BASICS OF BASICS OF CLINICAL RESEARCHCLINICAL RESEARCH

P. K. MitraP. K. MitraManager – Marketing ServicesManager – Marketing ServicesEurodrug Laboratories - IndiaEurodrug Laboratories - India

INTRODUCTION TO

DRUG DISCOVERY

Drug Discovery & Development Process involves Drug Discovery & Development Process involves

1.1. Target SelectionTarget Selection

2.2. Target ValidationTarget Validation

3.3. Drug / Lead SelectionDrug / Lead Selection

4.4. Lead OptimizationLead Optimization

5.5. Pre-Clinical testingPre-Clinical testing

6.6. Clinical TestingClinical Testing

INTRODUCTION

TO

CLINICAL TRIAL

• A Systematic Investigation in Human Subjects A Systematic Investigation in Human Subjects forevaluating the Safety & Efficacy of any New forevaluating the Safety & Efficacy of any New Drug.Drug.

• Clinical Trial is the main stay for bringing out NewClinical Trial is the main stay for bringing out New Drugs to the Market.Drugs to the Market.

• Clinical Trials done in 4 Phases ( I, II, III, IV )Clinical Trials done in 4 Phases ( I, II, III, IV )

• It takes Approx. 10-12 Years & USD 800 Mio to It takes Approx. 10-12 Years & USD 800 Mio to bring one New Drug to the Market.bring one New Drug to the Market.

• For Every 10,000 – 30,000 drug molecules For Every 10,000 – 30,000 drug molecules screened, only 1 reaches to the Market.screened, only 1 reaches to the Market.

TRIAL REGULATIONSTRIAL REGULATIONS

• DCGI under CDSCO has the Prime responsibility for Regulating CTs in India.

• Declaration of Helsinki by WMA provides Ethical Guidelines & Principles to the Physicians, Other Participants & Human Subjects.

• ICMR code includes statement of general & specific principles on research using human subjects in biomedical research.

• ICH-GCP Guidelines unified standard for EU, Japan & USA to facilitate the mutual acceptance of Clinical Data by the Regulatory Authorities in these Jurisdiction.

• Indian GCP Guidelines are in line with WHO, ICH, USFDA, and European GCP Guidelines as well as ICMR Code.

• Drugs & Cosmetics Act 1940, & Schedule Y tells the requirement and guidelines on Clinical Trials for Import & Manufacture of New Drug in India

TRIAL STAKEHOLDERS

Stakeholders of the Clinical Trials are:

• SPONSORS

• Contract Research Organization ( CRO )

• INVESTIGATORS

• ETHICS COMMITTEE

• REGULATORY AUTHORITY

• STUDY SUBJECT ( PATIENTS )

• Sponsor takes the responsibility for the Initiation, Management, and/or financing the Clinical Trial.

• CRO is the Organization Contracted by the Sponsor to Perform One or More of Sponsor’s Trial related Duties and Functions.

• Investigator is responsible for the Conduct of a Clinical Trial at a Site.

• Ethics Committee ensures prtection of Rights, Safety, and Wellbeing of the Subjects involved and to provide Public Assurance of the Protection

• Study Subjects ( Patients ) are Individual who Participate in the Study ( CT ) Voluntarily.

ESSENTIAL DOCUMENTS

• Essential Clinical Trial Documents individually and collectively evaluates the conduct of a Trial & Preserves the integrity of the Data.

• These Documents demonstrate the Compliance of the Investigators and Sponsors/ CRO with GCP & all applicable Regulatory Requirements.

• They include, Base Records, Laboratory Data, CRFs, Randomization Key, Other Investigational Records, EC-NOC, DCGI-NOC, ICF, CRO-Sponsor Agreement.

CLINICAL TRIAL

IN

INDIA

• Clinical Trials are different than routine Medical Care.

• India became a member of WTO in 1995 and agreed to adhere to Product & Process Patent regime from 2005.

