CTU Lecture Wieviel kostet meine Studie wirklich?
Transcript of CTU Lecture Wieviel kostet meine Studie wirklich?
CTU Lecture
Sven Trelle, CTU Bern
16. Mai 2019
Wieviel kostet meine Studie – wirklich?
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My conflicts of interest
CTU Bern depends on clients and people who seek help
The more I stress specialization and expertise the better
The more expensive a project is the more remains (usually) for CTUs
With regard to this talk
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Imagine the following situation …
Peter: «I want a house, how much does it cost?»
The question!
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Imagine the following situation …
Peter: «I want a house, howmuch does it cost?»
You: «What type of house do you want?»
Peter: «I do not know, a standard house, nothing fancy»
You google.com
You: «How many people areyou?»
Peter: «Me, my wife and twokids –
at the moment, but who knowswhat will happen in future …»
A possible first inquiry
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Uncertainty
The difficulty with trial budgets
Need to predict costs
Limited information
What is (thought) to be available/affordable↔ what is actually/truly needed
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Definitions (in this talk)
Trial budget and costs
Budget
The estimated amount of all money needed to do a clinical trial (or task)
From concept to completion
Costs
The actual amount of all money needed to do the whole clinical trial (or task)
Direct and indirect costs
Broderick & Spiker; Speich 2018b
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Categories
Costs
Direct costs
Fixed i.e. not directly related to number of participants
Variable i.e. directly related to the number of participants and certainevents
This separation is sometimes difficult to make for certain costs
Indirect costs
(Basic) Infrastructure e.g. space, IT network etc.
(Opportunity costs)
Often difficult to quantify
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Disentangled
Direct costs
Personnel
Services (consisting of personnel, equipment, indirect costs …)
Equipment
Consumables
Intervention costs e.g. the device
Lab consumables
Office supply including phone etc.
Travel
Insurance
… Hatfield 2008
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Disentangled
Direct costs
Personnel
Services (consisting of personnel, equipment, indirect costs …)
Equipment
Consumables
Intervention costs e.g. the device
Lab consumables
Office supply including phone etc.
Travel
Insurance
…Hatfield 2008
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Predicting the costs …
The clinical trial budget
The overall costs (sponsor), includes
Site budget (investigator)
Central coordination costs
Outsourced costs e.g. CTU/CRO
Principle: Trial characteristics + assumptions + contingency = budget
Trial characteristics: the more, the better …
Assumptions: predicting the unpredictable
Contingency: allow for unforeseen events/expenses (+ 10-30%)
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The take home messages
It is (very) difficult
Clinical research/trials is(very) costly
Communication takes time costs money. Doing research== communication
You will never overestimate the resources and time needed – no worries!
Do not underestimate thecosts …
First …
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Do not underestimate
If you underestimate, you will not have the resources to complete thetrial
Example
Plan was 5 sites
Enrollment low
Actual number of sites was increased to 12 (fees, start-up, …)
Experience tells us that this happens (very) often (in academia?)
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Empirical data
Do not underestimate
Two investigator-initiated trials (Basel)
Prednisone trial
7 sites (CH), 802 participants
Community-acquired pneumonia, prednisone versus placebo
Planned budget: 1,580,000 US$
Estimated costs: 2,301,884 US$ i.e. 46% increase
Oxantel trial
2 sites (Tanzania), 480 participants
Soil-transmitted helminths, 4 arms (pharmaceutical products …)
Planned budget: 100,000 US$
Estimated costs: 100,374 US$ i.e. no increaseSpeich 2018b
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You will never overestimate …
We forget to actually consider all time needed to complete a task
We forget to consider communication
We overestimate how much we work (productive working time)
30% is probably not an overestimate …
Bratt 1999
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Why research is not routine care
Communication
People might not be as familiar with each other as in clinical care
More different professions (speaking different «languages») involvedin research than in clinical care
Non-standard processes (e.g. central laboratory, non-standard assessments)
Non-standard equipment (e.g. trial-specific ECG-machine)
Quality standards may be higher/different
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Some examples reported in the literature
It is (relatively) costly
Multiple Risk Factor Intervention Trial (MR-FIT)
12,866 men with high risk cardiovascular disease
Apparently most expansive (known) trial : US$ 611,500,000
Cancer screening trial
154,901 participants, 13 years of follow-up
Overall costs: US$ 494,000,000
Speich 2018a
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It is (relatively) costly
A recent systematic review
Speich 2018a
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(Pharma)industry trials
It is (relatively) costly
Average trial costs (US; 2004-12; >30,000 trials)
Sertkaya 2016
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It is (relatively) costly
Budget of IIT grants
N=20, 2016-18, IICT call
All disciplines, variousintervention types
Sample sizes unclear
Budgetmedian CHF 1,585,000 (IQR 1.0 to 2.1 Mio., Max 3.4 Mio.)
N=125, 2007-16, German Clinical Trials Programme
All disciplines, variousintervention types
Sample sizemedian 278 (76 to 78,000)
Budgetmedian EUR 1,107,000(IQR 0.8 to 1.8 Mio,Max 15.5 Mio.)
