Schedule Y, FDA, Appendices, Post marketing surveillance,Clinical trial,WHO,ICH-GCP, FDA-CFR, Safety,Adverse Drug reaction, Adverse Event(AE), Serious Adverse Event(SAE),Reporting, IND , 3500A form

1. -BY
Asst.Prof.Dnyaneshwari M.Joshi
Department of Biotechnology
NACS college

5. “Requirement and guidelines for permission to import
and manufacture of new drugs for sale or to
undertake clinical trials.”

6. 1.Important considerations for CT under
Schedule Y
2.Appendices of Schedule Y
IT CONTAINS TWO IMPORTANT PARTS:

7. PART 1
• A. Application For permission.
• B. Clinical trial.
• C.Studies in Special populations.
• I]Geriatrics : health care specialty for elderly peoples.
• II]Pediatrics : health care specialty for infants,and childrens
• III]Pregnant womens .
• D. Post marketing Surveillance
• E. Bioavailability
• F. Requirement for Clinical trial

8. PART II: APPENDICES: A SECTION AT THE END
OF DOCUMENT OR BOOK WHICH GIVES EXTRA
INFORMATION
• A} Appendix 1:
This contains data to be submitted along with the
application to conduct trials for manufacturing of new drugs
for marketing in the country.
this includes : a) Introduction
b) Chemical and pharmaceutical information.
c) Marketing information
d) Special studies wrt Licensing authority.

9. • B } Appendix 2:
Format of study report.
this contains I) Title page
II) Protocol, name of investigational product,
developmental phase etc.
III) List of abbreviations and definitions.
IV) table of contents
V) Ethics committee.
This section should document that the study was conducted in
accordance with ethical principles of DOH.
VI) Study Team
VII) Study objective.
Etc.

10. C }Appendix 3: for Animal Toxicology and Dose standardization.
D} Appendix 4: Animal Pharamacology.
E} Appendix 5: Informed Consent ; informed consent
is a process as well as a legally required document. Throughout any
study, researchers must continue to keep study participants informed
about any new information with regard to the safety of the product and,
in particular, about any new developments or findings that may affect
participants’ willingness to remain in the study. Researchers must: Inform
participants, in a language that they understand, about emerging
developments in the study, related studies utilizing the same
Investigational Product(s), or pertinent pre-clinical studies that are
significant to participant safety. Offer participants the opportunity to ask
questions about the information they have been given. Ensure that
participants understand they may withdraw from the study at any time
and cannot be penalized for doing so.
each participant understands what he or she has been told and is making
a voluntary, informed decision to remain in the study

11. • APPENDIX 6
• Fixed Dose Combination(FDC); refers to any product which
contains one or more active ingredients used for same or
different indications.
• FDC’S are divided into 4 major groups . Group 1- Group4.
Appendix 7 Investigational studies
Appendix 8 Ethics committee(EC)
Appendix 9 Stability testing of New Drugs
Appendix 10 Protocol
Appendix 11: Reporting of SAE

12. FDA :Code of Federal Regulations (CFR)
FDA's legal authority to regulate both medical devices and electronic
radiation-emitting products is the Federal Food Drug & Cosmetic Act
(FD&C Act). The FD&C Act contains provisions, that is, regulatory
requirements, that define FDA's level of control over these products. To
fulfill the provisions of the FD&C Act that apply to medical devices and
radiation-emitting products, FDA develops, publishes and implements
regulations.
Federal Register (FR)
The FR is the official daily publication for rules, proposed rules, and
notices of Federal agencies and organizations, as well as executive orders
and other presidential documents. Proposed rules are initially published
in the Federal Register for public comment and subsequently published
in the Code of Federal Regulations after the rule is final. Final
regulations published in the FR are subsequently placed or codified into
the printed edition of the Code of Federal Regulations (CFR) on an
annual basis. You can find recently published FR's on the
Regulations.gov.

