SafeHer: MO28048 Information for Investigators and Site Staff Avoiding Protocol Violations...
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Transcript of SafeHer: MO28048 Information for Investigators and Site Staff Avoiding Protocol Violations...
SafeHer: MO28048Information for Investigators and Site Staff
Avoiding Protocol Violations
MO28048_Site Presentation_Avoiding Protocol Violations_Version 1_final_15Jul2013
Contents
Overview and Context
Current Status of Protocol Violations in SafeHer
Examples of Protocol Violations, and how to avoid them
Protocol Violations in SafeHer - Overview
• The current reported rate of 19.5% protocol violations* (9.6% major PVs) is far too high
• There has been an increase in the rate of protocol violations in last 4 months: March 2013: 17.8% total* (8.9% major PVs)
• This must be reduced to avoid compromising the integrity of the data
* only minor PVs relating to eligibility criteria are tracked and reported here
Why Protocol Violations are a Problem?
Compliance with protocol is an ICH-GCP Requirement, and non-compliance can have significant consequences
The protocol has been written to ensure patient safety and data integrity, and it has been approved by Ethics Committees and Regulatory Authorities accordingly
Deviation from the protocol is potentially detrimental to patient safety, and impacts on data integrity
Relation of Protocol to Standard Clinical Practice
Many protocol violations occur because standard clinical practice has been followed, but the protocol was not followed
It is an ICH-GCP requirement that the protocol is followed.
Investigators must ensure that all relevant site staff are appropriately trained on the protocol, and are aware of the inclusion of a patient in the clinical trial
Trend in Discovery of Violations in SafeHer
Type of Violations
Incidence of Violations Per Country (total Major and Minor PD99 violations)
Algeria
Austra
lia
Canad
aChil
e
Czech
Rep
ublic
Egypt
Franc
e
Germ
any
Greec
e
Hunga
ry
Indo
nesia
Irelan
dIta
ly
Korea
Lithu
ania
Mala
ysia
Mex
ico
Nethe
rland
s
Norway
Peru
Philipp
ines
Poland
Portu
gal
Russia
Saudi
Arabia
Serbia
Singap
ore
Slovak
ia
Sloven
ia
South
Afri
caSpa
in
Sweden
Switzer
land
Taiwan
Thaila
nd
Turke
yUAE
Ukrain
e
United
King
dom
0
10
20
30
40
50
60
70
80
90
Incidence of Violations Per Country (average per patient enrolled)
Algeria
Canad
a
Czech
Rep
ublic
Franc
e
Greec
e
Indo
nesia Ita
ly
Lithu
ania
Mex
ico
Norway
Philipp
ines
Portu
gal
Saudi
Arabia
Singap
ore
Sloven
iaSpa
in
Switzer
land
Thaila
ndUAE
United
King
dom
0.00
0.20
0.40
0.60
0.80
1.00
1.20
Average Total Viola-tions per Patient
Average Major Vio-lations per Patient
Violations pertaining eligibility criteria - Exclusion Criterion #6
Exclusion Criterion #6* (Impaired hepatic function)* Note the differences between protocol v3 and protocol v1/v2
Examples of Protocol Violations: ALP, ALT or AST not done ALP, ALT or AST outside of the ULN specified in the
protocol AST and ALT not done
NB: the protocol requires all of the following to be done, and the results within range specified in protocol – total bilirubin, ALP, ALT and AST
Violations pertaining eligibility criteria - Inclusion Criterion #6
Inclusion Criterion #6 **(LVEF ≥ 55% )
Examples and Reasons: Example: LVEF not performed within the protocol
required timeframe Reasons: miscalculation of dates; LVEF assessment
previously performed but not repeated within the appropriate timeframe
** Note the differences between protocol v2/v3 and protocol v1
Violations pertaining eligibility criteria - Exclusion Criterion #5
Exclusion Criterion #5* (Inadequate bone marrow function)
Examples: ANC not done ANC or Hb lower than specified ranges in protocol
* Note the differences between protocol v3 and protocol v1/v2
Violations pertaining eligibility criteria - Exclusion Criterion #17
Exclusion Criterion #17 (last chemotherapy cycle)
Examples: The investigator thought that this criterion is related
only to the adjuvant chemotherapy and there is no relation with neo-adjuvant therapy.
This eligibility issue was missed at first because the site misunderstood definition of 'the end of the last chemotherapy' in protocol.
Violations pertaining eligibility criteria - Inclusion Criterion #5
Inclusion Criterion #5 ** (Her2 testing)
Examples and reasons: Example: All patients were confirmed HER2-positivity
by other ISH testing. Reason: Site not aware of method being used.
** Note the differences between protocol v2/v3 and protocol v1
Violations pertaining eligibility criteria - Exclusion Criterion #2
Exclusion Criterion #2** (History of Malignancy)
Examples and reasons: Example: Previous history of invasive breast cancer. Reasons: Misunderstanding of the protocol exclusion
criterion. Now clarified in protocol amendment.
