Background • The design of most clinical trials is dominated either by ‘content’ specialists, usually clinicians, or, statisticians. • Both groups do not necessarily consider the costs of the study in its design.
Different Perspectives • Statisticians usually are interested in maximising the power of any study. • Clinicians want to demonstrate something ‘works’. • There should be a cost perspective.
Economist’s perspective • There is an opportunity cost to undertaking a trial. • Decisions about whether the trial should be placebo controlled or open the randomisation ratio the choice of comparator all have cost implications. • The costs and benefits of these decisions need considering in a trials.
Costs in Trials • Cost of treatments; • Research costs; • Participant costs; • Time costs - delayed trial completion results in costs. • NEED to consider these costs to maximise trial design efficiency.
Economics and Trials • Few trial designs are informed by economics. • Usually economists are only involved in the design of the economic evaluation alongside the clinical trial rather than the trial design per se.
Placebos • To use or not to use placebos • Placebos blind participant, physicians and researchers, which reduces problems of bias associated with ascertainment, Hawthorne, preference and dilution effects. • Use of placebos is not PRAGMATIC and can be costly.
‘Hidden’ Cost of Placebos • Whilst placebos are inexpensive their use is NOT; • Trials that use placebos have to have a screening process to remove patients to whom active treatment is contra-indicated; • An open trial can avoid this by including them and not giving active treatment. • This can lead to cost savings.
Including unsuitable participants • Including participants within the active group and NOT giving them active treatment WILL lead to dilution effects. • This could be dealt with by increasing the sample size to detect the smaller difference. • This may be worthwhile IF significant cost savings and dilution effects small.
Unequal Randomisation • Trial efficiency may be improved by allocating more participants to the less expensive treatment and more to the cheaper treatment. • Statistical power can be maintained by increasing the sample size.
Optimum Randomisation Ratio • The most efficient allocation ratio is calculated by the square root of the cost ratio of two treatments. • If treatment A costs 4 X as much as treatment B then the optimum allocation ratio is 2.
Cost Savings • By using an unequal allocation ratio the trial saved about £1 million. • Many studies do not have as dramatic cost difference but important savings can still be made.
Recruitment methods • Different trial recruitment methods have different costs and effectiveness. • Recruitment from clinics usually require the cost of a nurse or other clinician. • Alternative may be ‘database’ recruitment.
Database Recruitment • Database recruitment is a potentially inexpensive method of recruiting to clinical trials. • Members of a database (e.g. GP lists) are mailed to with trial information and asking them to take part. • Relatively inexpensive clerical time can be used to complete most of the recruitment process.
Examples of two trials • Both trials among people aged 70+; • Both trials used calcium and vitamin D supplementation; • Both trials sought a fracture reduction; • One trial cost £1.1 million the other cost £300,000. • Difference was partly due to low cost design.
Trials • MRC Record Trial £1.1 million factorial RCT of calcium with or without vitamin D for fracture prevention in women and men 70+ attending a fracture clinic. • Primary care calcium and D trial £300,000 RCT among women 70+ with 1+ risk factors for fracture.
RECORD Trial • Started in 1998 aimed to recruit 6,500 women and men from fracture clinics; • Factorial and placebo design to test the hypothesis that supplementation with or without calcium or vitamin D prevented further fractures; • Powered to show a 20% reduction in fractures.
RECORD Recruitment • Participants are recruited by research nurses. Potential participants have to be screened for eligibility, consent etc. • This can take up to an hour per participant and often results in non-recruitment. • This is a slow and EXPENSIVE process.
RECORD Recruitment • Because RECORD is a placebo controlled trial ALL participants need to be ‘screened’ to identify the few (1-2%) who have contra-indications to the use of calcium supplements (e.g. recent history of kidney stones).
RECORD treatment delivery • Because RECORD is placebo controlled ALL participants are mailed supplements every four months, which adds to cost of the trial.
Primary Care Trial • Trial aimed to recruit 2855 women to demonstrate a 33% reduction in fracture incidence. • Trial was an ‘open’ design with controls receiving an information leaflet about osteoporosis.
Primary Care Recruitment • All women registered with GPs taking part in the study are mailed a risk factor questionnaire, consent form and information. • Response rate for participation is 7.5%. • Relatively inexpensive method of identifying potential participants.
Primary Care Recruitment • Participants that are eligible are randomised. • Those allocated to the intervention group are seen by the practice nurse and given calcium and D IF there are no contra-indications. If there are contra-indications trial participation continues without the supplement.
Dilution Effects? • Including participants who can’t start therapy WILL dilute the effect size. • Small dilution is not a problem particularly if resources saved can be used to increase the sample size.
Primary Care Allocation Ratio • Women in intervention group would be seen by nurse costing £30 per woman in nurse time plus recruitment cost (£10) £40 in total. • Women in control group estimated cost about £10. • Efficient allocation was estimated at about 2:1.
RECORD Recruitment • Trialists underestimated the numbers of eligible participants. • This lead to recruitment difficulties, research nurses had to ‘screen’ many ineligible people.
RECORD Solutions • Close poor recruitment centres (some money wasted on minimum contracts) • Trial needed 12 month recruitment extension, more funds, and did not reach target - got 5272 NOT 6500.
RECORD - Cost implications • To meet recruitment target extra funds were required - increased cost. • Recruitment time was extended - time cost of uncertainty.
Primary Care Recruitment • Trialists overestimated numbers who would take part (10%). • Early indications only gave a 5% recruitment rate. • To meet recruitment target numbers of people mailed out to was doubled.
Primary Care Cost implications • To increase mail out increased cost per recruited subject. • This narrowed the cost differential between intervention and control as recruitment cost was a constant cost per participant.
Trial Budgetary Implications • Main fixed cost of trial - trial co-ordinators salaries. • Variable costs included postage costs and £30 ‘treatment’ cost. • The need to increase ‘mail-out’ expenditure led to the following scenarios.
Recruitment with fixed budget • Increase allocation to control using saved money to increase mail out. • Disadvantages will increase workload for local trial co-ordinators in terms of data entry and data management. • On the plateau of the ‘power’ curve need to recruit substantially more to make up loss of power.
Recruitment with small increased budget • If budget could be increased to account for increased mail out costs we could maintain 2:1 allocation ratio and meet target. • Disadvantage the allocation ratio is now suboptimal for the overall trial budget as cost ratio has declined - will be getting less power than is optimum.
Recruitment with slightly larger budget increase • If increased mail out was funded AND extra funds for optimal recruitment ratio (3:2) extra statistical power can be obtained for relatively small increased cost. • Disadvantage - need more money.
Solution • Pharmaceutical company agreed to increase funds for mail out and allow optimal allocation ratio (3:2) AND cover for recruitment overshoot (3400 instead of 2855). • Detectable difference fell from 33% to 30%.
Allocation Ratio - lessons • A fixed allocation ratio is unlikely to be correct through the lifetime of a trial. • Should plan for an adaptive allocation and change ratio during recruitment if cost ratio changes. • Budget planning should probably start with an ‘inefficiently’ high allocation (e.g. 3:2 or 1:1) ratio and adapt downwards (e.g. 2:1) as trial proceeds if necessary.
Database Recruitment • Recruitment from some sort of database is likely to be more cost effective than from clinics. • Need to make costs as variable as possible, that is as closely related to recruitment (e.g. a per patient cost).
Conclusions • Looking closely at the design of a trial can lead to important cost savings. • This can lead to trial designs that are faster and less expensive than normal designs. • WARNING - grant referees do NOT understand unequal allocation and some see it as UNSCIENTIFIC.