Good Clinical Research Start Up Activities

Suzanne PozsonyiSynCon International

June 7 2013

MedicReS Good Clinical Research CME June 7-8 2013 | Istanbul Turkey

Agenda

• Study preparation activities– Division of responsibilities : SPONSOR - CRO

• Concrete study set up activities– Focus on activities usually dedicated to CRO

Clinical Trial Preparation- Responsibility of Sponsor -

- Write Project Plan

- Write quality management system, SOPs, defining theprocess for conducting the clinical trial

Writing clinical trial documents ( protocol, investigators brochure, patient information , patient informed consent, case report form, local trial agreements, financial disclosure forms, FDA 1572, etc.)

- Define Adverse Events process

- Prepare labeling

Clinical Trial Preparation- Responsibility of Sponsor -

- Define the monitoring process/prepare monitoring manual

- Select and train monitor

- Qualify the indentified investigators and clinical trial sites

- Obtain clinical trial insurance *

- Prepare and submit documentations to ethics committees and authorities*

Clinical Trial Preparation- Usually by CRO -

1.Feasibility Study

2. Identification and Selection of Clinical Trial Sites/ Investigators

3.Pre-study Visits, Evaluation of Potential Sites

4.Contracting*

5.Prepare and submit documentations to ethics committees and authorities*

6.Traning for the Clinical Trial *

7. Initiation visits

1.Feasibility Study-definition-

• Process of evaluating the possibility of conducting a particular clinical program / trial in a particular geographical area

• With the objective to achieve:– optimum project completion of the target– on time– on budget

1.Feasibility StudyWhy, when, who, what,

• Globalization of clinical trials……go to various regions…– Local differences…….

• Results in various challenges

• To identify these challenges and address them

1.Feasibility StudyWhy, when, who, what,

HELPS SPONSOR TO KNOW :

• Which countries and sites can be selected• Recruitment rate• Quality of data that may be generated• Infrastructure and facility present at site

1.Feasibility StudyWhy, when, who, what,

FROM FINANCIAL PERSPECTIVE:

• Clinical trial related costs:– Labor costs– Costs of laboratory, various examinations ( CT, MRI…) – Costs of regulatory/EC approval– Investment required for particular site for setting up basic

infrastructure like internet, separate computer , telephone line, fax

1.Feasibility StudyWhy, when, who, what,

• To identify potential challenges before hand

thus before study start

1.Feasibility StudyWhy, when, who, what,

• Global or regional/ local level by study team member– Local affiliate of the sponsor– CRO / service provider (consultant, patient

recruitment organisation , etc.)

1.Feasibility Study Why, when, who, what,

• Investigator’s interest in conducting the proposed clinical trial

• Is the required patient pool available with physician ?

• If yes, how many patient can be provided for the clinical trial?

1.Feasibility Study Why, when, who, what,

• Is the disease under study relevant to the patient population

• Is the study design acceptable • What are the anticipated cultural, regulatory

and ethical challenges …….

1.Feasibility Study Why, when, who, what,

….……..• To know the whether site is under the supervision of

IRB or IEC or not• What are charges of IRB/IEC• What is frequency of meeting of IRB/IEC• How many days prior to meeting the documents are

needed to be submitted• How many days after meeting is approval for clinical

trial granted helps to know time from IRB submission to the approval date……..

1.Feasibility Study Why, when, who, what,

.…….• Has the site faced any regulatory audit like USFDA

and if audited, is certificate of audit present?• Was site suspended for any misconduct or fraud

during clinical trial?• Will there be any ethical concerns while using

placebo arm ?• Will there be any concerns re. a medical procedure

related to the trial ? ( ex. GI gastroscopy…)

1.Feasibility Study Why, when, who, what,

To know whether there are any suggestions from investigators regarding any of following• Protocol • Inclusion/exclusion criteria• Is there any safety concern for the patients of clinical trial

or any other safety concern like life threatening condition.• Concomitant medications• Overall conduct of clinical trial • Will there be any safety issue or ethics committee concern

/ placebo arm• Any other aspect

1.Feasibility Study Why, when, who, what,

• To know whether there are any competitive trial running at investigator site that may affect recruitment

• In case of competitive trial:– next step is to find out whether inclusion and

exclusion criteria are same for the other trial as proposed trial

• To know investigator’s and site staff ‘s experience in ICH GCP trials

1.Feasibility Study Why, when, who, what,

• Has he worked previously with the same sponsor - site performance can be evaluated by sponsor by previous details of the site

• What is the overall commitment of potential partners – patients, investigators, country offices, service providers

1.Feasibility Study Why, when, who, what,

To know

• If laboratory facilities available• Whether special investigation instrument like CT

scan, MRI scan , spirometer etc as required by trial is present at site, or not – At times sponsor provides investigator with some

instruments for conduct of clinical trial

• Overall patient load and clinical trial load of investigator– and to judge whether he shall be able to dedicate

appropriate time for conducting clinical trial

Relevant topics to feasibilityin ICH GCP E6

4.1 Investigator's Qualifications and Agreements• 4.1.1 The investigator(s) should be qualified by education,

training, and experience to assume responsibility for the proper conduct of the trial….

