global regulations in clinical trials by n.srinivas icri

8/6/2019 Global Regulations in Clinical Trials by N.srinivas ICRI

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Global Regulations inClinical Trials

Dr. N. SrinivasInstitute of Clinical Research India


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CLINICAL TRIAL

A systematic study in

Human Subjectsfor determining

Safety and Efficacyof a new drug.


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Clinical Trial Phases

Phase I (Human Pharmacology) Safety and Tolerability with theinitial administration of IND MTD, Kinetics and Dynamics

Phase II (Therapeutic Exploratory Trials) Effectiveness for aparticular indication, small group

Phase III (Therapeutic Confirmatory Trials) Therapeutic benefit inlarge number of patients

Phase IV (Post Marketing Trials) Related to approved indication


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Good Clinical Practice (GCP)

International and scientific quality standard

for:

Designing

Conducting

Recording

Reporting

trials that involve the participation of human

subjects


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Clinical TrialsPhases I, II, & III

Clinical TrialsPhases I, II, & III

Clinical Trials -- Phase IV

Clinical Trials -- Phase IV

3.5 Years 8.5 Years

8 Years Left on Patent

(patent applied for)

Drug Discovery PeriodDrug Discovery Period

(Pre-Clinical)(Pre-Clinical)

Drug Discovery PeriodDrug Discovery Period

(Pre-Clinical)(Pre-Clinical) Drug Development Period

Drug Development Period Drug Marketing

and Expansion

Drug Marketing

and Expansion

Idea

for

NewDrug

Synthesis

& Testing

of New Drug

Specific

Biological

ActivityFound

Additional

Compounds are

Made

Candidate

Compound Chosen

and More Testing

Compound

Evaluated

to Project Status

IND

Plan

Set

IND

Filed

With

FDA

Clinical

Studies

Planned and

StartedNDA Prepared

and Submitted

to FDA

NDA

Approval

Drug

Launched

Post-

Marketing

StudiesBegun

New

ClinicalUses

Pursued

Activities to

Support

Market

New Dosage

Forms and

Formulas

Developed

THE PIPELINE CONCEPT OF DRUG

DEVELOPMENT


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Clinical TrialClinical Trial

SubjectsSubjects

CRO / SMOCRO / SMO

IEC/IRBIEC/IRBRegulatoryRegulatory

BodiesBodies

InvestigatorInvestigator

Team /SiteTeam /Site

SponsorSponsor

Stake Holders


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Types of Projects in Clinical Trials

Develop NCE from discovery of activity

Develop line extension

Develop new indication

Develop combination medicine

Develop marketing oriented studies to compare safety, Efficacy, QoL or Cost Effectiveness


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A CLINICAL TRIAL PROJECT IS...A CLINICAL TRIAL PROJECT IS...

SPECIFICATIONS(QUALITY AND QUANTITY)

RESOURCES

(PEOPLE,E

QUIP,IN

R)

TIME

(SCHEDULE

S,DE

ADLINES)


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The traditional approach


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INTERNAL FORCESINTERNAL FORCES

TeamTeamTurfTurf

StrategicStrategicIntentIntent

MarketingMarketing

SelectionSelection

DecisionDecisionMakingMaking

TimeTime

QualityQuality

EvaluationEvaluation

YOURYOURPROJECTPROJECT


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Time

PatientNumbers

More realistic

Actionrequired

Patient recruitment rate


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Established Bulk drug

& formulation industry

Wide range of CROs

Vast Patient data

Diversity of

diseases

Compliant IT support

Cost Advantage

Highest number of

USFDA

approved plants

International Property

Rights

Advantages of conducting Clinical Trialsin India


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Career Prospects in Clinical Research

Career prospects

CRA

Clinical Trials Auditor

Data Manager

Clinical Research Investigator

Drug safety (PV)Associate

Regulatory Affairs Manager

Medical Writer

StudyCoordinator


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Sponsor Responsibilities

Study design

Select sitesRegulatory

Study management

Information

Clinical trial supplies

AE reporting

Monitoring

QC & QA

Termination

Study Report

DE & DM

Documentation

Communication

GCP


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Monitoring /

Audit

Regulatory complianc

Ethics approval

Informed

consent

InvestigatorSafety

reporting

Investigational

product

Medical careStaff supervision

Records

Reports


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IEC / IRB RESPONSIBILITIES

Safeguard rights, safety & well being

Protect vulnerable subjects

Obtain and maintain record of SOPs Ongoing review based on Periodic progress

report

If EC revokes its approval - Record reasons for it

- Inform the Investigator & LA immediately


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INSTITUTIONAL ETHICS COMMITTEE

At least seven members

Appropriate gender representation on the Ethics Committee.

EC members who are independent of trial and sponsor

should vote / provide opinion in matters related to the study.

