Appendix E : Ethics Template

APPLICATION FORM

Checklist

Document

Number of copies

Included

Research Protocol with checklist

Five

Yes No

Supplementary information (if applicable)

One

Yes No

Informed consent (English)

Fourteen

Yes No

Informed consent (local language)

Fourteen

Yes No

Study questionnaire

Fourteen

Yes No

Soft copy of IRB Application form

One / Soft

Yes No

------------------------------------------ ---------------------- Signature: Principal Investigator Date ------------------------------------------ ----------------------- Signature of supervisor (if applicable) Date ------------------------------------------- ------------------------ Signature of Chairman of the Department Date Institutional Review Board Institution / Organisation name

How to complete this form and begin the IRB review process

1. This form must not be handwritten. 2. Fill out all of the questions on this form completely. 3. Fill out and attach the appropriate appendices required by responses in this application. 4. Attach supporting documentation: consent form(s), protocol, survey instruments, interview

schedules, advertisements, letters of permission, etc. Consent form and questionnaire should also be submitted in other languages where applicable.

5. Complete the checklist that accompanies this form to ensure all requirements for submission are completed so that review is not delayed.

6. Submit this application and appendices along with the supporting documentation to the Institutional Review Board.

Principal Investigator Information:

Title: Professor

Name: Timothy R Walsh

Job Title: Professor

Department or Unit: Medical Microbiology and Immunology

Postal address: Room 174, 6th Floor Cardiff University School of Medicine UHW Main Building Heath Park Cardiff CF14 4XN Phone: +44(0)2920744725

Email: walshtr@cardiff.ac.uk

Signature of PI:

Date: 01/04/15

If more than three authors, please write down only name and institution for other authors. Project Information

1. Title of Research Project: Burden of Antibiotic Resistance on Neonates from Developing Societies

2. Select one of the category for your research project:

a. Clinical trial on a medicine/drug

b. Clinical trial on a medical device

c. Experimental surgical procedures

d. Study administering questionnaires/interviews for quantitative or mixed

qualitative/quantitative methods.

e. Study involving qualitative methods only

f. Study limited to working with human tissue samples, other human biological samples and / or

data

g. Research data base (secondary data analysis only)

h. Research involving animal subjects

If any other category then please write down in the space given below

__________________________________________________________________________

__________________________________________________________________________

__________________________________________________________________________

Note: Please provide details if study is related to Experimental drug(s) or Non-approved use or non-

approved dose for approved drugs

Not applicable

3. Do you plan to include any participants who are children or pregnant women?

Yes

(If yes please justify why it is important to take this study population)

The study is focusing on the burden of antibiotic resistance in neonates from developing societies, swabs

will be taken from expectant mothers and babies <60 days who present with sepsis will also be recruited

into the study.

4. Lay Summary of the Project

This study focusses on the burden of antibiotic resistance in neonates from developing societies. The

level of antibiotic resistance in neonatal infections and its impact on mortality in low-middle income

countries is unacceptably high. This study will provide the means, support, network and tools to

understand the impact of antibiotic resistance on neonatal morbidity and mortality, as well as to identify

possible solutions to minimise its impact.

5. Objectives of the Proposed Research

This study will be the first of its kind in the world to blend clinical and molecular epidemiology from low–

middle income countries with respect to neonatal Gram-negative infections. The data generated will be

used to inform, local, national and international health bodies and provide the means, support, network

and tools to understand the impact of antibiotic resistance on neonatal morbidity and mortality, as well

as to identify possible solutions to minimize its impact.

6. What is the scientific justification for the research?

The level of antibiotic resistance in neonatal infections and its impact on mortality in low-middle income

countries is unacceptably high. This study will provide the means, support, network and tools to

understand the impact of antibiotic resistance on neonatal morbidity and mortality, as well as to identify

possible solutions to minimize its impact.

7. Please list the principal inclusion criteria

All pregnant mothers coming into the clinic and all mothers returning with a child <60 days old presenting

with sepsis.

