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GCP Guidelines for ASU

National Institute of Siddha


19.06.2013


Why clinical research?
The purpose of clinical research is to
create knowledge needed to improve
health care. Without such knowledge,
action for health care may be impossible,
wasteful, expensive or harmful because it
will have no logical or empirical basis.

- IUTALD, 2001

India A major destination for
clinical trials
Large patient pool
Well trained
investigators
Premier medical
institutes
Considerably low cost
per patient
Language


3
.but?

Good Clinical Practices (GCP)
GCP = Good Clinical Research Practice
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance
that
the Data and Reported Results are Credible and
Accurate
the Rights and Confidentiality of Trial Subjects are
Protected

= Quality Data
= Ethics
Quality Data + Ethics = GCP


GCP
Purpose & Applicability of GCP
Purposes of GCP
To protect the rights of research subjects
(volunteers or patients)
To ensure credibility of the data

GCP is applicable to
Prophylactic, diagnostic and therapeutic trials
Drugs, devices and procedures
Epidemiological studies
Evolution
Nuremberg Code, 1947
Declaration of Helsinki,
1964 2008
ICH GCP guidelines, 1996
Ethical Guidelines for
Biomedical Research in
Human Subjects (ICMR),
2000
GCP Guidelines, CDSCO,
New Delhi, 2001
GCP guidelines for ASU -
2013
Players in GCP
Investigators
Sponsor
IRB/Ethics Committee
Regulatory Authorities


Headings
Definitions
Pre-requisites of the study
Responsibilities
Record keeping & Data handling
Quality assurance
Statistics
Special concerns
Pre-requisites of the study
Drug
Supportive data
Protocol
Ethical & Safety considerations & Approval

Drug
Physical
Chemical
Pharmaceutical
Formulation
Supportive data
Preclinical
Clinical

Adequate
Convincing
Protocol - components
General information
Objectives & Justification
Ethical considerations
Study design
Inclusion, Exclusion & Withdrawal criteria
Handling of medicine
Assessment of efficacy
Assessment of safety
Data handling/statistics
Quality control / Quality assurance
Finance / Insurance
Publication policy
Appendices


Protocol - General information
Title, Number, Date
Details of
Investigator
Sponsor
Institution
Disease review (Both Modern & ASU)
Trial drug review

Protocol Objectives & Justification
Objectives
Primary
Secondary
Relevant studies non-clinical/clinical
Gap in the knowledge
Summary of known/potential risks
Inclusion & exclusion criteria
Protocol Ethical considerations
General ethical considerations
Informed consent
What safety measures have been planned
Protocol - Study design
Phase of the trial
Type of the study
Design of the study
Blinding
Randomization
Mention of control
Phases of clinical trial
Phase I : Human Pharmacology
Phase II : Therapeutic exploration
Phase III : Therapeutic confirmation
Phase IV : Post-marketing surveillance
Phase - I
Non-therapeutic
Objectives
Maximum tolerable dose
Adverse reactions
Early measurement of drug activity
Healthy adults
Single and multiple dose administration
Each dose for at least two persons

Phase - II
Objectives
Evaluate the effectiveness of drug
Short-term side-effects/risks
Fix dose for Phase III trials
Group of patients

Phase - III
To confirm the therapeutic benefits
Dose-response relationships
Randomized, Controlled trial

Phase - IV
Not needed for approval
Additional drug-drug interaction
Dose-response relationship
Safety studies

Few designs of clinical trial
Cross-over design
Concurrent control
Historical control
Open-label
Protocol Sample size, Inclusion,
Exclusion & Withdrawal criteria
Sample size
Inclusion criteria
Exclusion criteria
Withdrawal criteria
Questionnaire for prakruti evaluation

Protocol Handling of trial drug
Safe handling measure
Storage
Dosage
Interval
Adjuvant
If blinding labeling, coding
Label For clinical trial only
Name of the study, name/contact number of the
investigator, institution
Protocol Assessment of efficacy
Symptomatic assessment
Diagnostic tests
Time and periodicity of tests
Other scoring systems
Protocol Assessment of safety

Strict adherence to the dose levels (especially
in case of mineral drugs)
If any adverse effect occurs
How it can be reported
What are the steps to be taken
Medical/other management
Follow up after ADR


Protocol - Statistics
Statistical methods to be applied
Sample size
Interim analysis
Managing missing data etc


Protocol - Budget
Apparatus
Reagents
Other non-clinical studies
Travel, if any
Payment to subjects
Printing/Stationery/Postage
Miscellaneous

Protocol - Appendices
CRF
Consent form
Other special procedures
Ethical & Safety considerations
Basic Principles of
Ethics
Justice
Respect for persons
Beneficence &
Nonmalaficence
Ethical principles
Principles of essentiality
Principles of voluntariness, informed consent and
community agreement
Principles of non-exploitation
Principles of privacy and confidentiality
Principles of precaution and risk minimization
Principles of professional competence
Principles of accountability and transparency
Principles of the maximization of the public interest and of
distributive justice
Principles of institutional arrangements
Principles of public domain
Principles of totality of responsibility
Principles of compliance
Ethics committee
Background
Basic responsibilities
Composition
Terms of reference
Review procedures
Submission of application
Decision making process
Interim review
Record keeping

