due to possible implications for their policy for future professional development within the discipline of general practice.

The aim of the present study was to establish a descriptive basis regarding clinical drug trials conducted in general practice by research areas and trial characteristics. As most clinical drug trials are multinational, this study also should concern research in general practice outside of Norway.

In Norway, the only complete national archive for drug trials is held by NoMA. Based on a hand search of the NoMA archive for the 10-year period 1998 to 2007, we describe all clinical trials planned to be carried out in general practice by their funding, clinical setting, drugs, diagnoses, patients, clinical investigators and economic compensations for the investigators. More detail will be given regarding one of the trials in year 2000, which the Norwegian College of GPs discouraged GPs to join [17], to give the reader a better sense of what we consider a seeding trial. Ethical approval for our study was not required.

The main findings in this study were that only about one-tenth of all clinical drug trials in Norway involved GPs as clinical investigators recruiting patients from their practices, and only 3.6% of these were non-industry trials.

We found that the proportion of researcher-initiated clinical drug trials in general practice in Norway was minute (3.6%) compared to clinical drug trials from other fields of medicine where 15% to 32% are non-commercial studies [13‐15]. Conducting clinical trials in general practice poses some typical challenges, like difficulties with study logistics and patient recruitment in a large number of small trial sites [4]. The lack of researcher-initiated trials has also been pointed out in the European Research Agenda for General Practice [5]. Irrespective of their commercial interests, this research agenda underlines that drugs mainly targeting primary care should be appropriately tested in primary care settings. Furthermore, that a stable funding and formation of research networks may facilitate non-commercial randomized controlled trials in general practice [5]. Although many have pointed to the need for clinical drug trials conducted independently of the industry, there was nonetheless a decline in the number of non-commercial randomized controlled trials in the UK between 1980 and 2002 [27]. Several systematic reviews have pointed out that drug trials financed by pharmaceutical industry tend to publish results more in favor of the manufacturer’s product than non-commercial trials, and that negative studies in this respect commonly remain unpublished [28‐32]. This publication bias combined with the lack of non-industry trials in general practice might therefore contribute to an evidence-biased knowledge base.

Over the last few years, there has been a decline in the number of clinical trials in several European countries [33, 34]. In Norway, the largest reduction has been in phase III studies [16]. For general practice studies we were not able to confirm this trend, even if the majority of trials in our material were phase III or IV. The trials where explicit information regarding trial phase was missing, were most likely also phase III or IV. The five companies funding most general practice trials were among the seven most profitable companies, thus largely reflecting their market positions [23].

A study from 2000 found that 84% of GPs in a part of England had been involved in research, 48% mainly in clinical trials [35]. Our figures indicate that Norwegian GPs’ participation rate in clinical trials is less than half of that in the UK; the 831 GPs involved correspond to about 20% of all Norwegian GPs in 2002 [1]. Surprisingly few GPs with university affiliations had participated in clinical drug trials, although many of them work part-time as GPs and are particularly interested in clinical research. Explanations for this finding may be that they judged the clinical relevance of the industry funded trials to be low, feared conflicts of interest, or had general negative attitudes towards collaboration with pharmaceutical companies [36]. Most GPs involved in clinical trials only participated once or just a few times, and did therefore not gain large incomes for participating. However, a number of GPs were involved in quite a few trials, giving them a substantial yearly income from trial participation. A few trials also gave outstandingly high payment for the doctors involved. Most GPs in Norway are self-employed with a major part of their income from patient payment and per capita reimbursement. It is therefore reasonable that extra workload due to participation in clinical trials is compensated. But how much is a reasonable level of compensation? Payment to clinicians for participation in clinical trials varies a lot [36, 37]. Andersen et al. report payments of US $800 per patient enrolled for a Danish industry initiated trial [37], which is approximately one-third of the median payment in our material. Raftery et al. point to the striking lack of transparency in guidelines for payments for involvement in research, where GPs are among the few individual clinicians where direct personal payment still is common [36]. Concerns have been voiced that high payments may create conflicts of interest and possibly lead to unethical recruitment processes [36]. This demands rigorous ethical standards from both the general practice community and the pharmaceutical industry.

We identified antidiabetic drugs and type II diabetes to be studied most frequently. Thomas et al. found few published articles on diabetes in UK primary care journals in the 1990s [11]. The general use of antidiabetics in Norway increased by 27% (in defined daily doses (DDDs)) from 2004 to 2008 [38]. This may both reflect increasing diabetes prevalence but also the introduction of new drugs. Andersen et al. found that physicians conducting a clinical trial, significantly increased the sponsor’s share of prescribed drugs for the disease compared to GPs not involved in the trials [37], and this might be important for expanding the market. The many post-marketing studies of new and expensive insulin analogues with large market potentials have recently been criticized for limited scientific value [9]. The three largest drug groups investigated in our study were among the four most consumed drugs in Norway (in terms of DDDs) [38]. These therapeutic areas were also among the six most frequently researched topics in general practice internationally between 2003 and 2008 [5]. In Norway in years 2000 and 2004 [14], and in the UK 1980 to 2002 [27], most clinical trials were in the field of cancer and antineoplastic and immunomodulating drugs. We only identified two trials in this field. This was as expected, as GPs rarely initiate antineoplastic drug prescriptions. Only one trial studied the effects of discontinuation of (unnecessary) medication use, although this is an important topic both for quality of care and general practice research [5].

Only one-tenth of all clinical drug trials in Norway involved patients recruited from general practice, and just one in four of these trials were solely general practice trials. Almost all trials were industry initiated without input from academic general practice. This shows that it is a challenge for general practice to increase the number of clinical trials in general and researcher initiated clinical drug trials in particular. Antidiabetic drugs were most commonly studied. There was a large variation in the number of patients, participating doctors, and economic compensation for trial investigators, with some investigators receiving substantial payments. We describe a study with several characteristics of a seeding trial, where none of the official approving bodies for clinical trials had any major remarks. It raises the important ethical considerations with regard to exposing patients to unnecessary risks in either an inordinately large or a small, underpowered trial.

In this descriptive study, we have addressed neither the relevance of the research questions for general practice nor the methodological quality or publication output of the trials beyond the case study. These are important issues that we intend to explore in forthcoming research.