8. Please list the principal exclusion criteria

• Mothers who are present with diarrhoea, therefore rectal swab is unable to be taken.

• Child older than >60 days old.

9. Methodology and procedures involved in this study.

The BARNARDS network is unique and will centre on monitoring and improving mother/infant wellbeing

including exploring the impact on infection control interventions. We will not only assess the burden of

antibiotic resistance but also determine the prevalence of multi-drug resistant Gram-negative bacteria

(MDRGNB) carried as normal flora and causing neonatal sepsis. BARNARDS questionnaires will identify

demographic indices such as population size, overcrowding, access to clean water, sanitation conditions,

family size, poverty level, antibiotic usage and their impact on MDRGNB. We will map dominant clones

in each centre and correlate mother’s normal flora and neonatal infections and also compare strains

between the 5 centres examining emergence of international domain MDR clones. During the period of

the study, the number and type of specimens will be able to monitor local outbreaks of bacterial clones

(see Appendix A). We have made provision to take surface (environmental) swabs and therefore can

identify risk factors for nosocomial outbreaks. Concordantly, we will also monitor hand-washing

practices and analyze differences between the five centres and their correlation with neonatal sepsis.

Rectal swabs will be collected from pregnant women prior to delivery, and will be sent to the UK to

screen for MDR (specifically ESBL and carbapenemase positive) GNB. Bacterial isolates from neonates

from these mothers who develop both early (<72 hours) and late onset bacterial sepsis (>72 hours) will

also be studied, and compared to isolates from the mother. Rectal samples taken from mothers whose

infants do not present with infection will be used as a control group. Moreover, we aim to implement an

infection control policy supported by an educational campaign to enhance local health awareness in

preventing neonatal sepsis.

The molecular platform is a dedicated genomic hub that will provide data on strain type,

virulence/pathogenic potential and novel genetic data / mechanisms of resistance. The genomic hub will

be run from the UK and visiting fellows from the five centers will travel to the UK to learn about

sequencing/molecular biology.

Figure 1: Flow of data pipeline. Activities in the blue sectors are what will take place in LMICs.

BARNARDS is unique in engaging LMICs with a comprehensive genomic platform – we aim to sequence

4000 isolates over the 36 months of the project and establish a comprehensive international neonatal

GN sepsis database – the first of its type worldwide (see figure above). BARNARDS will not only produce

unique and critical data but has a strong educational aspect – uniform and excellent microbiology

practice across the 5 centers and a world-class molecular/genomics education program to be based in

the UK (fellows from the 5 centers will attend workshops at Cambridge (SANGER) and have practicable

experience analyzing the genomes of their own strains in the UK. The genomics platform will also allow

a database depository as well as a strain depository – these will be open and accessible to all partners

with in BARNARDS and provide a unique research source for future national and international funding

opportunities. On publication of data, all data associated with that part of the study, or the study in

whole, will be released to the public. BARNARDS will establish and operate a website that will be made

accessible to all partners and allow limited access by the general public. Publicity events and ICAAC (USA)

and ECCMID (Europe) will also be encouraged exposing meeting delegates to aspects of MDR/XDR in

LMICs.

10. How long do you expect each participant to be in the study in total?

Dependent on potential required treatment, which will vary patient to patient. The maximum will be for

60 days.

11. Please complete the following for each intervention / procedure as follows:

a. Total number of interventions/procedures to be received by each participant as part of the research

protocol.

• Mother: 1-2 – rectal swab on enrolment, and again if she returns with her baby at a later date

(i.e. the baby presented with clinical signs of sepsis after returning home within the first 60 days

of life)

• Baby <72 hours: 0*-1 if baby presents with clinical signs of sepsis a blood culture is taken.

• Baby >72 hours: 2 if baby presents with clinical signs of sepsis a rectal swab and a blood sample

will be collected.

*none if the baby does not present with clinical signs of sepsis.

b. If this intervention/procedure would be routinely given to participants as part of their care outside

the research, how many of the total would be routine?