Basic responsibilities
To safeguard study subjects dignity, rights & welfare by:
Evaluation of study proposal
Evaluation of proposed subject consent materials
Evaluation of investigator qualifications
Ongoing review of study progress (at least yearly)
Evaluation of proposed subject compensation plans
Ensuring that universal ethical values and scientific
standards are followed
Composition
5-7 to 12-15 members
Composition
Chairperson
1-2 basic medical scientists (one pharmacologist and one
preferably from Dravyaguna / Rasshastra / Bhaishajya Kalpana
or Gunapadam or Ilm-ul advia /Taklis-Wa-Dawa-Sazi).
2 clinicians from various Institutes, one out of which should be
from respective system
One legal expert or retired judge
One social scientist / representative of non-governmental
voluntary agency
One philosopher / ethicist / theologian
One lay person from the community
Member Secretary
One expert member of ASU
As far as possible equal representation
Procedures of IEC
Schedule meetings & notify members
Conduct initial & ongoing review of studies
Determine ongoing review frequency
Provide expedited review of minor study changes, in
accordance with regulatory requirements
Specify that no subject should be enrolled in study
prior to IRB/EC approval


Procedures of IEC
Specify that no deviations from protocol should
be initiated without prior IRB/EC approval
Emergency situations require immediate notification of
IRB/EC after the fact
Specify that Investigator should promptly report:
Protocol deviations
Changes increasing subject risk or study procedures
Serious and unexpected adverse events


Procedures of IEC
Notify Investigator promptly of:
Study-related decisions
Reason for decisions
Procedures for appeal of decisions
IEC Required Records
Relevant records maintained 3 yr after study
completion
Records available for review by regulatory
authorities
What is reviewed in IEC
Investigator Brochure or Report of Prior Investigations
Study protocol & amendments
Investigator qualifications
Informed consent documents, including subject
recruiting tools
Other written information provided to subjects
Subject compensation plans
Adverse events
Protocol deviations
When IEC reviews Occur
Prior to study initiation at site
At least yearly during study
During study, as necessitated by:
Changes in protocol, consent documents,
etc.
Changes in study investigator
Reports of serious or unanticipated device-
related adverse events
At study completion or termination
Decision making process
Broad consensus / quorum requirement
In case of conflict, withdraw voluntarily
Members own proposal
Negative decision Reasons
Reversal of a positive decision
Discontinuation/Premature termination
For an ongoing study, the issues to be brought
to the IEC
Experts opinion
Minutes of the meeting

Responsibilities
Investigator
Sponsor
Monitor
Responsibilities of the investigator
Qualified to conduct study
Have adequate resources to conduct study
Selection and recruitment of study subjects
Provide medical care to study subjects
Regular communication with IRB/EC reviewing study
Compliance with study protocol
Maintenance of investigational product accountability
Compliance with study randomization & unmasking
procedures
Provide informed consent to study subjects
Records / Reports
Monitoring and Auditing of Records
Sponsor
Roles & Responsibilities
Study quality assurance
Appropriately qualified medical personnel to advise
on study
Utilization of qualified personnel in study design &
operations
Study management, data handling & record keeping
Investigator selection & training
Definition/allocation of study responsibilities


Sponsor
Roles & Responsibilities
Facilitation of communications between Investigators
Study compensation (investigators and/or subjects) &
financing
Regulatory authority notification/submission
Confirmation of IRB/EC review/approval
Investigational product information
Investigational product manufacturing, packaging,
labeling & coding
Investigational product supply & handling
Informed Consent Document
Components
Statement that study involves research & product
experimental (if applicable)
Study purpose
Number of expected study subjects to be enrolled
Study treatment(s) & probability for random
assignment
Study exams & procedures for duration of trial
Subjects responsibilities
Foreseeable risks to subject (embryo, fetus, nursing
infant)


Informed Consent Document
Components
Expected benefits
Alternatives procedures or therapies & associated
risk/benefit
Compensation available in event of study-related
injury or sickness
Anticipated payments to subject for study
participation
Anticipated expenses to subject for study
participation
Statement that participation is voluntary


Informed Consent Document
Components
Description of extent to which confidentiality can be
assured
Commitment to keep subject apprised on new
information that may affect subjects willingness to
participate in study
Contact info for questions re: subject rights; trial-
related adverse events
Circumstances under which subjects participation
may be terminated


Investigator Brochure
What It Is
A compilation of clinical & non-clinical data on the
product that is relevant to the products study in
humans

Necessary for Investigator & IRB/EC review to assess the
risks/benefits associated with study
Investigator Brochure
Components
Product formulation summary
Introduction/background info regarding product &
investigational plan
Investigational product physical, chemical &
pharmaceutical properties & formulation
Non-clinical studies
Human clinical studies
Summary of data & guidance for Investigator