Quorum at least 5 members with following representations:

1. basic medical scientists (preferably one pharmacologist).

2. clinicians

3. legal expert

4. social scientist / representative of NGO voluntary

agency /philosopher / ethicist / theologian or a similar

person

5. lay person from the community.


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IRB Review

The IRB shall review the following documents:

1. Protocol

2. Informed Consent Forms (ICF)

3. Patient Information Brochure (PIS)

4. Translations of the ICF & PIB

5. Investigators Brochure

6. Form 1572

7. CTA, Insurance & indemnity

8. Recruitment & advt.

9. Pt. diary & questionnaires


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Key Elements of CTM

Investigator selection Preinvestigational site visit PISV

Study initiation visits SIV

Trial conduct & execution

Legal aspects

Periodic monitoring visits

Product accountability, financial disclosure

AE/ADR reporting

Study close-out visits SCV

Records retention & inspections


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Site Criteria To Look For

Location

Specialty

PI and Team IRB

Lab support

Other Equipments Commercials

Space

Time of staffEnrollment timelines

Target enrollmentQuick off the blockTimeline for:

1. IRB Submission to

Approval2. Contract

agreement

3. Enrollment per

week/month


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Types of Site Visits


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Site Initiation (Training)1. Investigator Meetings

2. On-site-initiation visits (SIV)

3. Combination of both

Investigator Meetings

Large, multicenter studies -

Selected study personnel trained at common location

Advantages

All investigators hear same information

Open forums

Disadvantages

Does not allow one-on-one attention

Not all site personnel may attend

CRA can not check site supplies/drug


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Indian Drug Regulations

Schedule Y


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Phase I Phase II Phase III

Product Already

approved/marketed in anothercountry

Product neitherapproved/ nor marketed

in another country butphase III /II studies arein progress

if phase IStudiesAre over

Concurrently

Concurrently

Before 2005 amendment to Schedule Y, trials were

allowed to be initiated at one phase earlier to the phase

of trials in other countries

Which studies ? When ?

Therapeuticconfirmatorystudies


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Phase I

For new drug substancesdiscovered in other countries Phase I trials are not usually allowed to beinitiated in India unless Phase I data fromother countries are available. Exceptionwill be if product is of special relevance tothe health problem of India.

For new drug substancesdiscovered in India

Allowed in stages

Which studies ? When ?

Post Marketing Surveillance Phase IV

Periodic Safety Update Reports Mandatory

Unexpected SAE 14 days

Other investigators


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Investigator Sponsor Human Subject

CV IB Advertisement

Protocol ICF

Updates Compensation

Before CONSIDERING the study :IEC SHOULD OBTAIN


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IEC :HOW IT SHOULD COMMUNICATEAPPROVAL OR FAVOURABLEOPINION

NOTIFY

MODIFICATIONS REQUIREDPRIOR TO APPROVAL

PROVIDEREASONS

PROCEDURESFOR APPEAL

UNFAVORABLE OPINION PROVIDEREASONS


TERMINATION OR SUSPENSION OFPRIOR APPROVAL

PROVIDEREASONS


AFTER CONSIDERING the study :


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NDA vs. ANDA Review ProcessBrand Name Drug NDARequirements

Generic Drug ANDARequirements

1 Chemistry Chemistry

2. Manufacturing Manufacturing

3 Controls Controls

4. Labeling Labeling

5. Testing Testing

6 Animal Studies Bioequivalence Studies

7 Clinical Studies

8 Bioavailability Studies

PROCESS OF NEW DRUG DEVELOPMENT ININDIA


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Registration of Trials

Trials to be registered with CTRI since 15th June,2009

The CTRI has been set up by the ICMR's NationalInstitute of Medical Statistics (NIMS) which will help to

Improve transparency and accountability

Improve the internal validity of trials

Confirm to accepted ethical standards Reporting of all relevant results of trials in India


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APPLICATION PROCESS

APPLICATIONFORM 44-Imp ff-Imp rm-Mfg ff-Mfg rm-CT

NOC FOR CT + Test

License for Import

APPLICATION FORM46 A (MFG RM)

APPROVAL FORM

46 (MFG FF)

APPROVAL FORM

45 A (IMP RM)

APPROVAL FORM

45 (IMP FF)


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FORM 44 Contd2. Data submitted along with the application

A. Permission to market new drug

1. Chemical and Pharmaceutical information2. Animal Pharmacology

3. Animal Toxicology4. Human / Clinical Pharmacology5. Exploratory Clinical Trials6. Confirmatory Clinical Trials7. Bioavailability / dissolution and stability data8. Regulatory status in other countries

9. Marketing information :(a) Proposed product monograph(b) Drafts of labels and cartons

1. Application for test license :


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FORM 44 Contd

B. Subsequent approval / permission for manufacture of alreadyapproved new drug

a) Formulation :

