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Improving the Economic Efficiency of Clinical Trials. 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.
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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.