13. The CFR is a codification of the general and permanent rules that were
published in the FR by the Executive departments and agencies of the
Federal Government. It is divided into 50 titles that represent broad areas
subject to Federal regulation.
Most of FDA's medical device and radiation-emitting product regulations
are in Title 21 CFR Parts 800-1299). These final regulations codified in
the CFR cover various aspects of design, clinical evaluation,
manufacturing, packaging, labeling and post market surveillance of
medical devices. In addition, the regulations address standards and
product reports that apply to radiation-emitting products.
Code of Federal Regulations (CFR):

15. WHO states that
It is the pharmacological science relating to the collection,
detection, assessment, monitoring, and prevention of
adverse reaction with Pharmaceutical products.
"Pharmacovigilance” ( Pharmakon -drug +Vigilare to keep
watch)
Why Pharmacovigilance is important?
• To improve patient care & safety in relation to medicines & all medical &
para-medical interventions
• To improve public health & safety in relation to the use of medicines Public
Health
• To contribute to the assessment of benefit, harm, effectiveness and risk of
medicines Risk Benefit Assessment
• To promote understanding, clinical training & effective communication to
health professionals & the public Communication Patient Care
PHARMACOVIGILAN

17. The Minimum Requirements for a functional Pharmacovigilance
System
1. A National Pharmacovigilance Centre with designated staff (at least one full
time), stable basic funding, clear mandates, well defined structures and roles and
collaborating with the WHO Programme for International Drug Monitoring.
2. The existence of a National spontaneous reporting system with a national
individual case safety report (ICSR) form i.e. ADR reporting form.
3. A national database or system for collecting and managing ADR reports .
4. A national ADR or pharmacovigilance advisory committee able to provide
technical assistance on causality assessment, risk assessment, risk management case
investigation and where necessary crisis management including crisis
communication .

18. The Good Clinical Practice (GCP) guidelines of the International Council for
Harmonization (ICH) define an adverse event (AE) as:
“any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and that does not necessarily have a causal
relationship with this treatment” (ICH GCP, E6(R2) 1.2).
The term adverse event is defined in the U.S. Code of Federal Regulations (CFR) Title
21 Section 312.32(a) as follows:
"any untoward medical occurrence associated with the use of a drug in humans,
whether or not considered drug related." ICH guidelines for Clinical Safety Data
Management: Definitions and Standards for Expedited Reporting uses the ICH GCP
definition. An AE may be “any unfavorable or unintended" sign, symptom, or disease
that occurs in a person who has taken a medication. The occurrence does not need to be
related to the drug treatment.
An adverse event (AE) may be:
A physical event (e.g., a rash).
A psychological event (e.g., depressed mood).
A laboratory event (e.g., elevated blood sugar). An increase in the severity or frequency
of a pre-existing symptom or condition (e.g., increased pain in a painful tooth) An
adverse event may also be referred to as an “adverse experience.”

19. What is an Adverse Drug Reaction?
FDA regulations define an ADR as “an undesirable effect, reasonably associated with
the use of a drug, that may occur as part of the pharmacological action of the drug or
may be unpredictable in its occurrence” (21 CFR 201.57(c)).
Remember: Although every ADR is also an AE,
only some AEs will also be ADRs.
Therefore, it is very important to collect clear and complete information about every
AE.
What is a Serious Adverse Event ?
An AE is considered serious if it poses a threat to the patient’s life or functioning. The
FDA defines a serious adverse event (SAE) as any untoward medical occurrence that:
Results in death, or Is life-threatening (places the patient at risk of death), or Requires
hospitalization or prolongs an existing hospitalization, or Causes persistent or
significant disability or incapacity, or Is a birth defect, or Requires medical intervention
to prevent one of the above outcomes (e.g., an asthma attack that requires intensive
treatment in an emergency room, a seizure that does not result in hospitalization but
requires medical treatment).

20. • Regardless of who reports an AE, the event should always be
documented in the participant’s source documents including
progress notes. When an AE is reported by a third party, the
Research Assistant should make every effort to contact the
participant directly to verify the report. In some cases, a report of
an AE may turn out to be false. As more information about the
event is gathered and assessed, the Research Assistant must ensure
that source documents and reports are updated with accurate
information about the AE.
• AE reporting is an essential part of participant safety protection
during a clinical study. Determining whether an incident is a
reportable AE—and if so, what should be reported about it, to
whom, and when—depends on many factors, including: Previous
experience and knowledge of the drug or intervention, The disease
being treated, and Regulatory requirements. In addition to the
factors listed above, investigators must consider incident reporting
requirements for NIH-funded studies, including reportable AEs.

