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Table 2 Differences between randomized controlled trials with and without poor recruitment and conclusions on the possible reasons for poor recruitment

From: Comparison of randomized controlled trials discontinued or revised for poor recruitment and completed trials with the same research question: a matched qualitative study

Groups of RCTs with a common research question

Observed differences with respect to study characteristics (design, conduct, sponsor) between RCTs with and without poor recruitment

Context-specific conclusions on the possible reasons for poor recruitment

#1: Surgical treatment compared to proton-pump inhibitors in gastroesophageal reflux disease

RCTs with poor recruitment n = 2

RCTs without poor recruitment n = 2

1) Study sponsor: RCTs with poor recruitment were investigator-sponsored whereas RCTs without poor recruitment were industry-sponsored

Absence of industry sponsoring could mean less professional trial organization and limited funding in general; narrower eligibility criteria may correlate with overestimation of recruitment rates and with slow recruitment; and a higher burden for patients during follow-up may have lowered the motivation of reflux patients to participate

2) Eligibility criteria: more restrictive in the RCTs with poor recruitment with respect to disease duration and duration of prior proton-pump inhibitor usage

3) Patient burden during follow-up: patient assessment during follow-up more frequent in one of the RCTs with poor recruitment (Anvari et al. 2011) than in the RCTs without poor recruitment (e.g., assessment of quality of life every 3 months vs. every 12 months)

#2: Anthracyclines with or without any taxanes compared to anthracyclines plus any anticancer treatment or compared to single-agent taxanes in metastatic breast cancer

RCTs with poor recruitment n = 3

RCTs without poor recruitment n = 3

1) National/international: RCTs with poor recruitment were conducted in one country (national) whereas the RCTs without poor recruitment were international (1 not reported)

Absence of an international network of recruiting centers may be associated with limited recruitment capacities for patients with metastatic breast cancer; narrower eligibility criteria may correlate with overestimated recruitment rates and with slow recruitment; and the fact that evidence on the effectiveness of anthracycline combination therapy from previous RCTs was already available may have compromised the motivation of recruiters in the RCTs with poor recruitment

2) Eligibility criteria: more restrictive in 2 of 3 RCTs with poor recruitment (Bonneterre et al. 2004 and Bontenbal et al. 2005) with respect to adjuvant therapy prior to enrolment, i.e., adjuvant therapy had to be stopped at least 12 months before

3) Publication chronology/available evidence: RCTs with poor recruitment were published (years: 2004, 2005, and 2010) after 2 of the 3 RCTs without poor recruitment (Biganzoli et al. 2002 and Jassem et al. 2001); the other RCT without poor recruitment was published in 2005 (Nabholtz et al. 2005)

#3: First-line treatment with the aromatase inhibitor exemestane compared to anastrozole in postmenopausal women with advanced breast cancer

RCTs with poor recruitment n = 1

RCTs without poor recruitment n = 1

Eligibility criteria: more restrictive in the RCT with poor recruitment with respect to metastases and disease stage (visceral metastases only vs. advanced stage or any metastases in the RCT without poor recruitment)

Narrower eligibility criteria for postmenopausal women with advanced breast cancer may correlate with overestimated recruitment rates and with slow recruitment

#4: Antiarrhythmic agents compared to placebo or background therapy with beta-blocker in ventricular arrhythmia

RCTs with poor recruitment n = 1

RCTs without poor recruitment     n = 2

1) Intervention tested: RCTs without poor recruitment tested a new intervention, i.e., celivarone (Kowey et al. 2011) or azimilide (Dorian et al. 2004) whereas the RCT with poor recruitment [8] tested available drugs (beta-blocker, amiodarone, and sotalol)

The fact that already available antiarrhythmic drugs and no new drugs were tested may have compromised the motivation of recruiters or patients; recruitment capacities might have been insufficient due to too few study centers; and narrower eligibility criteria for patients with ventricular arrhythmia may correlate with overestimated recruitment rates and with slow recruitment

2) Number of study centers: 3 to 4 times lower in RCT with poor recruitment

3) Eligibility criteria: more restrictive in the RCT with poor recruitment [8] with respect to usage of antiarrhythmic agents prior to enrolment and the implantable cardioverter defibrillator device (only one specific type allowed)