** Note the differences between protocol v2/v3 and protocol v1
Violations pertaining eligibility criteria - Incomplete/Incorrect Study Procedures - Imaging
Radiologic evidence of the absence of residual/recurrent/ metastatic disease:
Inclusion Criterion #4
Exclusion Criterion #4
and refer to protocol section 4.5.1.8**
** Note the differences between protocol v2/v3 and protocol v1
Violations pertaining eligibility criteria - Incomplete/Incorrect Study Procedures – Imaging (Cont’d…)
Examples of Protocol Violations: Chest X-ray (Chest CT) not done (minor) Bilateral mammogram and chest X-ray performed > 6 months
prior to C1 (major) Bilateral mammogram performed > 6 months prior to C1 (major)
– patients had unilateral mammograms performed < 6 months prior to C1
Reasons: PI explained X-rays are not routinely done at site to rule out
metastases unless patient had a chest condition.; metastases wouldn't be seen on X-ray; CT would only be done for high risk patients.
Sites standard of care is performing bilateral mammograms every 12 months.
Violations pertaining Eligibility criteria – Neoadjuvant Trastuzumab SC: Inclusion Criterion #4, Exclusion criteria #1 & 16
Inclusion #4 **
Exclusion #1
Exclusion #16 *
** Note the difference between protocol v2/v3 and protocol v1
* Note the difference between protocol v3 and protocol v1/v2
18
Violations pertaining eligibility criteria - Inclusion Criterion #7
Inclusion Criterion #7 (Contraception)
Examples of protocol violations: Hormonal contraception - hormonal implant Patient randomized less than 1 year after the onset of
menopause and without any agreement to use an adequate non-hormonal contraception
Violations pertaining Eligibility criteria - Incomplete/Incorrect Screening Procedures - Pregnancy Test
Exclusion Criterion #13 (Pregnancy)
And also protocol section 4.5.1.7.3 **
Examples of protocol violations: Serum pregnancy test not done and urine pregnancy test done
> 14 days prior to C1 Serum pregnancy test done 14 days prior to C1, but no
confirmatory urine pregnancy test Inclusion #7 and Exclusion #13 (Major) - Patient randomized
less than 1 year after the onset of menopause without agreement to use adequate non-hormonal contraception and no pregnancy test performed.
** Note the difference between protocol v2/v3 and protocol v1
20
Violations pertaining eligibility criteria - Exclusion Criterion #8
Exclusion Criterion #8** (serious cardiac illness/medical conditions)
Example protocol violations (Minor) Blood Pressure > 140/90 mmHg despite treatment. ECG not performed within 28 days prior to cycle 1.
** Note the difference between protocol v2/v3 and protocol v1
Violations pertaining eligibility criteria - Exclusion Criterion #10
Exclusion Criterion #10 (prior dose of doxorubicin/epirubicin)
Example protocol violation: Patient received maximum cumulative dose of
epirubicin >720 mg/m2
Violations pertaining eligibility criteria - Incomplete/Incorrect Screening Procedures - ECOG
Inclusion Criterion #3 (ECOG)
And also protocol section 4.5.2.1
Example protocol violation ECOG performed > 28 days prior to C1 (minor -
ECOG result was within protocol required ranges)
Violations during study conduct – Major Neoadjuvant Trastuzumab
Protocol Section 4.3.2.2 (requirements for neoadjuvant trastuzumab treatment)
Example protocol violation: Surgery performed after 4 cycles of neoadjuvant
treatment with trastuzumab SC
Violations during study conduct - Major
Other Examples: trastuzumab SC was administered in the abdomen
instead of thigh The Appendix 5 – “Algorithm for continuation and
discontinuation of trastuzumab SC based on LVEF assessment in asymptomatic patients” - was not followed
Patient received a reduced dose of trastuzumab SC Use of prohibited therapy concomitantly
Violations not pertaining to specific eligibility criteria, but related to safety assessments: minor
Protocol section 4.5.1.7.2 Safety laboratory assessments required (Haematology and Biochemistry)
Example protocol violations: Missing Lab Parameters - Albumin, Urea (BUN),
Calcium, Sodium, Potassium, Lymphocytes, Monocytes
Violations not pertaining to specific eligibility criteria, but related to safety assessments: minor
Protocol section 5.1.1 (general safety assessments)
Example protocol violations Temperature not done Height not done
CONCLUSION: Tips to avoid some of the most common protocol violations Required tests of hepatic function must be done, and results
must be within protocol limits Ensure LVEF assessed within required protocol timeframe Ensure ANC and Hb are assessed, and are within limits specified
by protocol Previous chemotherapy – check dates of last cycle; if
anthracyclines – correctly calculate cumulative dose Ensure all the radiological examinations required by protocol
have been conducted Trastuzumab in the neoadjuvant setting must be as stipulated in
the protocol , and only treat patients in neoadjuvant setting if you will give 8 cycles trastuzumab, not less.
Ensure all screening procedures are within the timeframe required by the protocol, and that procedures are conducted as per protocol throughout the study
Thank you for your attention !
If you have any doubts, do not hesitate to contact your monitor to confirm eligibility of a patient in screening, or for clarification of
protocol procedures.