Global Regulations in Clinical Trials

Dr. N. Srinivas
Institute of Clinical Research India

CLINICAL TRIAL
A systematic study in Human Subjects for determining Safety and Efficacy of a new drug.

Clinical Trial Phases

Phase I (Human Pharmacology) Safety and Tolerability with the initial administration of IND MTD, Kinetics and Dynamics Phase II (Therapeutic Exploratory Trials) Effectiveness for a particular indication, small group Phase III (Therapeutic Confirmatory Trials) Therapeutic benefit in large number of patients Phase IV (Post Marketing Trials) Related to approved indication

Good Clinical Practice (GCP)

International and scientific quality standard for:
Designing Conducting Recording Reporting

trials that involve the participation of human subjects

THE PIPELINE CONCEPT OF DRUG DEVELOPMENT

Drug Discovery Period Drug Discovery Period (Pre-Clinical) (Pre-Clinical)
Idea for New Drug Synthesis & Testing of New Drug Specific Biological Activity Found Candidate Compound Chosen and More Testing

Drug Development Period Drug Development Period

Clinical NDA Studies Approval Planned and Started NDA Prepared Compound IND and Submitted Drug Filed Evaluated to FDA Launched to Project Status With FDA IND Plan Set

Drug Marketing Drug Marketing and Expansion and Expansion

PostMarketing Studies Begun New Clinical Uses Pursued Activities to Support Market

Additional Compounds are Made

New Dosage Forms and Formulas Developed

(patent applied for)

Clinical Trials Phases I, II, & III 8.5 Years

Clinical Trials -- Phase IV 8 Years Left on Patent

3.5 Years

Stake Holders
Sponsor Subjects
Investigator Team /Site

Clinical Trial Regulatory Bodies CRO / SMO

IEC/IRB

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

A CLINICAL TRIAL PROJECT IS...

S IP CE QU UR , E SO LE RE EOP (P
DE AD LIN ES ) TI (S M E CH ED UL ES ,

,I NR )

SPECIFICATIONS (QUALITY AND QUANTITY)

The traditional approach

INTERNAL FORCES
Evaluation Team Quality Time
YOUR PROJECT

Turf

Strategic Intent

Decision Marketing Making Selection

EXTERNAL FORCES
Competition Commercial Potential Time YOUR DCGI PROJECT
PROJECT

Activists

Government

Reimbursement

Patient recruitment rate

Patient Numbers

Action required

More realistic

Time

Advantages of conducting Clinical Trials in India

Established Bulk drug & formulation industry Cost Advantage Vast Patient data

Highest number of USFDA approved plants

Diversity of diseases

International Property Rights

Wide range of CROs

Compliant IT support

Career Prospects in Clinical Research

CRA
Drug safety (PV) Associate Clinical Trials Auditor

Study Coordinator

Career prospects

Data Manager

Medical Writer
Regulatory Affairs Manager

Clinical Research Investigator

Sponsor Responsibilities
Study Report Termination DE & DM QC & QA Monitoring Study design Select sites Regulatory Study management Information

GCP

AE reporting Clinical trial supplies

Documentation Communication

Monitoring / Audit Records Reports Safety reporting

Regulatory compliance

Investigator Ethics approval

Informed consent Medical care

Investigational product Staff supervision

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

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. 2. 3. 4. basic medical scientists (preferably one pharmacologist). clinicians legal expert social scientist / representative of NGO voluntary agency /philosopher / ethicist / theologian or a similar person 5. lay person from the community.

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

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

Site Criteria To Look For

Location Specialty PI and Team IRB Lab support Other Equipments Commercials Space

Time of staff Enrollment timelines Target enrollment Quick off the block Timeline for: 1. IRB Submission to Approval 2. Contract agreement 3. Enrollment per week/month

Types of Site Visits

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

Indian Drug Regulations Schedule Y

Which studies ? When ?

Phase I Product Already approved/ marketed in another country Product neither if phase I approved/ nor marketed Studies in another country but Are over phase III /II studies are in progress Concurrently Phase II Phase III Therapeutic confirmatory studies

Concurrently

Before 2005 amendment to Schedule Y, trials were allowed to be initiated at one phase earlier to the phase 27 of trials in other countries

Which studies ? When ?