#5: Prophylactic antibiotics compared to placebo or usual care in acute necrotizing pancreatitis

RCTs with poor recruitment n = 3

RCTs without poor recruitment n = 0

No differences observed because only RCTs with poor recruitment were identified

The fact that 3 RCTs were discontinued due to poor recruitment in this research area suggests that it seems generally problematic to recruit patients with acute necrotizing pancreatitis, which is associated with a high mortality rate (vulnerable patients)

#6: Late postnatal (> 7 days) corticosteroid treatment compared to placebo or usual care in preterm neonates

RCTs with poor recruitment n = 3

RCTs without poor recruitment n = 7

1) Number of study centers: all RCTs without poor recruitment were single-center studies, whereas 2 (Kari et al. 1993 and Doyle et al. 2006) of the 3 RCTs with poor recruitment were multicenter studies

The fact that 3 RCTs recruited poorly in this research area suggests that it seems generally problematic to recruit preterm neonates (vulnerable patients). In a setting with vulnerable patients, a single-center RCT may prove advantageous due to more motivated and better prepared/trained recruiters and closer monitoring of recruitment). Particularly problematic appeared the choice of primary outcome in Doyle et al. 2006; to focus on a potential side effect of the intervention may have compromised the motivation of recruiters and parents to include children in such an RCT. Equipoise may be compromised for RCTs conducted later in a group of RCTs addressing the same research question (leading to lower motivation of recruiters and parents), because evidence on the effectiveness of an intervention from previous RCTs was already available

2) Primary outcome: the primary outcome chosen in one RCT with poor recruitment (Doyle et al. 2006) focused on a potential side effect of the intervention (major neurosensory disability), whereas the other trials had an effectiveness outcome

3) Publication chronology/available evidence: a large RCT with poor recruitment (Doyle et al. 2006) was the last published RCT in this area of research whereas all other RCTs (discontinued or completed) were published earlier and already showed benefits in terms of better respiration of infants

#7: Ventilatory gas with nitric oxide compared to ventilator gas without nitric oxide in preterm neonates

RCTs with poor recruitment n = 2

RCTs without poor recruitment n = 5

1) Number of study centers: The number of study centers was consistently smaller among the RCTs without poor recruitment

In a setting with vulnerable patients (preterm neonates) a smaller number of study centers within 1 country may prove advantageous due to less complex trial organization and recruitment monitoring and potentially more motivated and better prepared/trained recruiters.

2) National/international: whereas all RCTs with poor recruitment were international studies, all but one RCT without poor recruitment (Hascoet et al. 2005) had a national setting

#8: Primary angioplasty compared to on-site thrombolytic therapy in acute myocardial infarction (within 12 h)

RCTs with poor recruitment n = 3

RCTs without poor recruitment n = 3

Target sample size: the number of patients planned to be enrolled was consistently higher in RCTs with poor recruitment

The fact that 3 RCTs recruited poorly in this research area suggests that it seems generally problematic to recruit acute care patients. The comparison of angioplasty (rapid patient transfer to center necessary) to on-site thrombolytic therapy was logistically very challenging at the time.

All RCTs with poor recruitment were meant to include more patients than the completed RCTs, consequently requiring more centers and often international collaboration, which additionally increased challenges with trial logistics

#9: Moxifloxacin compared to other antibiotics in patients with pneumonia

RCTs with poor recruitment n = 2

RCTs without poor recruitment n = 4

1) Patient population: both RCTs with poor recruitment included patients with hospital-acquired pneumonia, at least in part mechanically ventilated (potentially sicker/more vulnerable patients), while RCTs without poor recruitment included patients with community-acquired pneumonia without mechanical ventilation

Recruitment of sicker/mechanically ventilated patients appeared more challenging (informed consent etc.); patients who acquired pneumonia in a hospital may have been less motivated to participate in an RCT conducted at that hospital, particularly if severely affected (mechanically ventilated) In addition, all 6 RCTs were designed as non-inferiority trials, i.e., the tested antibiotics were not hypothesized to have superior effects but may have been cheaper or easier to apply, so patients with hospital-acquired pneumonia could not expect a more efficacious treatment and might have therefore been less motivated to participate. For the same reasons (sicker patients, hospital-acquired infection, non-inferiority design) recruiters may have been less motivated, too.