Bioavailability / bioequivalence

Name of the investigator / centre

Source of raw mat and stability

b) Raw Material

Manufacturing Method

QC parameters, specs, stability

Animal toxicity


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FORM 44 ContdC. Approval / permission for FDC

Justification

Pcokinetic / Pcodynamic data

Any other data

D. Subsequent approval or approval for new indication newdosage form :

Number and date of Approval already granted Justification Data on safety, efficacy and quality

PSUR


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PSURNew drugs should be closely monitored for their clinical safety;

submission of Periodic Safety Update Reports (PSURs) in order to-

report all the relevant new information (patient exposure) summarize the market authorization status in different countries and

any significant variations related to safety; and

indicate whether changes should be made to product information

PSURs shall be submitted every 6 months for the first two years afterapproval

For subsequent two years the PSURs need to be submitted

annually

PSURs due for a period must be submitted within 30 calendar days ofthe last day of the reporting period.


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Indemnity by Sponsor usuallyIndemnity by Sponsor usuallyexcludes malpractice, negligence,excludes malpractice, negligence,error, omission, or protocol violation,error, omission, or protocol violation,

etc.etc.

Indemnity by Sponsor usuallyIndemnity by Sponsor usuallyexcludes malpractice, negligence,excludes malpractice, negligence,error, omission, or protocol violation,error, omission, or protocol violation,

etc.etc.

Insurance

company

Sponsor Study sitesInvestigators

Indemnifier Indemnitee

IndemnifierIndemnitee

Research subjects

Indemnity & Insurance

An insurance backed indemnity is mostpreferable

It is desirable for a research institute toacquire additional insurance for research


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The Impact of ICH

Enhanced patient safety

Streamline development programs

Common quality standard

Reduce resource requirements Forum for Communication

Opportunity for Industry & Regulators to sitacross the table

Discuss drug development procedure with acommon goal of identifying best scientific practiceand applying the same uniformly across the globe


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Registration of CROs

Draft guidelines and requirements for registration of suchorganisation in the country have been developed.

Proposed to be incorporated as new schedule Y1 to drugs

and cosmetics rules,1945. The guidelines will also provide credible image to those

who head the CROs.

The function of the Ethics Committees will also be

scrutinized.


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USFDA DRUG APPROVAL

PROCESS - - An Overview


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USFDA DRUG APPROVAL PROCESS Biologics Control Act 1902

FEDERAL FOOD AND DRUGS ACT OF 1906 Federal FD&C Act 1938

Kefauver-Harris amendments 1962

The controlled substances act 1970 The orphan drug act 1983, Amend. 1984 The Drug Price Competition & Patent Term Restoration

Act 1984

FDA Modernization Act of 1997

Clinical holds 21 CFR 312.42


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Clinical holds 21 CFR 312.42

FDA may impose a clinical hold if it finds that

human subjects are or would be exposed to anunreasonable and significant risk of illness or injury

A clinical hold is an order issued by FDA to the

sponsor to delay a proposed clinical investigation orto suspend an ongoing investigation (21 CFR

312.42)

A clinical hold may be complete or partial. Delayor suspension of all clinical work under an IND is

considered a complete clinical hold

sets forth grounds for imposing a hold

What Actions Can FDA Take PI Misconduct?


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What Actions Can FDA Take PI Misconduct?

First, if the inspectional findings indicate that the

investigator has repeatedly or deliberately

violated FDA regulations or repeatedly or

deliberately submitted false information, FDAmay move to disqualify the investigator from

conducting future studies regulated by FDA.

Second, FDA may initiate a civil or criminalenforcement action in federal court.

Such actions can take several months and

frequently years to complete

T di lif PI FDA d i i i


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To disqualify PI - FDA administrative process

Issues a Notice of Initiation of Disqualification

Proceedings and Opportunity to Explain (NIDPOE)

letter, which furnishes the investigator with written

notice of the matter and offers the investigator anopportunity to explain the matter in writing, or, at the

option of the investigator, in an informal conference.

Center must offer the investigator an opportunity for a

regulatory hearing, whose procedures are governed by

21 CFR Part 16 (21 CFR 312.70)

T di lif PI FDA d i i t ti


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To disqualify PI - FDA administrative process

At a regulatory hearing, the investigator may offer the testimonyof witnesses, documentary evidence, and supporting briefs.

After the hearing, the presiding officer issues a report or decision

on whether the investigator has repeatedly or deliberately

violated the regulations and should be disqualified.The report is forwarded to the Commissioner, who issues decision

on disqualification (21 CFR Part 16).

PI may appeal the Commissioner's decision in federal court.

(many months or years to complete)


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IND A l R t


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IND Annual Reports

Due within 60 days of IND anniversary

Individual study information

Summary information for all studies, including:

Summary of safety results & significant changes in product

manufacturing, pre-clinical study statusGeneral investigational plan for upcoming year

Any Investigator Brochure revisions

Significant Phase I protocol modifications

Significant foreign marketing developments during prioryear


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TYPES OF INDs

Commercial INDs.