N/A

c. Details of who will conduct the intervention / procedure, and where it will take place.

Rectal swabs will be collected from pregnant women prior to delivery, and will be sent to the UK to

screen for MDR (specifically ESBL and carbapenemase positive) GNB by research nurses within the

healthcare facility / clinic. Bacterial isolates from neonates from these mothers who develop both early

(<72 hours) and late onset bacterial sepsis (>72 hours) will also be studied, and compared to isolates

from the mother. Rectal samples taken from mothers whose infants do not present with infection will

be used as a control group. Moreover, we aim to implement an infection control policy supported by an

educational campaign to enhance local health awareness in preventing neonatal sepsis.

12. What are the potential risks and burden for research participants and how will you minimise them?

(Describe any potential adverse effects, pain, discomfort, distress, intrusion, inconvenience or changes

to lifestyle. Only describe risks or burdens that could occur as a result of participation in the research.

Say what steps would be taken to minimize risks and burdens as far as possible)

There are no side effects of the study.

13. Will interviews / questionnaires or group discussions include topics that might be sensitive,

embarrassing or upsetting?

o Yes

o No

14. What are the potential benefits for the research participants?

There is no personal benefit.

15. How and by whom will potential participants first be approached?

Participants will be approached by research nurses in each local healthcare facility.

16. How long will you allow potential participants to decide whether or not to take part?

Approximately 20 minutes to go through the consent form. Sample collection will take approximately

****** please complete ****. Participants have the right to withdraw from the study.

17. What arrangements have been made for persons who might not understand verbal explanations or

written information given in local language/English, or who have special communication needs? (E.g.

translation, use of interpreters)

The research nurses will be able to translate to the local language, if the participant cannot communicate

in this language, they will not be able to provide informed consent and therefore cannot be recruited

onto the study.

18. Please describe the physical security arrangements for storage of personal data during the study.

The questionnaires and consent forms completed by nurses after will be given to the data entry operator

at institution name will then keep all the forms locked in a drawer until the data is electronically entered.

After data entry, the forms will be retained on site until collection by the UK team / postage arranged at

the end of the study.

19. How will you ensure the confidentiality of personal data? Please provide a general statement of the

policy and procedures for ensuring confidentiality, e.g. anonymisation or pseudonymisation of data.

To maintain confidentiality participant will be given a study ID and all data collected will be coded, name

of participant will not be displayed only study ID given will be used.

20. Who will have access to participants' personal data during the study?

Staff related to the study.

21. Laboratory and Radiological studies

a. Will any tests be performed which are not routinely included as part of the work-up for these types

of patients?

Yes rectal swabs will be taken from the mothers, and in many sites it’s not standard practice to take

blood cultures from the infant.

b. Who or what agency will pay for these tests?

This will be covered by the funding of the grant

c. Who or what agency will pay for these tests?

Bill and Melinda Gates Foundation. (via Cardiff University)

22. How do you intend to report and disseminate the results of the study?

The grant will cater for the visitation of the Senior Research Scientist from each center at the end of the

project (30-36 month) to visit the UK and work on the bacterial genomes from their own projects. They

will also be enrolled on courses on molecular genomics and antimicrobial resistance and provided with

teaching materials to disseminate these materials in their own centers. When full genome sequences

are compiled, data on strain ID, strain type and a full virulence and antimicrobial resistance profile will

be sent back to each clinical center so that they have access to their own data and use it effectively

towards improving quality of healthcare. A central database will be stored in the UK that will capture all

demographic data, clinical and molecular information. When appropriate data will be uploaded on the

BARNARDS website which will be made fully public.

Findings will be disseminated to all partners and the funder.

Findings will be presented in peer reviewed journals.

23. Will you inform participants of the results of the study?

Yes, on the participant’s request.

Please give details of how you will inform the participants or justify if not doing so.

After patient’s consent, we’ll ask her if she wants to be conveyed the results of the study. If the

participant wants to, we’ll record her contact no. After the paper has been accepted in a journal, we’ll

contact the participants and inform them of the outcomes.

