1. Avoiding Protocol Violations
SafeHer: MO28048
Information for Investigators and Site Staff
MO28048_Site Presentation_Avoiding Protocol Violations_Version 1_final_15Jul2013

2. Contents Overview and Context
Current Status of Protocol Violations in SafeHer
Examples of Protocol Violations, and how to avoid them

3. 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
Currently more than 1900 patients have been enrolled worldwide
386 protocol violations processed (355 pertaining eligibility criteria , 23 during study conduct and 8 under review)
192 Major violations and 194 minor violations*
52 potential violations under discussion with sites
* only minor PVs relating to eligibility criteria are tracked and reported here

4. 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
ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1), 1996, section 5.20
“ Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.
If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial. When an investigator's/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).”
Deviation from the protocol have two main implications:
Potentially detrimental to patient safety
Impact on data integrity
Protocol violations damage the scientific integrity of the study.
They negatively impact the credibility of the study results
A high number of protocol violations can compromise the future acceptance of data from the study by Regulatory bodies

5. 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
ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1), 1996, section 4.5.2
4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).

6. Trend in Discovery of Violations in SafeHer

7. Type of Violations

8. Incidence of Violations Per Country (total Major and Minor PD99 violations)

9. Incidence of Violations Per Country (average per patient enrolled)

10. 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
Exclusion Criterion #6:
Impaired hepatic function (as indicated by any of the following, according to Protocol v3):
o Serum total bilirubin > 1.5 x upper limit of normal (ULN)
o Alanine amino transferase (ALT) > 2.5 x ULN
o Aspartate amino transferase (AST) > 2.5 x ULN
o Alkaline phosphatase (ALP) > 2.5 x ULN

11. 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
Inclusion Criterion #6 :- Protocol v1 and Protocol v2 and v3:
Screening left ventricular ejection fraction (LVEF) ≥ 55% as measured by echocardiography, Multi Gated Acquisition (MUGA) scan or Magnetic Resonance Imaging (MRI) per local practice
LVEF is to be assessed within 14 days prior to the first study treatment (Protocol v2 and v3: if patients received anthracycline, or 28 days prior to first study treatment for patients who received anthracycline‑free regimens) by echocardiography (ECHO), multigated acquisition (MUGA) scan or MRI. (Note: ECHO is the preferred method)

12. 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
Exclusion Criterion #5 - Protocol v2 and v3:
Inadequate bone marrow function (as indicated by any of the following):
o Total white blood cell count (WBC) < 2,500 / mm3 (<2.5 x 109/L)
o Absolute neutrophil count (ANC) < 1,500 / mm3 (< 1.5 x 109/L) – Protocol v3 states, Neutrophil count < 1,500 / mm3 (< 1.5 x 109/L)
o Platelets < 100,000 / mm3 (< 100 x 109/L)
o Haemoglobin < 10 g/dL

13. 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.
Exclusion Criterion #17 (last chemotherapy cycle)
More than 12 weeks between the end of the last chemotherapy cycle and the first dose of study treatment, in case these treatments are initiated sequentially. This criterion does not apply to patients who are starting trastuzumab SC without previous or concurrent chemotherapy or concurrently with chemotherapy.

14. 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
Inclusion Criterion #5 – Protocol v1 and Protocol v2 and v3:
HER2-positive EBC, defined as IHC 3+, or FISH/CISH positive (Protocol v2 and v3: or a positive in situ hybridization (ISH testing) by validated and approved methods within a certified laboratory), as determined in a local laboratory that is experienced/certified in HER2-expression testing using an accurate and validated assay

15. 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
Exclusion Criterion #2 – Protocol v1 and Protocol v2 and v3:
History of other malignancy which could affect compliance with the protocol or interpretation of results (Protocol v2 and v3: including previous invasive ipsilateral or contralateral breast cancer). Patients with curatively treated carcinoma in situ of the cervix or basal cell carcinoma, and patients with other curatively-treated malignancies, (Protocol v2 and v3: other than breast cancer) who have been disease-free for at least 5 years, are eligible.

16. and refer to protocol section 4.5.1.8**
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 **
** Note the differences between protocol v2/v3 and protocol v1
Inclusion Criterion #4
Histologically confirmed early invasive HER2-positive carcinoma of the breast with no evidence of residual, locally recurrent or metastatic disease and defined as clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for treatment with trastuzumab
Exclusion Criterion #4
Metastatic disease
Protocol section
Patients will be assessed for residual disease (as per institutional practice) not more than 4 weeks before the first dose of study drug. Screening radiologic examinations to exclude metastatic disease should include a bilateral mammogram or breast MRI, and chest X-ray (CXR). (Protocol v2 and v3: Should a previously taken chest CT or PET scan be available then these results can also be used for eligibility assessment.) These imaging tests do not need to be repeated if completed within 6 months (Protocol v2 and v3: 12 months) prior to the first study treatment. In addition, bone scan and liver imaging should be performed if clinically indicated.

