Strategies to accelerate recruitment to NHMRC multi-centre clinical trials

Dear Editor,

We estimated the average recruitment period in reports of multicentre randomised controlled trials (RCTs) funded by the National Health and Medical Research Council (NHMRC) in the New England Journal of Medicine between January 2001 and December 2011. The terms ‘trial’ and ‘Australia’ were entered into the New England Journal of Medicine Advance Search facility on its website (http://www.nejm.com), yielding 177 articles, from which 20 RCTs that were fully or co-funded by NHMRC were identified. The mean recruitment period for all 20 RCTs was 4 years 11 months (range 1 year 9 months to 9 years 10 months). However, the mean recruitment period was 18 months longer for the 11 RCTs with primary neonatal or paediatric outcomes than for the other nine adult trials (Table 1). These recruitment periods do not include the time needed for follow-up.

Table 1. Reports of NHMRC-funded multicentre randomised controlled trials in N Engl J Med, 2001–2011

Date	Authors/title	Patient group	Primary outcome	No. of patients	No. of sites	Recruitment period
†,‡Secondary reports of the same trial were excluded from the calculations. NHMRC, National Health and Medical Research Council; RCT, randomised controlled trial.
2011	INIS Collaborative Group (NHMRC 301973). Treatment of neonatal sepsis with intravenous immunoglobulin. NEJM 365: 1201–11.	Newborn infants	Death or disability	3 493	113	6 years
2011	Stenson et al. Increased 36 week survival with high oxygen target in very preterm infants. NEJM 364: 1680–82.	Preterm infants	Death	2 316	36	5 years
2011	Cooper, et al. Decompressive craniectomy in diffuse brain injury. NEJM 364: 1493–502.	Adults	Death or disability	155	15	9 years 5 months
2010	Zoungas et al. Severe hypoglycemia and risks of vascular events and death. NEJM 363:1410–18.	Adults	Death or vascular events	11 140	215	1 year 9 months
2010	Cooper et al. A randomized, controlled trial of early vs. late initiation of dialysis. NEJM 363: 609–19.	Adults	Death	828	32	8 years 4 months
2009	Craig et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. NEJM 361: 1748–59.	Children	Urinary infection	576	–	8 years 4 months
2009	RENAL Replacement Therapy Study Investigators. Intensity of continuous renal replacement therapy in critically ill patients. NEJM 361: 1627–38.	Adults	Death	1 508	35	2 years 9 months
2009	NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. NEJM 360: 1283–97.	Adults	Death	6 104	43	4 years
2009	Buchbinder et al. A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures. NEJM 361: 557–68.	Adults	Pain	78	–	4 years 7 months
2008	Karunajeewa et al. A trial of combination antimalarial therapies in children from papua new guinea. NEJM 359: 2545–57.	Children	Treatment response	677	2	2 years 3 months
2008	Rowan et al. Metformin vs. insulin for the treatment of gestational diabetes. NEJM 358: 2003–15.	Women	Neonatal morbidity	751	10	4 years 2 months
2008	Morley et al. Nasal CPAP or intubation at birth for very preterm infants. NEJM 358: 700–8.	Preterm infants	Death or BPD	610	17	6 years 10 months
2007	Schmidt et al. Long term effects of Caffeine Therapy for Apnea of Prematurity. NEJM 357: 1893–1902.†	Preterm infants	Death or Disability	2 006	36	5 years
2007	Crowther et al. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. NEJM 357: 1179–89.	Infants	Disability free survival	1 047	23	6 years 2 months
2007	SAFE Study Investigators. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. NEJM 357: 874–84.‡	Adults	Death
2006	Schmidt et al. Caffeine therapy for apnea of prematurity. NEJM 354: 2112–21.†	Preterm infants	BPD
2006	Elkins et al. A Controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. NEJM 354: 229–40.	Adults	Lung function	164	15	2 years 4 months
2006	Rumbold et al. Vitamins C and E and the risks of pre-eclampsia and perinatal complications. NEJM 354: 1796–806.	Women	Pre-eclampsia, death or morbidity, SGA	1 877	7	3 years 1 month
2005	Crowther et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. NEJM 352: 2477–86.	Women	Infants: death, morbidity or prematurity	1 000	18	9 years 10 months
2004	SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. NEJM 350: 2247–56.‡	Adults	Death	6 997	15	1 years 8 months
2003	Askie et al. Oxygen-saturation targets and outcomes in extremely preterm infants. NEJM 349: 959–67.	Preterm infants	Growth and development	358	8	4 years
2003	Wing et al. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. NEJM 348: 583–92.	Adults	Cardiovascular events	6 083	–	3 years 3 months
	Average recruitment period in RCTs in infants or children (n = 11)					5 years 6 months
	Average recruitment period in RCTs in adults (n = 9)					4 years 0 month
	Average recruitment period in all RCTs (n = 20)					4 years 11 months

All these trials are likely to have significant impact on clinical practice, because they were reported in the world's most highly cited medical journal. They illustrate the need to invest considerable resources and time, often well beyond 5 years, to address important study questions, rather than curtailing recruitment, diminishing power and scientific validity.

What strategies might accelerate recruitment? Several trials in the table employed international collaboration to achieve samples of hundreds or thousands. Another strategy to accelerate recruitment, not yet widely employed in Australian trials nor exemplified in the Table, is to establish fully funded networks of local research coordinators, in sites with adequate volumes of patients.[1]

Government-funded clinical networks, which include local site research nurses or coordinators to support clinical trials, have already been established to improve the co-ordination, speed and quality of randomised controlled cancer trials in Australia[2, 3] and of paediatric and neonatal trials in the United Kingdom.[4] Similar investment merits consideration in other specialties in Australia, particularly in perinatal, neonatal and paediatric clinical trials, where life expectancy in survivors spans several decades.

A third strategy is to engage consumers and parents as full partners in all aspects of the design, conduct and implementation of trials. This may enhance their relevance to patients and accelerate recruitment and the implementation of their results.[4]