• India provides excellent environment for CT: in terms of Less Cost, Speed, Quality Parameters

of Global Clinical Trials leading to Significant Growth in Clinical Trial outsourcing to India.

STUDY TEAM

AT

TRIAL SITE

• Study Team at Trial Site include Investigator, Co-Investigator, Study Coordinator, Nurse, Pharmacist.

• Unblinded Personnel (Coordinator/Nurse/Pharmacist) are required in blinded Trials for dispensing the Trial Medications to the Study Subjects

• Clear delegation of duties to the study team members is essential for the smooth execution of a clinical Trial.

Individual Member of the Study Team can be delegated specific Trial Duties such as:

• Administration of ICF• Recruitment of Subjects• Correspondence with EC / CRO / Sponsors• Stoarge, Dispensing & Accountability of Drugs• Completion of Source Documents• Completion of CRF• Medical Management of the Trial Subject• Reporting of SAE ( Adverse Events )

• Escalations, Resolutions, Management of Deviations• Logistics Management• Resolution of Data Enquiries• Patient’s Visit Scheduling, Protocol Compliance & Follow Up• Maintenance of Site Master File.• Compliance with GCP & Regulatory Guidelines• Tracking of Payments / Study Grants

REVIEW OF

ETHICS COMMITTEE OPERATIONS

• EC must have written SOP on its Compositions, Functions & Operations.

• The Composition of EC must have 7 Members

• The Chairman of EC should be from outside of the Institution ( Non Affiliated member ).

• The Quorum of EC should have min. 5 Members ( Medical Scientist / Pharmacologist, Clinician, Theologian / Social Scientist / Ethicist, Legal Expert, Lay person. )

• No CT should be initiated at any Site without obtaining written NOC from the respective EC.

• If any Investigator or Study team Member is a part of EC, they should abstain from voting on their research proposal.

• Version Number of all the essential trial documents approved by EC should be clearly mentioned on the approved letter.

• All serious & unexpected ADR should be reported to EC within 7 working days of their occurrence.

• EC should maintain its records for at least 5 years after the completion / termination of the study

SOURCE DOCUMENTS

• Source data/documents refer to the documents where the informations on patient’s medical condition and treatment is recorded for the first time.

• SD should contain accurate, authentic, and complete information on patient’s medical condition, laboratory results, treatment administered, adverse events & corrective medications.

• SD should have proper control & access.

• Should reveal what was done & when

• All the information regarding patient’s Physical Laboratory, Medical Tests should be kept in one file with valid signatures & dates of the concerned personnel.

• SD should be properly archived for preservation

• Electronic data for SD should be ensured for Security, Validation & Back up control.

INFRASTRUCTRUAL

REQUIREMENTS

• Space for storing Trial documents & materials• Communication facility• Local laboratory facility• USG / Biopsy / CT-Scan / MRI Scan facility• Wards / ICU / Operation Theatre facility• Archival Facility• SOP • Lockable Trial Rooms / Storage Cabinets• Lockable Cabinets, Fridge• National or Internationally accredited Laboratories• Well defined Quality control standards

ADMINISTRATIVE

POLICIES

• Well defined rules & regulations of the site.

• SOP for Trials & Subject recruitment

• Recruit Study Coordinator, Research Staff

• Ensure Storage & Archival facility

• Tripartite / Bipartite Agreement

SITE EVALUATION

• Ensurance of Non Disclosure of Agreement by the Site / Invetsigator as per Sponsor / CRO.

• Maintain Confidentiality of Information given by Sponsor / CRO to the Site / Investigator.

• Sponsor / CRO evaluates the Site, reviews the Qualification of Study Team Members.

• Evaluates Composition,Operations, EC Operating System, Source Documentation Practices & Infrastructures of the Site.