Swiss National Science Foundation German Ministry of Research
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UK CTUs providing budget
It is very difficult
Common protocol
Randomized-controlled two-arm trial in anesthesia (interventionunspecified)
2x130 (260) patients at 15-20 UK sites
Project duration 66 months (24 m enrollment, 24 months follow-up)
Self-reported primary outcome
Hind 2017
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6 industry experts
It is very difficult
Common protocol
Double-blind randomized controlled three-arm trial
Two drugs (single and combined)
14,500 congestive heart failure patients at 800 sites
Eisenstein 2005
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Data management
The budget
CTU Bern approach regarding cost estimation, relevant trialcharacteristics
Number of sites
Number of users
Number of (unique) variables
Overall complexity
…
Extend of service
Randomization, emergency unblinding, online surveys, training, reports, …
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Monitoring (central and on-site)
The budget
CTU Bern approach regarding cost estimation, relevant trial characteristics
Number of sites
Location of sites
Number of on-site visits
Number of variables
Overall complexity
…
Extend of service
Source data verification, training, reports, …
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Monitoring (central and on-site)
The budget
In industry trials, monitoring accounts for 25-50% of the budget
This is not the case in most of academic trials
From CTU Bern experience this is unfortunate given what we see …
From our perspective every CHF invested in monitoring is worth it
You cannot budget too much monitoring costs
p.s. see conflict of interest at beginning, though …
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Site costs/case payments/patient fees
The budget
Workload measurement instruments
Mainly from oncology (US)
Review by US National Cancer Institute
https://www.dcpaquip.com/Documents/Media/Assessing%20Clinical%20Trial%20Workload_Full%20Slide%20View.pdf
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Dissecting the protocol and more …
The site budget
Protocol workload Start-up costs
Submissions, fees, training, organising, communication, preparing Investigator Site File, initiation visit, …
Close-out costs Queries, documentation, close-out visit, invoicing, sending back/destroy material,
archiving, …
Case workload Invoicables (variable)
On-site monitoring visits, serious adverse events, audits, regular reports to ethicscommittee, screen failures, …
Per participant Organising appointments, information and consent, assessments, data entry,
queries, treatment, …
Driven by schedule of events (procedures and assessments as per protocol)
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Possible benchmarks for specific tasks …
The site budget
Clinical Research Associate at 24 National Cancer Institute ofCanada Cooperative Trial Group member sites, 1996
Site approval procedure (N=132)
Mean 96.9 min (SD 135.2 min), max 1006 min per trial
Training and review of case report forms (N=116)
Mean 76.9 min (SD 92.4 min), max 590 min per trial
Monitoring visit (preparation, visit, post-visit) (N=183)
Mean 120.4 min (SD 141.1 min), max 780 min per trial
Phone liaison with sponsor, lab, staff, pathology, … (N=333)
Mean 41.9 min (SD 10.2 min), max 90 min per trialRoche 2002
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Possible benchmarks for specific tasks …
The site budget
Eligibility and Entry (mean of 11 tasks added; N≈300)
≈ 4.5 h/patient (SD ≈ 1.5 h)
Quality of life/diary review (N=108-362)
Eligibility: mean 16.6 min (SD 13 min), max 60 min per patient
Treatment: mean 14.6 min (SD 11.2 min), max 80 min per patient
Follow-up: mean 13.0 min (SD 8.7 min), max 55 min per patient
Waiting time (N=160-523)
Eligibility: mean 26.3 min (SD 22.8 min), max 120 min per patient
Treatment: mean 16.9 min (SD 13.0 min), max 90 min per patient
Follow-up: mean 17.4 min (SD 13.3 min), max 90 min per patient
Roche 2002
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Study nurse/coordinator workload
The site budget
University of Michigan Comprehensive Cancer Center (UMCCC) Clinical Trials Office (CTO)
Mean 28.3 FTEs data management staff (site initiation, patient enrollment, case report form completion, adverse event reporting (documentation?))
Mean 8.9 FTEs regulatory staff (institutional review board (≈ independentethics committee) submission, adverse event submission (reporting?), drafting patient information and consent form, submission of amendments)
No responsibility for: consenting, scheduling, blood draws
Clinical trials
2006-2009
239-284 clinical trials/year
mean 554 patients/yearJames 2011
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The site budget
Data management workload per patient
James 2011
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The site budget
Regulatory workload per trial
James 2011
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The take home messages
You will never overestimate the resources and time needed – no worries!
Start early and discuss with others
Separate routine care (in different sites …) and research
Communication takes time costs money
Placebos and trial specificmedication is (very) costly
Every CHF invested in monitoringis worth the money
Do not underestimate the costs …
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Finding the right balance
Having a too high budget might meanthat a project is neverstarted having a toolow budget might meanthat a project is neverfinished …
is key …
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SNSF
Reminder
Investigator-Initiated Clinical Trials (IICT) Call
1st July: Letter of intent (topic, not peer reviewed)
1st Nov: Full proposal
Please contact CTU as early as possible if youwant to involve us
Project funding
1st Oct and April: clinical projects can be funded
Please contact CTU as early as possible if youwant to involve us
Thank you
for your attention!
References
• Bratt 1999: Health Policy and Planning; 14: 374.
• Broderick & Spiker: How to prepare a clinical trial budget. Available at https://bit.ly/2ZXl7am.
• Eisenstein 2005: Am Heart J; 149: 482.
• Hatfield 2008: In: Barrett B., Parfrey P. (eds) Clinical Epidemiology. Methods in Molecular Biology™ (Methods andProtocols); 473: 299.
• Hind 2017: Trials; 18: 203.
• James 2011: J Natl Compr Canc Netw; 9: 1343.
• Roche 2002: J Clin Oncol; 20: 545.
• Sertkaya 2016: Clin Trials; 13: 117.
• Speich 2018a: J Clin Epidemiol; 96: 1.
• Speich 2018b: J Clin Epidemiol; 96: 73.
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