17. Examples of Protocol Violations:
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.

18. Inclusion #4 ** Exclusion #1 Exclusion #16 *
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
Inclusion #4
Histologically confirmed early invasive HER2-positive carcinoma of the breast with no evidence of residual, locally recurrent or metastatic disease and defined as clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) that is eligible for (adjuvant) treatment with trastuzumab.
Exclusion #1
Previous neoadjuvant or adjuvant breast cancer treatment with an approved or investigational anti-HER2 agent
Exclusion #16 – Protocol v1, v2 and Protocol v3 :
Major surgical procedure or significant traumatic injury within 28 days prior to the first dose of study treatment for major surgery during the course of study treatment (Protocol v3: except for breast cancer surgery for patient receiving study drug in the neoadjuvant setting or anticipated need).

19. 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
Inclusion Criterion #7
Agreement to use an adequate, non-hormonal means of contraception by women of childbearing potential (defined as pre-menopausal and not surgically sterilized or < 1 year after the onset of menopause) and by male participants with partners of childbearing potential only. Examples of adequate contraceptive measures are an intra-uterine device, a barrier method (condoms, diaphragm) in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not acceptable for females participating in the study.

20. Exclusion Criterion #13 (Pregnancy)
Violations pertaining Eligibility criteria - Incomplete/Incorrect Screening Procedures - Pregnancy Test
Exclusion Criterion #13 (Pregnancy)
And also protocol section **
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
Exclusion Criterion #13
Pregnancy or lactation
Females of childbearing potential (defined as pre-menopausal and not surgically sterilized or less than 1 year after the onset of menopause) will undergo a serum pregnancy test within 7 days prior to the first dose of trastuzumab SC (or within 14 days, with a confirmatory urine pregnancy test within 7 days prior to the first study treatment).

21. 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
Exclusion Criterion #8
Serious cardiac illness or medical conditions including but not confined to:
History of documented heart failure or systolic dysfunction (LVEF < 50%)
High-risk uncontrolled arrhythmias such as atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV) block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
Angina pectoris requiring anti-anginal medication
Clinically significant valvular heart disease
Evidence of transmural infarction on electrocardiogram (ECG)
Poorly controlled (Protocol v2 and v3: or uncontrolled) hypertension (Protocol v2 and v3: blood pressure consistently over 140/90 mmHg, despite treatment), or history of hypertensive crisis or hypertensive encephalopathy

22. 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
Exclusion Criterion #10 (prior dose of doxorubicin/epirubicin)
Prior maximum cumulative dose of doxorubicin >360 mg/m2 or maximum cumulative dose of epirubicin >720 mg/m2 or equivalent

23. Inclusion Criterion #3 (ECOG) And also protocol section 4.5.2.1
Violations pertaining eligibility criteria - Incomplete/Incorrect Screening Procedures - ECOG
Inclusion Criterion #3 (ECOG)
And also protocol section
Example protocol violation
ECOG performed > 28 days prior to C1 (minor - ECOG result was within protocol required ranges)
Inclusion Criterion #3 (ECOG)
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Protocol section
After consenting, patients will undergo the following screening procedures and assessments within 28 days prior to the first study treatment (denoted as Day 1), unless otherwise specified or unless the procedure/assessment has already been conducted during this time period as part of the patient’s routine clinical care:
ECOG performance status

24. Violations during study conduct – Major Neoadjuvant Trastuzumab
Protocol Section (requirements for neoadjuvant trastuzumab treatment)
Example protocol violation:
Surgery performed after 4 cycles of neoadjuvant treatment with trastuzumab SC
Protocol Section : For neoadjuvant treatment, the following will be applied:
In patients with early breast cancer eligible for neoadjuvant treatment, trastuzumab SC should only be used concurrently (protocol v3:with anthracyclines in chemotherapy-naive patients and only patients and only) with low-dose anthracycline regimens (maximum cumulative doses: doxorubicin 180 mg/m2 or epirubicin 360 mg/m2).
If patients have been treated concurrently with low-dose anthracyclines and trastuzumab in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.
After the neoadjuvant phase (8 cycles) of trastuzumab SC patients will undergo surgery without interruption of trastuzumab treatment. After surgery patients will receive additional 10 cycles of SC trastuzumab to complete 1 year of treatment with trastuzumab.
Surgery should be planned after dosing at Cycle 8 without interruption of trastuzumab treatment.

25. 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

26. Example protocol violations:
Violations not pertaining to specific eligibility criteria, but related to safety assessments: minor
Protocol section Safety laboratory assessments required (Haematology and Biochemistry)
Example protocol violations:
Missing Lab Parameters - Albumin, Urea (BUN), Calcium, Sodium, Potassium, Lymphocytes, Monocytes
Protocol section Safety laboratory assessments
Haematology tests include: haemoglobin, WBC and differential, ANC, and platelet count.
Biochemistry tests include: creatinine, urea/blood urea nitrogen (BUN), serum ALT/glutamic pyruvic transaminase (SGPT), AST/serum glutamic oxaloacetic transaminase (SGOT), total bilirubin, ALP, albumin, sodium, potassium and calcium.

27. Protocol section 5.1.1 (general safety assessments)
Violations not pertaining to specific eligibility criteria, but related to safety assessments: minor
Protocol section (general safety assessments)
Example protocol violations
Temperature not done
Height not done
Protocol section (general safety assessments)
Patients will be assessed by prior medical history, vital signs (including blood pressure, heart rate, temperature), weight and height (screening only), physical examination, adverse events and concomitant medications.

28. 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

29. 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.