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.