Record keeping & Data handling
Documentation
Corrections
Electronic Data Processing
Validation of Electronic Data Processing Systems
Language
Responsibilities of the Investigator
Responsibilities of the Sponsor and the Monitor

Quality assurance
Sponsors responsibility
GLP compliant lab
Protocol
GCP
SOP and Others, if any
Findings should be verifiable
Every stage
Independent audit
All should be kept ready for audit
Statistics
Role of a biostatistician
Study design
Randomization & Blinding
Statistical analysis
Special concerns
Clinical Trials of Contraceptives
Clinical trials with Therapies /surgical
procedures/medical devices
Ayurveda, Siddha & Unani (ASU)
A historical plethora of
Health practices, approaches, knowledge & beliefs
Plant, animal &mineral based medicines, spiritual
therapies, manual techniques & exercises
Applied singly or in combination
To maintain well-being, to treat, diagnose or
prevent illness
WHO country cooperation study, 2006-2011
Concepts of Ethics in Siddha/Ayurveda
Purity of mind, intellect & word
Compassion
Physician is equal to mother
It is a sin if proper care & treatment are not
given
Prior consent (Charaka Samhitha)

Why GCP in ASU?
In use through ages
Gaps in contemporary
medicine
Make ASU evidence-based
Increase acceptability
Increase credibility
Refine & Advance ASU
Improve understanding


















Indian data?
Categorization of ASU drugs for
clinical research
Category I :
Traditional formula for Traditional indications
Category II :
Traditional formula, plant/extract mentioned in
text for New indication
Different method of preparation
Category III :
Not in use, not mentioned in literature
Categorization of ASU drugs for
clinical research
Category I :
Traditional formula for Traditional indications
Start from Phase II
Non-inferiority group / Superiority trial
Pilot trials
Category II :
Traditional formula, plant/extract mentioned in text
for New indication
Different method of preparation
Start from toxicity studies
Category III :
Not in use, not mentioned in literature
Start from toxicity studies
Criteria for herbal formulations
before clinical trial
Description of the plant
Processing
Analytical procedures
Specification
Storage conditions
Good Agricultural Practices (Phase III)
Good Wildcrafting Practices (Phase III)

Operational Guidance: Information needed to
support clinical trials of herbal products (2005) - WHO
Comparison between ASU & CM
ASU Contemporary
medicine
Basic approach Individual based Population based
Data on drugs Historical
Multicomponents
Recently developed
Individual
components
Updation ??? Continuous inputs
through
pharmacovigilance,
Phase IV
Safety Assumption Safety-first
approach
Comparison between ASU & CM
ASU Contemporary
medicine
Ancillary
interventions
External therapies
Varmam
Yoga
Primarily medical
and surgical
Defining the disease Whole system
approach
Pathology / Organ
viewed in isolation
Process or product Both are important Product centric.
Chemical equivalent
is enough
Scheme of things
NCEs

Proof of
concept

Toxicity study

Dose fixation

Clinical trials

PMS

Used in
population

Anecdotal
evidence

Multi-
component
formulations
in use

Contemporary
relevance

How to
validate,
refine,
increase use?

CLINICAL RESEARCH
S
T
A
R
T
S
HERE
Challenges for ASU Clinical
Research
Lack of uniform standards
Safety
Efficacy
Lack of specific research
methodology
Poor pharmacodynamic kinetic correlation
Limited & scattered clinical data
Absence of structured pharmacovigilance system
Lack of regulatory control
Issues with clinical trials
Most clinical trials (i.e., studies in people) of
Ayurvedic approaches have been small, had
problems with research designs, lacked
appropriate control groups, or had other
issues that affected how meaningful the
results were. Therefore, scientific evidence for
the effectiveness of Ayurvedic practices varies,
and more rigorous research is needed to
determine which practices are safe
and effective.
NCCAM nccam.nih.gov
Concerns in ASU clinical trials
ASU clinical trials are mainly academic
exploratory studies
Mainly investigator driven
Lack of commercial interest

Greater need for industrial-academia
collaboration
CTRI
Free online record system 2007
Registration is mandatory since 2009
Only registered trials will be
accepted for publication
Before enrollment of the
first patient
Mandatory for AYUSH trials also
Even for dissertations!
Item to ensure Quality data & Ethics
Quality data
Protocol
Quality assurance
Audit
Statistical analysis
Blinding
Documentation

Ethics
IEC approval
Informed consent
Confidentiality
Medical care
Our unique
values &
methods
Contemporary
guidelines
(GCP-ASU etc., )
More
relevant &
More useful
guidelines
Reference
Good Clinical Practice guidelines for Clinical
trials in Ayurveda, Siddha and Unani
Medicine, Dept. of AYUSH, 2013
ICH Harmonized Tripartite Guideline,
Guideline for GCP, 1996
Ethical Guidelines for Biomedical Research on
Human Participants, ICMR, 2006
Good Clinical Practices for Clinical Research in
India, CDSCO, 2001


Thank you!