21. • Adverse Event Reporting:
• FDA Requirements For IND(Investigational new drug) studies FDA guidelines (21
CFR 312.32) require expedited reporting by the sponsor of all AEs that are
associated with the use of the drug, serious, unexpected and reasonably related to the
investigational product. Related and unexpected fatal or life–threatening AEs
(severity grade 4 or 5) that are associated with the use of the drug must be reported
to FDA by telephone or fax no later than 7 calendar days after the sponsor first
learns of the event.
• This initial report must be followed within 8 additional calendar days by a written
safety report that is as complete as possible. FDA must be notified of serious, related
and unexpected AEs associated with the use of the drug that are not fatal or life-
threatening in a written safety report no later than 15 calendar days after the sponsor
first learns of the event. The sponsor should report pertinent follow-up information
for previously submitted reports to the FDA as soon as it is available, including for
AEs that were not initially deemed reportable if the follow-up information causes a
change in assessment.

22. Reporting SAE’s:
SAEs will be recorded on the FDA Form 3500A (MedWatch)
FDA Reporting Requirements (IND studies only)
• The Sponsor-Investigator will be responsible for reporting applicable SAE’s to the FDA. • All
SAEs must be reported to the FDA using FDA Form 3500A (MedWatch) • All SAEs must be
reported via fax to the CDER review division that has responsibility for review of the IND. o 7-
day safety reports must be submitted to the FDA review division that has responsibility for the
review of the IND.
• Fatal or Life Threatening AND Unexpected AND Suspected to be RELATED to the
investigational product must be reported no later than 7 calendar days after the sponsor-
investigator’s receipt of the information. • Serious AND Unexpected AND Suspected to be
RELATED to the investigational product must be reported no later than 15 calendar days after the
sponsor-investigator’s receipt of the information • Events occurring at higher rate (i.e. expected)
than anticipated that are both Serious and Suspected to be RELATED to the investigational
product must be reported no later than 15 calendar days after the sponsor determines the results
from the aggregate analysis of the specific events qualifies for reporting o FDA considers an
aggregate analysis of specific safety events reportable if the results of the analysis indicate the
events are occurring more frequently in the drug treatment group than in the control group (if the
study does not contain a control group, historical controls maybe referenced).

23. ICH GCP requirements for AE reporting
The investigator must report all Serious Adverse Events to the sponsor immediately.
The immediate reports should be followed promptly by detailed, written reports. In
the event of a death, the investigator should supply the sponsor and the IRB with
any additional requested information. In addition, the investigator must comply with
the applicable regulatory requirements as well as protocol specific requirements
related to the reporting of safety issues. In some instances, the local laws or network
requirements may request more stringent reporting of emergent or safety events.
• Findings from animal / in vitro / epidemiological studies that suggest a significant
risk to human subjects no later than 15 calendar days after the sponsor’s receipt of the
information
• Any relevant additional information must be submitted to the FDA (i.e. IND Follow
Up Safety Report).

24. • Yellow card schemes (YCS) were applied to spontaneous reporting systems. It was
established in 1964 as a result of the thalidomide tragedy. Since then, the system has
become one of the major international PV resources [47]. The yellow cards are
classified into seven priorities by a member of the scientific staff according to the
drugs and the nature of the ADR shown in Figure
• The YCS is run jointly by the Medicines Control Agency (MCA) which is the
regulatory agency and the Committee on Safety of Medicines (CSM) which is the
experts committee. Since 1991, the YCS has been enhanced by a new computer
system, the ADROIT (Adverse Drug Reaction Online Information Tracking) system.

25. REFERANCES:
• Basics of clinical reseach , S.D.Shewale et al 1st ed.
• Role of Pharmacovigilance in India: An overview
Online Journal of Public Health Inform. 2015; 7(2):
e223. Published online 2015 Jul 1.
• Code of Federal Regulations (CFR): FDA.