CTU Lecture

Sven Trelle, CTU Bern

16. Mai 2019

Wieviel kostet meine Studie – wirklich?

2

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

3

Imagine the following situation …

Peter: «I want a house, how much does it cost?»

The question!

4

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

5

Uncertainty

The difficulty with trial budgets

Need to predict costs

Limited information

What is (thought) to be available/affordable↔ what is actually/truly needed

6

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

7

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

8

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

9

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

10

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%)

11

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 …

12

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?)

13

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

14

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

15

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

16

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

17

It is (relatively) costly

A recent systematic review

Speich 2018a

19

(Pharma)industry trials

It is (relatively) costly

Average trial costs (US; 2004-12; >30,000 trials)

Sertkaya 2016

20

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

21

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

23

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

25

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, …

26

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, …

27

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 …

28

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

30

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)

31

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

32

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

33

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

34

The site budget

Data management workload per patient

James 2011

35

The site budget

Regulatory workload per trial

James 2011

36

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 …

37

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 …

38

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.

• Photos

• Baby by Victoria Borodinova from Pexels

• Balance by Shiva Smyth from Pexels

• Other photos from www.pexels.com