Phase I For new drug substances discovered in other countries Phase I trials are not usually allowed to be initiated in India unless Phase I data from other countries are available. Exception will be if product is of special relevance to the health problem of India. Allowed in stages

For new drug substances discovered in India

Post Marketing Surveillance Periodic Safety Update Reports Unexpected SAE

Phase IV Mandatory 14 days Other investigators

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Before CONSIDERING the study :IEC SHOULD OBTAIN

Investigator CV

Sponsor IB Protocol Updates

Human Subject Advertisement ICF Compensation

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AFTER CONSIDERING the study :

IEC :HOW IT SHOULD COMMUNICATE

APPROVAL OR FAVOURABLE OPINION MODIFICATIONS REQUIRED PRIOR TO APPROVAL UNFAVORABLE OPINION NOTIFY PROVIDE REASONS PROVIDE REASONS PROCEDURES FOR APPEAL PROCEDURES FOR APPEAL PROCEDURES FOR APPEAL

TERMINATION OR SUSPENSION OF PROVIDE PRIOR APPROVAL REASONS

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PROCESS OF NEW DRUG DEVELOPMENT IN NDA vs. ANDA Review Process INDIA
Brand Name Drug NDA Requirements 1 2. 3 4. 5. 6 7 8 Chemistry Manufacturing Controls Labeling Testing Animal Studies Clinical Studies Generic Drug ANDA Requirements Chemistry Manufacturing Controls Labeling Testing Bioequivalence Studies

Bioavailability Studies
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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 National Institute 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

APPLICATION PROCESS APPLICATION FORM 44 -Imp ff -Imp rm -Mfg ff -Mfg rm -CT APPROVAL FORM 45 (IMP FF) APPROVAL FORM 45 A (IMP RM) APPROVAL FORM 46 (MFG FF) APPLICATION FORM 46 A (MFG RM) NOC FOR CT + Test License for Import

FORM 44 Contd
2. A. 1. 2. 3. 4. 5. 6. 7. 8. 9. Data submitted along with the application Permission to market new drug Chemical and Pharmaceutical information Animal Pharmacology Animal Toxicology Human / Clinical Pharmacology Exploratory Clinical Trials Confirmatory Clinical Trials Bioavailability / dissolution and stability data Regulatory status in other countries Marketing information : (a) Proposed product monograph (b) Drafts of labels and cartons Application for test license :

1.

FORM 44 Contd
B. Subsequent approval / permission for manufacture of already approved 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

FORM 44 Contd
C. Approval / permission for FDC Justification Pcokinetic / Pcodynamic data Any other data

D. Subsequent approval or approval for new indication new dosage form : Number and date of Approval already granted Justification Data on safety, efficacy and quality

PSUR
New 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 after approval For subsequent two years the PSURs need to be submitted annually PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period.

Indemnity & Insurance

Indemnity by Sponsor usually excludes malpractice, negligence, error, omission, or protocol violation, etc. Indemnitee
Insuran Sponsor ce compan Indemnifier Indemnitee y Indemnifier Study sites Investigators Research subjects

An insurance backed indemnity is most preferable It is desirable for a research institute to acquire additional insurance for research

The Impact of ICH

Enhanced patient safety Streamline development programs Common quality standard Reduce resource requirements Forum for Communication Opportunity for Industry & Regulators to sit across the table
Discuss drug development procedure with a common goal of identifying best scientific practice and applying the same uniformly across the globe

Registration of CROs
Draft guidelines and requirements for registration of such organisation 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.

USFDA DRUG APPROVAL PROCESS - - An Overview

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 FDA may impose a clinical hold if it finds that human subjects are or would be exposed to an unreasonable 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 or to suspend an ongoing investigation (21 CFR 312.42) A clinical hold may be complete or partial. Delay or 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? First, if the inspectional findings indicate that the investigator has repeatedly or deliberately violated FDA regulations or repeatedly or deliberately submitted false information, FDA may move to disqualify the investigator from conducting future studies regulated by FDA. Second, FDA may initiate a civil or criminal enforcement action in federal court. Such actions can take several months and frequently years to complete

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 an opportunity 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)

To disqualify PI - FDA administrative process

At a regulatory hearing, the investigator may offer the testimony of 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)

When Will FDA Lift a Clinical Hold ?

When the grounds for the hold no longer apply. If FDA concludes, based on this evidence, that the study subjects are no longer exposed to an unreasonable and significant risk of illness or injury, the hold will be lifted. In all instances, if a sponsor of a study that has been placed on clinical hold requests in writing that the clinical hold be removed and responds to the issues identified in the clinical hold order, FDA will respond in writing to the sponsor within 30 calendar days of receipt of the request and response

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 status General investigational plan for upcoming year Any Investigator Brochure revisions Significant Phase I protocol modifications Significant foreign marketing developments during prior year

TYPES OF INDs
Commercial INDs. Noncommercial INDs . - Investigator INDs. - Emergency Use INDs. - Treatment INDs.

IND Application Promotion & Charging for Investigational Drugs

No representation that drug is safe or effective for indicated use No commercial distribution or test marketing No prolongation of study Prior written approval from FDA required to charge for drug, unless being used under treatment IND

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.

IND Information Amendments 21 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

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 analyze the 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 an admission that the drug caused or contributed to an adverse experience.

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 marketing developments 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 the sponsor requests or expects a reply, comment, or meeting

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 otherwise disposed 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.

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.

312.45 Inactive status If no subjects are entered trials for a period of 2 years 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.

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.

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 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

THANK YOU