A presentation by Niklas Nielsen at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All available content from SSAI2017: https://scanfoam.org/ssai2017/ Delivered in collaboration between scanFOAM, SSAI & SFAI.

1. Challenges in clinical research
NIKLAS NIELSEN, MD, PHD, HELSINGBORG, LUND UNIVERSITY

2. Disclosure and rationale
• I have been principal investigator of one published clinical trial
• One more will soon start

3. Complexity of a large clinical trial
• 10 countries, 36 sites, 250 investigators, 950 patients
• 14-16 countries, 70-90 sites, 500 investigators, 1900 patients
• Patients, relatives, investigators, clinicians, clinical trial units, managers, R and D
units, ethical boards, data safety committees, industry and pharmaceutical
companies, drug agencies, monitors, data platform providers, hospital lawyers,
insurance companies, funders, academic societies, competing groups, journals,
peer reviewers, colleges, family and friends

4. JNK/SAPK
MAPKs
Pro-death
Activity
RTK
Ras
Raf
MAPK
ERK
Pro-
Survival
Activity
PLCg
PI3-K
PKC
Growth
Factors
Stress Signals
PKB
PCD Hour to Days
Ischemia-reperfusion injury

5. Clinical trials are often one off projects

6. Industry versus Investigator initiated!
• A world of a difference!

7. Internal and external validity

8. Internal and external challenges

9. CHALLENGES
• INTERNAL
• Knowledge
• Experience
• Status
• Structure
• Internal fear….
• EXTERNAL
• Funding
• Ethics
• Insurance
• Monitoring
• Agreements
• Culture
• Pharmaceutical interventions
• The world around!

10. INTERNAL

11. Knowledge
• You probably have a research interest…
• You must get to know your field…
• If there is no systematic review available, perform one!
• Post knowledge gaps in databases (DUETs, SBU, others)
• Try to team up with an observational registry to get to know the essential basics
– Frequency of the disease of interest
– Background event rate of the outcome of interest
– Variability of the outcome
– Major independent predictors of the outcome
– Number of patients in specific hopsitals/regions
– Etc, etc

12. Experience
• With experience you will know what challenges will face you
• If you have limited experience, team up with someone who knows what to do
– Clinical Research Unit
– Statisticians
– Methodologists
– Experienced trialists

13. Guidelines will help you!
equator-network.org

14. Status
• Some brass will also help!
• Take advantage of a Bigwig!

15. Structure
• Find your accomplices!
• Build networks (nationally/internationally)
• Multi-diciplinary work force
– Clinicians
» Various specialities and professions
– Trialists
– Statisticians
– Health economists
– Clinical trial managers
– Trial unit/CRO
– Mentors

16. Internal fear and conscience….

17. EXTERNAL

18. Funding
• A large scale multicenter international industry sponsored trial may cost multiples
of 10th of M Euro

20. Funding
• A large scale multicenter international industry sponsored RCT may cost
multiples of 10th of M Euro
• A large investigator led RCT may have a budget of 2-3 M Euro
• Same standards should anyway be met (GCP)
• Infrastructure at hospitals and institutions must be financed
• A large gap between what would be ideal and what is realistic
• Reimbursement to sites lower than actual costs
• Some diesease will attract funding easier…

21. Luke 19:26
• ”I tell you, whoever has, will be given more….”

22. Catch 22 situation…
• Some funders will only give money if the trial can prove it is fully funded
• You will only become fully funded when you receive the money
• You ask for 100% and receive 50-70%
• Money is given for certain periods of time
• Money starts to go stale and disappear before the project has started
• …and then you aren’t fully funded anymore….
• ”Yes, we are fully funded, but actually we need more….”

23. Academic currency
• Steering group positions
• Author positions
• Possibility to perform additional research
• Publications, Impact Factor, H-index, Research-Gate-score…..

24. Ethics and consent
• Etchical application processes vary significantly
• Local Institutional Review Boards, Regional Ethical Committees, Central Ethical
Committees
• The view of what should be regarded as part of an ethical review vary
• Special challenge in intensive and emergency care

25. Declaration of Helsinki

26. Article 20

27. Article 28-CONSENT

28. Article 30-CONSENT

29. Insurance
• Hundreds of thousand of euro for insurance certificates
• Hundreds of millions in reimbursements
• Many providers/insurance companies, difficult to assess the differences
• Limited interest in investigator led trials

30. Monitoring
• External examination of trial conduct
– Screening, inclusion logs
– Source data verification
– Legal documents in order
– List of investigators
• Previously neglected area
• Today mandatory
• Time consuming
• Expensive

31. Agreements
• Sponsor issues template approved by legal department
• Site reads and amends after discussions with their legal people
• Sponsor has another round of legal counseling
• Sites reads and amends…
• People very far from the trial will sign the important signatures
• THIS CONSUMES TIME!

32. Agreements and law text
• Sponsor (the “Indemnifying Party”) shall indemnify, defend and hold harmless the
PC, its trustees, officers, employees, agents and representatives (collective, the
“PC Indemnitees”) from and against any and all losses, liability, cost and
expenses, including attorney’s fees and costs, awards, judgments, damages,
fines, penalties, claims and causes of action (collectively, “Claims”) arising out of
or related to the negligent acts or omissions of the Indemnifying Party or any of
its officers, directors, employees, agents, representatives, contractors,
successors, assigns or anyone acting on their behalf in connection with, arising
from or related to the performance of obligations under this Agreement, including
Claims for (i) personal injury, including death, and damage to property, (ii) the
breach by the Indemnifying Party of any term, representation, warranty or
covenant under this Agreement, or (iii) the use by Indemnifying Party of the
research results provided hereunder.

33. Culture
• Swedes can’t follow command
• A consultant from country X may think that one of the interventions is better
• Email communication is difficult
• In some countries you say ”yes”, but mean ”no”
• Biobanking is not always so easy
• Some colleges can’t understand why it is impossible to have a beer with the
lunch payed by the Research Council
• Sometimes you should just not crack that joke…

34. The world around…
• You have to realize that you may be criticized!
– Colleges (Clinicians, fellow researchers)
– Authorities
– Patient organizations
– Industry

35. Standard care and guideline wordings…
• Guidelines are mostly needed when we don’t know what to do
• Strong recommendations and wording of guidelines will influence what
would be considered standard practice
• Established standard practice is hard to randomize against
• Guideline text may therefore lead to stagnation and dogma
• Ought to be compulsory to include areas of uncertainty

36. Pharmacological interventions
OMG!

37. Internal fear and conscience….
• Are we causing harm?
• Random care versus randomized
allocation of care….

39. Thank you!
www.ttm2trial.org