Progress and Regression in clinical trials 1950-1990: False POSITIVES increasingly well controlled by randomisation 1990-2000: False NEGATIVES increasingly well controlled by “mega-trials” and “meta-analyses”
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
1950-1990: False POSITIVES increasingly well controlled by randomisation
1990-2000: False NEGATIVES increasingly well controlled by “mega-trials” and “meta-analyses”
2000 & beyond: Increasing regulation,complexity and costs may prevent many important public health questions from being answered reliably (REGRESSION)
URGENT NEED TO SIMPLIFY TRIALS TO ENHANCE THE CONDUCT OF IMPORTANT TRIALS ESP IN VULNERABLE AND UNDERSERVED POPULATIONS BOTH IN DEVELOPED AND DEVELOPING COUNTRIES
In the current era, where multiple effective therapies for a condition already exist, the incremental effects of a new treatment may be harder to detect:
THEREFORE, THE FUTURE GENERATION OF TRIALS COMPARING TWO ACTIVE AGENTS MAY HAVE TO BE SEVERAL TIMES LARGER THAN INITIALTRIALS OF ACTIVE VSCONTROL OR FOR NON INF TRIALS.
Antiplatelet agents: Chronic CAD:ASA vs Control: 25% RRR in vascular events, Thienopyridine vs ASA : 10% RRR, Oral GP IIb/IIIa inhibitors vs ASA : no diff. AMI: 20% RRR of ASA v plac but Clop v plac on top of ASA:10% RRR.
Thrombolytic agents: SK vs Control: 25% RRR in mortality tPA vs SK: 10% RRR (in mortality/disabling strokes)
Bolus new agents vs infusion: No diff in mortality, but increase in intracranial bleeds by 30%
Thrombin inhibitors: UFH/LMWH vs Control in UA: 45% RRR, Fonda v Enox : 0%(20%) RRR but 50% RR in major bleeds.
CUMULATIVE BENEFITS ARE LIKELY TO BE IN EXCESS OF
75% RRR, WHICH IS SUBSTANTIAL
Large No. Events
Good adherence and complete followup
Large No. Events
Complex “informed” consent procedures
Clinical trial conduct:ICH Guideline for GCPEU Clinical Trials Directive
NHS Research Governance
Data access/confidentiality:1998 Data Protection ActGMC guidance on confidentialityHealth & Social Care Act/PIAG
Ethics & consent:Helsinki Declaration
-IRBs/ethics committees should be encouraged to agree to this
2 and 3 can be facilitated by obtaining the consent of the participant
Reg requirements that can be substantially simplified/eliminated
“Non-commercial clinical trials conducted by researchers without the participation of the pharmaceutical industry may be of great benefit to the patients concerned……. The conditions under which the non-commercial research is conducted by public researchers, and the places where this research takes place, make the application ofcertain of the details of good clinical practice unnecessary or guaranteed by other means.”
No agreement in place between sponsor and third parties that allows use of trial data for regulatory or marketing purposes; and
“… extent and nature of monitoring should be based on considerations such as the objectives, purpose, design, complexity, blinding, size and endpoints of the trial. In general there is a need for on-site monitoring before, during and after the trial; however … central monitoring …can assure appropriate conduct of the trial in accordance with GCP”
ICH GCP 5.18.3
”(...) the trial management procedures ensuring validity and reliability of the results are vastly more important than absence of clerical errors. Yet, it is clerical inconsistencies referred to as ’errors’ that are chased by the growing GCP-departments.”
Refs: Lörstad, ISCB-27, Geneva, August 28-31, 2006
Grimes et al, Lancet 2005;366:172
-Added complexities related to monitoring,and perceived regulatory requirements , escalated costs to $140 million. Funding withdrawn.
-Revised simple trial with 10,000 (higher risk) individuals ongoing at $30 million
The purpose of quality assurance is not to ensure that individual data items are 100% error-free.
Its purpose is to ensure that the clinical trial results are reliable, i.e.
Random errors (Random with respect to treatment assignment and unlikely to materially influence study results , unless large).
Systematic errors(Differential with respect to treatment assignment and could substantiallybias results).
- Type (Academic vs Private)
- Location (Paris vs Province)
Group A (site visits)
Group B (no visits)
Ref: Liénard et al, Clinical Trials 2006;3:1-7
fraud is probably rare (but possible underestimation esp in era of paying more than the costs of trials?)