• 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.

• 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).

Relevant topics to feasibilityin ICH GCP E6

4.2 Adequate Resources• 4.2.1 The investigator should be able to demonstrate

(e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.

• 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period.

Relevant topics to feasibilityin ICH GCP E6

• 4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

Sample feasibility form

• Cover letter• Feasibility questionnaire• Feasibility summary

– Include suggestions

Good feasibility questionnaire indicators

• Adequate patient pool• Experienced PI with ICH GCP knowledge• Appropriate infrastructures available • Presence of experienced staff • Presence of IRB/IEC as per regulatory

requirement

2.Identification of Selection of Clinical Trial Sites/ Investigators

It is a process• Usually as a result of a good feasibility• Assessed during pre-study visits• Evaluate ………..select………..

3.Pre-study Visits, Selection of Sites

Pre-study visits (PSVs), = Site Selection Visits (SSVs)• Conducted at a potential study site • To introduce the prospective investigator to the

study protocol and to familiarize the staff with regulatory obligations and sponsor procedures.

• The visit provides an occasion for you to assess the investigator's interest in and ability to carry out the study– this includes determining whether the potential

investigator has the time, facilities, equipment, access to subjects, and staff necessary to conduct the study

3.Pre-study Visits, Selection of Sites

3.Pre-study Visits, Selection of Sites

Objectives are:• Validate site claims made on Site Feasibility Questionnaire and

in previous discussions during site identification• Evaluate condition of site• Ensure that sponsor’s representatives have the opportunity to

tour the facilities, such as: – Exam rooms for subject evaluation and treatment – Laboratory area – Any special testing areas – Pharmacy (satellite pharmacy, if appropriate) – Hospital unit – Work areas for research staff – Storage areas for study drug and supplies– Monitoring or data entry area, if appropriate

3.Pre-study Visits, Selection of Sites

• Review essential study documents– Protocol– Source Docs– Patient Information (PIF ) & Informed Consent Form ( ICF)

• Discuss patient recruitment strategies– advertising campaigns– home care study nurses– patient transportation

• Provide training

Notes

Investigators claim:Protocols are often developed without real world input from experienced

clinician investigator and coordinators.

• 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator’s Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

• In the US and Europe, protocols to support drug registration are developed by the study sponsor with input from outside experts, investigators and regulatory agencies.

• In Japan, protocols to support drug registration are often developed by the investigator with input form the study sponsor, outside experts and the regulatory agency.

• “Investigator Initiated” studies• Written and developed by investigators requesting financial support • Usually Phase IV studies• Almost never a pivotal registration study

4. Contract

ICH GCP E7 ..1.7 Contract:

A written, dated, and signed agreementbetween two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.

Challenges

• Various country differences• Governing law and language

– Sponsors’s country of origin vs. Investigator country of origin

• Contract with PI only/investigator only vs with each staff member

• Difference between investigator fees in various countries

• Various institutional ( hospital ) regulations• Length of obtaining investigators contract

5.Prepare and submit documentationsto ethics committees and authorities*

• Site / study staff selected• Agreements are in place• All study related documentation is available

( inc. translations, pts recruitment materials, …INSURANCE..)

Submit to Ethics Committees and AuthoritiesParallel or consequent *

6. & 7. Training–Investigator Meeting – Initiation visit

• ICH GCP 8.2.20, the sponsor of a clinical study must carry out a trial initiation visit or training to ensure the principal investigator understand the study procedures of the protocol, his/her duties, among other things.

• The study initiation visit is usually conducted after the site has been selected by the sponsor to participate in study conduct, but just before the site starts enrolling patients for the study.

6.Traning for the Clinical Trial- Investigators Meeting -

• Review protocol and procedures• Get better acquainted with the sponsor and other

investigators• Answer outstanding questions• Generate enthusiasm for the trial and for recruitment• Identify / fine tune further potential problems …. how

to support pts recruitment……( pts transportation, etc. )• May serve as the initiation visit

6.Traning for the Clinical Trial- Investigators Meeting – c’td

• Study Coordinators and sub-investigators should also attend the meeting

• Sponsor participants include the medical expert, biostatistician, CRAs, and CRO personnel

• Investigators meeting can be organized , prepared and led ( jointly with sponsor ) by CRO

• Key Opinion Leader / Medical expert – to hold scientific presentation

7. Initiation visits

Some of the activities that may be discussed during this visit:

• Study protocol (study objectives, purpose, endpoints)• Reporting AEs and SAEs• Investigational drugs (storage, dispensing, destruction,

accountability)• Inclusion/Exclusion criteria of protocol• Patient Enrollment• CRF completion and error correction• Randomization procedures, including breaking the blind• Protocol compliance and deviation issues

Conclusion

• Well defined process• Good planning is needed• On going process• Good communication between parties , and

adaption to local situation is needed• Be flexible ( reasonably ) to change….even during

the study