1. Dirk Hasenclever Oana Brosteanu
ADAMON Risk adapted monitoring is not inferior to extensive on-site monitoring
Dirk Hasenclever Oana Brosteanu
Institute for Medical Informatics,
Statistics & Epidemiology (IMISE) Clinical Trial Centre (ZKS)
University of Leipzig
on behalf of the
ADAMON project group
ICTMC/SCT 2017
May, 8th Liverpool

2. ADAMON objective and design
Is trial-specific, risk-adapted, focused on-site monitoring
as effective as
extensive on-site monitoring
in avoiding the occurrence of major or critical findings as ascertained in a final audit?
Rando-misation
risk-adapted monitoring
extensive monitoring
Trial Sites
Clinical Trials
ADAMON audit in every trial site
final
Stratified, cluster-randomised study
Trials are included (strata in analysis)
Trial sites are randomised (cluster)
Individual patients are evaluated (observation unit)

3. Planned interim analysis
ADAMON trial
Trial sites monitored with risk-adapted strategy
End of trial or
Planned interim analysis
Participating clinical trial
Preparation
trial conduct
Trial sites fully monitored
12 clinical trials to be included:
broad range of medical conditions
differences in complexity of design
different methods of data capture (paper-based, eCRF)
non-commercial sponsor
multi-centre (at least 6 sites)
risk classification K2 (intermediate) or K3 (low)
Definition of risk-ADApted MONitoring strategies
based on the risks identified
by published, structured procedure for
risk analysis in clinical trials.
Brosteanu O et al.
"Risk analysis and risk adapted on-site monitoring
in non-commercial clinical trials" Clin Trials 2009

4. Planned interim analysis
ADAMON trial
Trial sites monitored with risk-adapted strategy
Participating clinical trial
End of trial or
Planned interim analysis
Preparation
trial conduct
Trial sites fully monitored
Trial specific risk analysis and classification
Definition of key data
Preparation of the 2 monitoring manuals for the trial
Training of the trial monitors (at least 2 persons!)
Check of requirements for central oversight and data management
Central randomisation of the trial sites
Risk: Major or critical findings concerning GCP objectives:
Rights, integrity and confidentiality of trial subjects protected
Safety ensured
Data and reported results credible.

5. Planned interim analysis
ADAMON trial
Trial sites monitored with risk-adapted strategy
Participating clinical trial
End of trial or
Planned interim analysis
Preparation
trial conduct
Trial sites fully monitored
Supervision of the trial on site monitoring,
if necessary additional training for monitors
Assessment of monitoring parameters
Extensive monitoring on-site
Check existence / informed consent for all patients
Source data verification (SDV) of all data for all patients
Risk-adapted monitoring on-site according to risk class
K2 – intermediate risk  key data of 20 – 50% of patients
K3 – low risk  one visit, 20% key data
versus

6. Planned interim analysis
ADAMON trial
Trial sites monitored with risk-adapted strategy
End of trial or
Planned interim analysis
Participating clinical trial
Preparation
trial conduct
Trial sites fully monitored
Assessment of the primary endpoint
Trial specific definition of major audit findings;
Audit manual
On site audits
in each trial site
assessing each patient
Patients with at least one major or critical finding in five error domains
Informed consent
Patient selection
Intervention
Endpoint assessment
SAE reporting

7. 11 trials participated Indication 6 Oncology 2 Hematologic
4 Solid tumours
Trauma surgery
Parkinson‘s disease
Heart failure & depression
Severe sepsis
Neonatology
Type of intervention
8 pharmaceutical
2 surgical methods
1 surgery on top of standard of therapy
Monitoring risk class
8 K2 (intermediate)
3 K3 - low

8. Effort of extensive monitoring compared to risk-adapted monitoring
Monitoring time on site
Monitoring time
on-site
Total monitoring time
Number of monitoring visits per patient
Overall
2.7
2.2
2.1
Monitoring class K2
1.8 K3
5.2
3.6
3.5
Factor:
Effort with extensive monitoring /
Effort with risk-adapted monitoring
(geometric mean of factors in individual trials)

9. Primary and secondary endpoints
Patient-level finding rate
996 / 1618 patients (62%)
with 1+ findings in any error domain:
IC-process
241/1618
~15%
patients with
1+ findings
Total: 292
Selection
331 /1618
~ 20%
patients with
1+ findings
Total: 436
Intervention
405 /1618
~25%
patients with
1+ findings
Total: 758
Endpoints
420 /1618
~26%
patients with
1+ findings
Total: 614
SAE-reporting
295 /1618
~18%
patients with
1+ findings
Total: 356
2456 individual ADAMON audit findings
Observed finding rates
varied by trial
between 18 and 99%.

10. Primary Endpoint No evidence of heterogeneity
No risk class subgroup effect.
pre-specified tolerance margin
0.6 on log odds scale
Non-inferiority shown

11. Secondary endpoints 95%-Confidence intervals of primary endpoint
and all its components
pre-specified tolerance margin.

12. Interpret log adds ratios in terms of rates
Observed finding rates %.
Potential benefit of
extensive on-site monitoring
is small
relative to overall finding rates.

13. Typical types of findings I
Informed Consent (N=292)
dating the signature by the participating patient (N=180)
not by qualified staff (N=38)
Patient Selection (N=436)
measurements required for the assessment of eligibility (N=175)
not performed,
not performed in a timely manner,
out of range in
Prohibited co-medication (N=89 in one trial)
Not in target population (N=18)
Eligibility not verifiable (N=53).

14. Typical types of findings II
Intervention (N=758)
Treatment modification rules in complex treatment schemes:
ignored (N=227)
trigger not measured (N=166)
Relevant dose deviations (N=90)
Endpoint assessments (N=629)
Not assessed (N=95)
Measured inadequately (N=181)
Not on schedule (N=68)
Serious Adverse Event reporting (N=356)
Not reported (N=73)
Reported with delay (N=217)

15. error prone trial rules error prone complex clinical settings.
High finding rates
Evidence for
error prone trial rules
error prone complex clinical settings.
Room for improvement in study rule formulations.
Explorative analysis: At least half of formal trial rule violations could be avoided by improved rules serving the same clinical objective.
Domain of methodical/biometrical research
Recurrent problem areas:
Wrong granularity/ pseudo-precision
Over-specification and unnecessary interference with standard clinical practice
Non-transparent modality of study rules:
strict rule versus loose guidance of local decision making

16. Risk adapted monitoring
Conclusions
Risk adapted monitoring
is not inferior to extensive on-site monitoring
requires less than 50% of extensive on-site monitoring resources.
Complicated, overly specific or not properly justified protocol requirements contributed to the overall frequency of findings.
Risk-adapted monitoring has a part to play in quality control and source data verification.
However, no monitoring strategy can remedy defects in quality of design.
Monitoring should be embedded
in a comprehensive quality management approach covering the entire trial lifecycle.

17. ADAMON project group Ulrike Zettelmeyer CTC Cologne Anke Strenge-Hesse
ECRIN Office / KKS Network
Ursula Paulus
formerly: CTC Cologne
Gabriele Schwarz
BfArM
Dirk Hasenclever
IMISE Leipzig
Oana Brosteanu
CTC Leipzig
Peggy Houben
Anja Schneider
ADAMON project group