Global Regulations in Clinical Trials by N.Srinivas ICRI

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Global Regulations in Clinical Trials:

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:

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):

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 Trials Phases I, II, & III Clinical Trials -- Phase IV 3.5 Years 8.5 Years 8 Years Left on Patent (patent applied for) Drug Discovery Period (Pre-Clinical) Drug Development Period Drug Marketing and Expansion Idea for New Drug Synthesis & Testing of New Drug Specific Biological Activity Found 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 Started NDA Prepared and Submitted to FDA NDA Approval Drug Launched Post-Marketing Studies Begun New Clinical Uses Pursued Activities to Support Market New Dosage Forms and Formulas Developed THE PIPELINE CONCEPT OF DRUG DEVELOPMENT

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Clinical Trial Subjects CRO / SMO IEC/IRB Regulatory Bodies Investigator Team /Site Sponsor Stake Holders

Types of Projects in Clinical Trials:

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



The traditional approach:

The traditional approach


INTERNAL FORCES Team Turf Strategic Intent Marketing Selection Decision Making Time Quality Evaluation YOUR PROJECT


EXTERNAL FORCES Commercial Potential DCGI Government Reimbursement Activists Time Competition YOUR PROJECT

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Time Patient Numbers More realistic Action required Patient recruitment rate

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CLINICAL RESEARCH: INDIAN BENEFITS Established Bulk drug & formulation industry Wide range of CRO’s Vast Patient data Diversity of diseases Compliant IT support Cost Advantage Highest number of USFDA approved plants International Property Rights Advantages of conducting Clinical Trials in India

Career Prospects in Clinical Research:

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 Study Coordinator

Sponsor Responsibilities:

Sponsor Responsibilities Study design Select sites Regulatory 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 compliance Ethics approval Informed consent Investigator Safety reporting Investigational product Medical care Staff supervision Records Reports


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

IRB Review :

IRB Review The IRB shall review the following documents: Protocol Informed Consent Forms (ICF) Patient Information Brochure (PIS) Translations of the ICF & PIB Investigator’s Brochure Form 1572 CTA, Insurance & indemnity Recruitment & advt. Pt. diary & questionnaires…

Key Elements of CTM:

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:

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: IRB Submission to Approval Contract agreement Enrollment per week/month

Types of Site Visits:

Types of Site Visits

Site Initiation (Training):

Site Initiation (Training) Investigator Meetings On-site-initiation visits (SIV) 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:

Indian Drug Regulations Schedule Y

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

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28 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. For new drug substances discovered 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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29 Investigator Sponsor Human Subject CV IB Advertisement Protocol ICF Updates Compensation Before CONSIDERING the study :IEC SHOULD OBTAIN

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NDA vs. ANDA Review Process:

31 NDA vs. ANDA Review Process Brand Name Drug NDA Requirements Generic Drug ANDA Requirements 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 IN INDIA

Registration of Trials:

Registration of Trials Trials to be registered with CTRI since 15 th 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

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FORM 44 Contd:

FORM 44 Contd 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 :

FORM 44 Contd:

FORM 44 Contd Subsequent approval / permission for manufacture of already approved new drug Formulation : Bioavailability / bioequivalence Name of the investigator / centre Source of raw mat and stability Raw Material Manufacturing Method QC parameters, specs, stability Animal toxicity

FORM 44 Contd:

FORM 44 Contd Approval / permission for FDC Justification P’cokinetic / P’codynamic data Any other data 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. Insurance company Sponsor Study sites Investigators Indemnifier Indemnitee Indemnifier Indemnitee Research subjects Indemnity & Insurance An insurance backed indemnity is most preferable It is desirable for a research institute to acquire additional insurance for research activities

The Impact of ICH:

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:

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 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 :

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? :

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 :

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 :

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 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 :

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:

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:

FDA Form 3674 Required by law - Section 113 of the FDA Modernization Act mandates registration with of IND efficacy trials for serious diseases or conditions. 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:

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:

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:

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:

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:

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:

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:

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 :

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)

FDA’s First Cycle Review :

FDA’s 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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