Ref: Buyse et al, Statist in Med 1999;18:3435
Most frauds have little impact on the trial results(unless widespread or at central) because:
Refs: Altman, Practical Statistics for Medical Research 1991
Peto et al, Controlled Clin Trials 1997;18:1
-fax consent forms centrally
-central faxing of key documents (e.g. ECGs, laboratory reports, discharge summaries)
3. On Site Monitoring:
a) Random and infrequent
b) Guided by Central Monitoring
c) Onsite “mentoring” instead of “monitoring”
A combined approach of central with directed onsite monitoring(random and for cause) is likely to be both efficient and effective.
Any event including those that are the outcomes of interest,and events that are common in the condition of that age are considered to be AE
-They(sometimes even the primary outcome) are often recorded, reported (expedited)
-Reviewed individually,so difficult to discern patterns
-Unblinded, and SAEs in the active group only are reported to investigators, their IRBs and to regulatory authorities
-Enormous amount of effort (upto about 25 hrs/SAE reported) BUT is it useful and worthwhile?
-Misleading as to the “safety” situation of the trial,as no between group comparisons are possible and impossible to reliably attribute causality on a case by case basis (except perhaps for very unusual events eg thrombocytopenia or liver failure).
-Lack of a balance between safety and efficacy, e.g.in OASIS 5, catheter thrombosis (excess of 0.2%), bleeding (reduced 2.5%), mortality (reduced 1.0%) with fonda in OASIS-5
Central Events Committe versus Site Investigator?
# Events % Agee
Cause of Death 2897 66%
CHF 3841 73%
MI 2159 63%
Resucitated Death 636 27%
Stroke 541 91%
Who is correct? Investigator with more clinical info
or the comm thousands of miles away?
Effect of Adjudication on Estimated Treatment Effect: McMaster Experience(108,000 pts)
Adjud. Investigator OR
OASIS-1 0.70 0.71 0.99
OASIS-2 0.90 0.85 1.06
HOPE 0.78 0.80 0.98
HOPE-2 0.95 0.93 1.02
CURE 0.82 0.80 1.03
OASIS-5 1.01 1.01 1.00
OASIS-6 0.86 0.86 1.00
CREATE 0.87 0.87 1.00
WAVE 0.82 0.94 0.87
ACTIVE-W 1.43 1.42 1.01
Treated Placebo P-value
Adjudicated 8.3% 12.8% 0.009
Investigator 9.0% 12.4% 0.120
Adjudicated 9.2% 11.4% 0.063
Investigator 5.5% 7.8% 0.018
Adjudicated 8.9% 9.8% 0.058
Investigator 8.4% 9.6% 0.016
Adjudicated 14.2% 15.7% 0.04
Investigator 8.0% 10.0% 0.0007
Adjudicated 22.0% 24.3% 0.12
Investigator 21.4% 24.7% 0.028
Fundamental need is to avoid BIASES and LARGE MISCLASSIFICATIONS
Accuracy may be enhanced by collecting information on CRFs on outcomes in a structure than matches protocol definitions
Percent therapy for intracranial hypertension
1995 USA 1996 UK No.pts(trials) OR(CI)
Barbiturates 33% 56% 208(3) 1.09(.91,1.47)
Corticosteroids 64% 49% 2119(16) 0.96(.85,1.08)
CSF drainage 44% - 0(0) --
Hyperventilation 83% 100% 77(1) 0.73(.36,1.49)
Mannitol 83% 100% 44(1) 1.75(.48,6.35)
893 / 4 979
1 052 / 4 985
p < 0.001
CRASH Trial :Death within 14 days
Consider trials with consent of relatives or surrogates and when time is of the essence; perhaps without any consent but IRB approvals
1. Most CVD trials include LIC/MIC to reduce costs and speed enrollment, and are primarily aimed at answering questions relevant to the West.
BUT, these trials may also have applicability in LIC/MIC if the condition is common and the treatments are affordable.
2. Need trials in LIC & MIC of locally relevant conditions and treatments, and locally conducted.
PARADOXICALLY LESS MONITORING, ADJUDICATION, AUDITING etc,AND DELIBERATE SIMPLIFICATION LEAD TO MORE RELIABLE RESULTS