24. What is the primary outcome measure for the study?

• Establish a neonatal (<60 days of age) network in Africa (Nigeria, Ethiopia and Rwanda) and

South Asia (Pakistan, India and Bangladesh) addressing the burden of antibiotic resistance.

• Determine the prevalence of GNMDROs colonising and / or causing infections in neonates and

compare this to the prevalence of these organisms in the mother (GNMDROs will be used as a

convenient resistant marker).

• Describe the dominant bacterial clones of those bacteria causing infections in neonates, and

compare this with the dominant clones carried by mothers (which likely reflect the dominant

clones in the community).

• Provide a comprehensive genomic platform of approximately 4000 isolates over the duration of

the 36 month (?) project and establish an informatics database.

• Provide microbiome data on neonate and mother's normal flora and map bacteria causing

sepsis to the microbiome database.

• Monitor local outbreaks especially caused by GNMDROs and correlate this with samples

obtained from NICU hospital equipment as noted in Appendix A.

• Monitor hand hygiene practices towards establishing risk factors for GNMDRO transfer using the

5 Moments of hand hygiene (WHO).

• Microbiology laboratory technical support and capacity building in LMICs.

• Establish training in molecular biology and implement workshops in genomics/informatics (UK

based workshop/training) for interested participants from this study

• Investigate and identify risk factors for carriage of GNMDROs and infections in neonates.

• Evaluate and record the human and financial burden of antimicrobial resistance associated

infections amongst neonates (hospital stays, clinical outcome etc.)

• Establish a publically owned centralised international neonatal antimicrobial resistance

database and international strain repository. Develop and maintain a website linking existing

networks in LMI countries and promote their research and clinical experiences.

• Monitor and report changes in GNMDRO genomic profiles associated with transmission in

neonatal units.

25. What is the sample size for the research? How many participants / samples / data records do you

plan to study in total?

• 400 CRO/Site/Year will be forwarded for sequencing

• 1700 swabs per site per year.

• We aim to sequence 4000 isolates over the 36 months of the project and establish a

comprehensive international neonatal GN sepsis database

Please refer to Figure 1: Flow of data pipeline. Activities in the blue sectors are what will take place in

LMICs.

26. How was the sample size decided upon? If a formal sample size calculation was used, indicate how

this was done, giving sufficient information to justify and reproduce the calculation.

There are absolutely no studies gauging the burden of antibiotic resistance in neonates from developing

societies internationally. A sample size of 4000 was chosen to appropriately answer our research

questions.

27. Has funding for the research been secured?

Funding secured from one or more funders

28. Has this or a similar application been previously rejected by a Research Ethics Committee in local

country?

o Yes

o No

29. How long do you expect the study to last in local country?

48 months

30. Is this study?

o Single centre

o Multicentre

30. Where will the research take place?

Detail the wards / hospitals

Declaration by Principal Investigator

1. The information in this form is accurate to the best of my knowledge and belief and I take full

responsibility for it.

2. I undertake to abide by the ethical principles underlying the Declaration of Helsinki and good practice

guidelines on the proper conduct of research.

3. If the research is approved I undertake to adhere to the study protocol, the terms of the full application

as approved and any conditions set out by review bodies in giving approval.

4. I undertake to notify review bodies of substantial amendments to the protocol or the terms of the

approved application, and to seek a favourable opinion from the Ethical Review Board before

implementing the amendment.

5. I undertake to submit annual progress reports setting out the progress of the research, as required by

review bodies.

6. I am aware of my responsibility to be up to date and comply with the requirements of the law and

relevant guidelines relating to security and confidentiality of patient or other personal data, including

the need to register when necessary with the appropriate Data Protection Officer. I understand that I

am not permitted to disclose identifiable data to third parties unless the disclosure has the consent of

the subjects’ data.

7. I understand that research records/data may be subject to inspection by review bodies for audit

purposes if required.

------------------------------------------ ----------------------

Signature: Principal Investigator Date