PROCESS OF SITE EVALUATION

Sponsor / CRO approaches the investigator site for discussing a Clinical Trial Proposal

Investigator’s concensus / approval is obtained based on Study Protocol discussion

NDA is executed between Investigator & Sponsor/CRO

Investigator Provides his details on Study Feasibility Questionnaire

If Investigator’s response is satisfactory & meets the expectations of Sponsor / CRO, Site Evaluation Visit ensured.

Site is either selected / rejected based on the report of Site Evaluation done by Sponsor / CRO Representative

SITE ACTIVATION

Sponsor/CRO forwards the following documents to the

Clinical Investigator for Review & Completion:

1. Study Protocol

2. Patient Information Sheet & PIC (English & Vernacular)

3. Investigator Brochure

4. Case Record Form

5. Insurance / Indemnity Certificate

6. Patient Diaries / Questionnaire

7. Format of Undertaking by Investigator

8. Draft of CTA between Investigator & Sponsor / CRO

9. Regulatory Clearance ( DCGI ) NOC

10. No. of copies of above documents for EC application

• Site is selected for CT after successful Evaluation of the Site by the Sponsor / CRO.

• Careful CTA drafting & Suggestions can avoid issues like, Payment Delays, Frequent Amendments, Retain Dedicated Study personnel.

• Investigators Training Meeting is conducted to provide a uniform understanding of Protocol & process to all the Participants.

SITE INITIATION VISIT

Site Initiation Visit by Sponsor verifies that Investigator & his Team are Trained on the Study Requirements.

1. Essential Trial Documents

2. Roles & Responsibilities of each Team Member

3. Facilities, Role of Sponsor, Study Time lines

4. ICF & CRF

5. SAE / ADR Reporting

6. EC – NOC Application Requirements

7. Source Documents

8. Study Drug Storage / Accounatbility

9. Randomization Procedures

10. Data Management

11. Audits / Inspections & Archival

• Performed to evaluate the preparedness of the Investigator Site for Subject Enrollment.

• It is done after EC-NOC obtained & fulfillment of all the Protocol Requirements.

• Review the preparedness of the Study Team on all the Requirements for the Study

• Revisit the Critical Study Supplies for the Study before Enrollment of the Subjects.

• Opportunity to check the Critical Aspects of The Trial after initial Training & before implementation Phase.

SUBJECT ENROLLMENT

&

ICF ADMINISTRATION

• ICF is a procedure to take the consent of the participant after being completely briefed about the Trial & Outcome, etc.

• Sponsor has the responsibility to detail all the risks, regulatory needs & procedures of the Trial in the ICF in vernacular of the subject.

• ICF must be obtained before non-routine screening procedures are performed and/or before any change in the subject’s current medical therapy.

• The subject & the Investigator obtaining the ICF must sign the ICF with date at the appropriate places.

• One copy of the signed ICF should be given to the subject and ICF should be obtained by the Investigator.

• In case the Subject is illiterate, one impartial person should be present during ICF discussion & signing.

• Any amendment done in the obtained ICF should be subjected to EC approval & the subject should be re-consented.

• Only EC approved ICF should be used for all enrollment.

• Data required in the Protocol should be carefully recorded in the source documents & later transcribed in the CRF.

MAINTENANCE OF SOURCE DOCUMENTS

• Source Documents should tell the complete story of the trial & aid in reconstruction of total information.

• CRFs as SD refer to Quality of Life Questionnaire, Evaluation Scales, Patient demographics and it should be mentioned in the protocol.

• Documentation of all Transactions of the Study Drug would lead to 100% drug accountability.

• Incomplete & Inappropriate SD can lead to Audit Issues & well maintained SD helps in reconstruction of the Study at

any point of time.

• All SD are required to be archived for a specific period of 10-15 years after completion of the Study for future Audit.

A Good Source Document should be able to

address the following. :

1. ICF Process

2. Pre-existing Conditions & Relevant History

3. Laboratory Reports & Results

4. Efficacy Evaluations

5. Adverse Events & Corrective Medications

6. Drug Accountability

7. Progress Notes

8. Ongoing Patient’s Status

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