The eligibility criteria required the application of a complex scoring system (e.g., APACHE score) to determine patient eligibility, this may have increased the burden for recruiters and reduced their motivation

2) Eligibility criteria: one of the RCTs with poor recruitment used the APACHE (Acute Physiology And Chronic Health Evaluation) score to define eligible patients (Höffken et al. the RCTs without poor recruitment did not

#10: Temozolomide (chemotherapeutic agent) alone or in combination with radiotherapy compared to no chemotherapy (e.g., radiotherapy), non-temozolomide-based chemotherapy or temozolomide at different doses in glioma patients

RCTs with poor recruitment n = 1

RCTs without poor recruitment n = 3

 

In this group of RCTs with glioma patients, all trials were published after the completed and published RCT conducted by Stupp et al. 2005. Subsequent to this publication, it was probably difficult to recruit patients in RCTs that did not include the intervention that was shown to be superior in Stupp et al. 2005 (combination of radiotherapy and chemotherapy). However, neither the RCT with poor recruitment (Malmström et al. 2012) nor another RCT without poor recruitment (Wick et al. 2012) included such a combination therapy, both RCTs were very similar with respect to patient population (elderly) and compared interventions (temozolomide vs. standard radiotherapy). The only other RCT without poor recruitment compared temozolomide to another chemotherapeutic treatment in patients not suitable for radiotherapy (Brada et al. 2010)

#11: Capecitabine-based chemotherapy compared to non-capecitabine chemotherapy in metastatic breast cancer

RCTs with poor recruitment n = 4

RCTs without poor recruitment n = 5

Intervention tested: except for 1 RCT with poor recruitment (Bachelot et al. 2011) the RCTs with poor recruitment allocated patients to either an oral monotherapy with capecitabine or an intravenous application of a capecitabine-free chemotherapy either as monotherapy or as combination therapy. In contrast, in all but 1 RCT without poor recruitment (O’Shaughnessy et al. 2001), the route of administration was identical for both treatment arms (always included an intravenous application) and capecitabine was (with the same exception of O′Shaughnessy et al. 2001) given as combination therapy. The RCT without poor recruitment O′Shaughnessy et al. 2001, similar to the RCTs with poor recruitment also allocated patients either to intravenous or oral treatment, but at the time of trial conduct, oral monotherapy with capecitabine was relatively new and a 2:1 randomization was done to make it more likely for patients to get allocated to the anticipated patients’ preferred treatment option

Patients’ preferences regarding the form of application might have played a role in this research area, i.e., patient recruitment in RCTs comparing different interventions that, in addition, use different routes of application is hampered if patients have preferences about the route of application and therefore are less willing to be randomized.

Two other reasons for poor recruitment related to patients’ or recruiter preferences are possible, but could be specific for the respective RCT. (1) In 1 RCT with poor recruitment (Talbot et al. 2002) the tested drug was applied continuously whereas intermittently might have been preferred by patients. (2) In another RCT with poor recruitment (Stockler et al. 2011) the control treatment (cyclophosphamide, methotrexate, and fluorouracil, CMF) was, at the time, outdated and therefore the motivation of recruiters and patients might have been reduced. In the discussion authors stated: “The main limitations of our trial are the ambiguity of broad, pragmatic eligibility criteria and the use of an unfashionable control regimen.”(Stockler et al. 2011)

#12: Primary thromboprophylaxis (heparin) compared to placebo or usual care in ambulatory cancer patients receiving chemotherapy

RCTs with poor recruitment n = 2

RCTs without poor recruitment n = 2

1) Study sponsor: both RCTs with poor recruitment were investigator initiated whereas both RCTs without poor recruitment were industry-sponsored