Noncommercial INDs .

- Investigator INDs.

- Emergency Use INDs.

- Treatment INDs.

IND Application


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IND ApplicationPromotion & Charging for

Investigational Drugs

No representation that drug is safe oreffective for indicated use

No commercial distribution or testmarketing

No prolongation of study

Prior written approval from FDArequired to charge for drug, unlessbeing used under treatment IND


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FDA Form 3674 Required by law - Section 113 of the FDA Modernization Act

mandates registration with ClinicalTrials.gov of IND efficacy

trials for serious diseases or conditions.

ClinicalTrials.gov accepts registration of all clinical trials

(1) approved by a human subject review board(2) conforming to the regulations of the appropriate national

health authorities

Prior to the enrollment of the first participant.

Required for journal publication.


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IND Information Amendments21 CFR 312.31

Information amendments advise the FDA of:New toxicity, CMC or other technical information

Notice of discontinuance of a clinical study

Information Amendment: CMC Information Amendment: Pharmacology-Toxicology

Information Amendment: Clinical

If sponsor desires - Request for FDA to comment


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21 CFR Part 312.32 IND safety reports

Review of safety information IB

Each notification shall be made not later than 15 calendar days ,

submitted on FDA Form 3500A

sponsor shall identify all safety reports previously filed with the

IND concerning a similar adverse experience, and shall analyzethe significance of the adverse experience in light of the previous,

similar reports

Disclaimer. ---- A sponsor need not admit, and may deny, that the

report or information submitted by the sponsor constitutes anadmission that the drug caused or contributed to an adverse

experience.


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312.33 Annual reports

A description of any significant Phase 1 protocol

modifications made during the previous year and

not previously reported to IND in a protocol

amendment.

A brief summary of significant foreign marketingdevelopments with the drug during the past year

If desired by the sponsor, a log of any outstanding

business with respect to the IND for which thesponsor requests or expects a reply, comment, or

meeting


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312.38 Withdrawal of an IND

At any time a sponsor may withdraw an effective IND

If an IND is withdrawn, FDA shall be so notified, all

clinical investigations conducted under the IND shall be

ended, all current investigators notified, and all stocks

of the drug returned to the sponsor or otherwisedisposed of at the request of the sponsor in accordance

with 312.59.

If an IND is withdrawn because of a safety reason, the

sponsor shall promptly so inform FDA, all participating

investigators, and all reviewing IRBs, together with the

reasons for such withdrawal.


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312.44 Termination

The drug is being promoted for commercial purposes

IND, or any amendment or report to the IND, contains an

untrue statement of a fact or omits material

The sponsor fails promptly to investigate SAEs

sponsor fails to submit annual report

The IND has remained on inactive status for 5 years

Not approved protocols submitted in the IND.

convincing evidence that the drug is not effective

Opportunity for sponsor response.


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312.45 Inactive status

If no subjects are entered trials for a period of 2years or an IND remain on clinical hold for 1 year

or more, IND may be placed by FDA on inactive

status.

A sponsor is not required to submit annual reports

A sponsor who intends to resume, shall submit a

protocol amendment under 312.30

An IND that remains on inactive status for 5 years

or more may be terminated under 312.44.


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312.48 Dispute resolution Administrative and procedural issues -beginning with the consumer

safety officer assigned to the application, Then ombudsman, whose

function shall be to investigate what has happened and to facilitate a

timely and equitable resolution resolving difficulties in scheduling

meetings & timely replies to inquiries

Scientific and medical disputes - sponsors may request meeting with

the appropriate reviewing officials.

FDA may, in its discretion, invite to the meeting one or more of its

advisory committee members.

FDA may refer matter to one of its standing advisory committees for

its consideration & recommendations.

M ti T With CBER/CDER


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Meeting Types With CBER/CDER

Type A

Meeting to get a stalled drug development program moving

forward

Scheduled within 30 calendar days

Type B (60 calendar days)Pre-IND meeting / End of phase 1 meeting

End of phase 2 / pre-phase 3 meeting

Pre-BLA/PLA/ELA/NDA meeting

Type C (75 calendar days)

Other types of meeting (e.g., facility design, general product

issues)

FDAs First C cle Re ie


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FDAs First Cycle Review

early on-going dialog with sponsors is the most

important factor in identifying issues

Early meetings (end of Phase 2) were more useful than

later meetings (end of Phase 3)

Submission deficiencies

Sponsors were often unwilling to adopt FDA

suggestions

Underlying sponsor causes

Lack of personnel with US regulatory experience

Poor internal regulatory processes


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THANK YOU

global regulations in clinical trials by n.srinivas icri

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