Global Regulations in Clinical Trials by N.srinivas ICRI
Transcript of 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
PROCEDURESFOR APPEAL
TERMINATION OR SUSPENSION OFPRIOR APPROVAL
PROVIDEREASONS
PROCEDURESFOR APPEAL
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