Testing thromboprophylaxis with heparin in cancer patients may be challenging in general, because the intervention was not focused on combating the cancer, and therefore recruiters’ and patients’ interest in such an RCT may be reduced and seen as burden; competing RCTs testing antitumor agents might be preferred. In addition, the absence of industry sponsoring could mean less professional trial organization and limited funding in general, and a focus on only 1 type of cancer (narrow eligibility criteria, Perry et al. 2002) may have contributed to poor recruitment

2) Eligibility criteria: only glioma patients were eligible in 1 of the RCTs with poor recruitment (Perry et al. 2002) while both RCTs without poor recruitment included patients with various types of cancer

#13: Recombinant tissue plasminogen activator (rtPA) compared to placebo in acute ischemic stroke

RCTs with poor recruitment n = 1

RCTs without poor recruitment n = 5

1) Patient population and eligibility criteria: the RCT with poor recruitment focused on patients who did not fulfil the license criteria of rtPA (i.e., elderly patients > 80 years), whereas RCTs without poor recruitment did (focus on patients < 80 years)

The fact that the RCT with poor recruitment focused on elderly patients (> 80 years; i.e., narrow eligibility criteria, vulnerable patients) to be recruited in an acute care setting may have contributed to poor recruitment. The more complex subgroup hypotheses in the RCT with poor recruitment could have made the trial more difficult to explain to colleagues and patients. Finally, it is possible that the motivation of recruiters and patients was reduced, because evidence on the effectiveness from previous RCTs was already available (compromised equipoise)

2) Target sample size: the number of patients planned to be enrolled was higher in the RCT with poor recruitment due to planned subgroup analyses (more complex design/hypotheses)

3) Publication chronology/available evidence: the RCT with poor recruitment (Sandercock et al. 2012) was the last RCT conducted for this research question to date

#14: Transdermal nitroglycerin compared to placebo or usual care in laboring women (gestational age between 24 and 32 weeks)

RCTs with poor recruitment n = 1

RCTs without poor recruitment n = 1

1) Patient burden during follow-up: longer follow-up with more complex assessments of the neonates in the RCT with poor recruitment

Laboring women in both RCTs had to be at high risk of preterm delivery but also not too advanced so that they could still be randomized; however, the RCT with poor recruitment imposed a higher burden on patients with longer follow-up and a more complex assessment of the neonates, probably reducing the motivation of patients and recruiters to participate; in contrast, the primary outcome (i.e., number of days from randomization to delivery) in the RCT without poor recruitment did not require any effort from patients. A few well-picked study centers may have been advantageous in this acute care setting. The motivation of recruiters and patients was probably further reduced in the trial with poor recruitment, when evidence on the effectiveness of the tested intervention (nitroglycerin) from other RCTs became available (compromised equipoise, Smith et al. 2007).

Only 2 RCTs were considered in this group of RCTs, because the majority (n = 7) of RCTs included in the same systematic review did not report any sample size calculation/target sample size potentially hiding recruitment problems in these trials

2) Primary outcome: the RCT with poor recruitment had a more complex primary outcome (neonatal morbidity associated with long-term morbidity and perinatal mortality vs. number of days from randomization to delivery)

3) Number of study centers: the RCT with poor recruitment had over 3 times more study centers than the RCT without poor recruitment

4) Publication chronology/available evidence: the RCT with poor recruitment was still ongoing when the RCT without poor recruitment was published

#15: Vasopressin-containing regimen compared to epinephrine in cardiac arrest

RCTs with poor recruitment n = 1

RCTs without poor recruitment n = 5

Number of study centers: the RCT with poor recruitment was a multicenter RCT whereas all but one RCT without poor recruitment (Gueugniaud et al. 2008) were single- center RCTs.

In this acute care setting with vulnerable patients a single center RCT may be advantageous due to higher motivation and better prepared/trained recruiters and trial team and closer monitoring of recruitment). The RCT with poor recruitment was conducted in 44 community-based emergency rooms. One other RCT without poor recruitment (Gueugniaud et al. 2008) had a similar number of study centers as the discontinued RCT, but authors reported that the network of centers was well stablished and experienced in running acute care RCTs.

  1. RCT randomized controlled trial; All of the articles cited in Table 2 are referenced in Additional file 3