Adverse Events

Reporting

Dr. Rashmi Gurao

MD. PhD
Assistant Professor,
National Institute of Ayurveda, Jaipur
 Objectives
• Identifying Adverse Events in Clinical Trial

• Reporting Adverse Events in Clinical Trial

• Safety monitoring in Clinical Trial

• Managing Adverse Events in Ayurveda Studies

 Identifying Adverse Events
in Clinical Trial

23 April 2025 Dr. Rashmi Gurao 3

 What is Adverse Event (AE)
ICH GCP Guidelines E6 R (2) Nov. 2016
Any unfavorable and unintended sign (including an abnormal
laboratory findings), symptom or disease temporarily
associated with the use of a medicinal (investigational) product,
whether or not related to the medicinal (investigational)
product.

ICH GCP Draft Guidelines E6 R (3) May. 2023

Any unfavorable medical occurrence in a trial participant. The
adverse event does not necessarily have a causal relationship
with the treatment.

Ex
Transfusion reactions, Accidental injury, surgery, etc.
 Key Definitions
Adverse Drug Reaction (ADR)
A noxious and unintended response to a medicine that occurs
at normal therapeutic doses used in humans for prophylaxis,
diagnosis or therapy of disease, or for the modification of the
physiologic function.

Side effect
Any unintended effect of a pharmaceutical product occurring
at normal therapeutic doses and is related to its
pharmacological properties. Such effects may be well known
and even expected and require little or no change in patient
management.
 Key Difference between ADR & AE
Aspect ADR AE

Any injury related to

Harmful response to a
Definition medication use, including
drug at normal doses.
errors.
Related to the drug’s Can result from errors,
Cause
pharmacological action. misuse, or ADRs.
Typically non- May be preventable (e.g.,
Preventability
preventable. medication errors).
Narrower, focused on Broader, includes all
Scope
drug reactions. medication-related harm.
Overdose due to wrong
Examples Anaphylaxis to penicillin. dosage or missed
interactions.
 Points to Remember
An adverse event can arise from any use of the drug (e.g., off-label
use, use in combination with another drug) and from any route of
administration, formulation, or dose, including an overdose.

Indicates a change in the subject’s health status ‘since baseline’ right

before taking the study drug.
Baseline would include all of the below:
• Pre-existing conditions that are ongoing during the clinical trial-
Ex: Hypertension- Diabetes
• Concomitant medications taken prior to participation in the
clinical trial
Ex: Anticoagulants to prevent thrombosis,
Steroids for autoimmune condition
All ADRs are Adverse events….
But not all AEs are ADRs

AEs ADRs
 Expected vs Unexpected Adverse Event
Expected AE Unexpected AE
Anticipated Unforeseen

Described in the study protocol or relevant Not mentioned in the study protocol or is
documentation listed at a lower severity or frequency than
listed as a potential risk, side effect, or observed.
adverse reaction, along with its expected may prompt further investigation into the
severity and frequency. event's nature, severity, and potential
relationship to the study or treatment.

Do not require expedited reporting to A new, unexpected side effect of a medication

regulatory authorities. that wasn't previously known or documented.

Common side effects like nausea, headache, or A new, unexpected side effect of a medication
fatigue associated with a particular that wasn't previously known or documented.
medication.
 Expected vs Unexpected Adverse Event

 Is the adverse event unexpected?

 Is the adverse event related or possibly related to participation in
the research?
 Does the adverse event suggest that the research places subjects
or others at a greater risk of harm than was previously known or
recognized?

If answer to all the three questions is YES, then the AE is

Unexpected.
Serious Adverse Event (SDE) / Serious Adverse Reaction (SAR )
/Suspected Unexpected Suspected Unexpected Serious
Adverse Reaction (SUSAR)
21 CFR 312.32, ICH GCP OHRP Guidance
Any AE occurring at any dose that results in any of the following
outcomes:

• Death
• Life-threatening adverse drug experience
• Inpatient hospitalization or prolongation of existing
hospitalization
• Persistent or significant incapacity or substantial disruption of
the ability to conduct normal life functions
• Congenital Anamoly or birth defect

OR
 SAE/ SAR / SUSAR

• Important medical events that may not result in death, be life-

threatening, or require hospitalization may be considered as
serious when, based on appropriate medical judgement, they
may jeopardize the patient or the subject and may require
medical or surgical interventions to prevent one of the outcome
listed in the definition.

Ex:
• Bronchospasm requiring intensive treatment in an emergency
room or at home,
• Blood dyscrasias or convulsions that do not result in inpatient
hospitalization,
• Development of drug dependency or drug abuse.
 Methods of Detection of AE
Method Description Advantages Limitations
Captures patient
Participants
1. Spontaneous experience; may High risk of
voluntarily report
Reporting detect unexpected underreporting
symptoms
effects
May still miss
Investigators ask
2. Direct Improves AE events if
about symptoms
Questioning detection rates questions are not
during visits
comprehensive
Detects non- Limited to what
3. Physical Routine clinical
verbalized or can be externally
Examination assessments
observable effects examined
May require
Detects follow-up testing
Blood, urine,
4. Laboratory asymptomatic or to confirm
organ function
Testing early-stage significance
tests
abnormalities
 Methods of Detection of AE
Method Description Advantages Limitations
Regular checks
Identifies Non-specific;
5. Vital Signs on BP, HR,
physiological may not directly
Monitoring temperature,
changes indicate an AE
etc.
May be
Detects
Cardiac infrequent;
structural or
6. ECG/Imaging monitoring, X- costly; some
functional organ
rays, MRIs, etc. changes may be
changes
incidental
Requires careful
Monitoring
7. Concomitant Can reveal documentation
additions/chang
Medication indirect signs of and
es in
Review AEs interpretation
medications
 Methods of Detection of AE
Method Description Advantages Limitations
Compliance
Reduces recall
Real-time self- issues; relies on
8. Patient bias; detailed
reporting tools participant
Diaries / ePROs symptom
for symptoms literacy/tech
tracking
comfort
9. Documentation
Retrospective;
Hospital/Emerg
of serious or Critical for SAE
may miss minor
ency Visit urgent health identification
AEs
Records events
Independent Ensures
committee unbiased safety Not real-time;
10. DMC /
evaluates oversight; can periodic review
DSMB Reviews
aggregated stop unsafe only
safety data trials
 Reporting Adverse Events
in Clinical Trial

23 April 2025 Dr. Rashmi Gurao 17

 Regulatory Guidelines
AE reporting is guided by:
•ICH-GCP (E6) – International Council for Harmonisation –
Good Clinical Practice

•21 CFR Part 312 – U.S. FDA regulations

•EudraLex Volume 10 – EU clinical trial guidelines

 Regulatory Frameworks in India
Governed by:
• Drugs and Cosmetics Rules, 1945 (as amended)
• Schedule Y – outlines requirements for clinical trials
• New Drugs and Clinical Trials Rules, 2019

Monitored by:
• Central Drugs Standard Control Organization (CDSCO)
• Drug Controller General of India (DCGI)
Minimum Dataset to report AE
An Identifiable Patient

An Identifiable Reporter

Product Exposure

Event
SAE Reporting Framework
 SAE Reporting Framework for AYUSH DRUGS
The National Coordination Centre for the
Pharmacovigilance Programme of India (PvPI) is
located at the Indian Pharmacopoeia
Commission, which is situated in Ghaziabad, Uttar
Pradesh.

The All India Institute of Ayurveda in New Delhi • National Institute of Ayurveda,
is the National Pharmacovigilance Centre (NPvCC) Jaipur
• Institute of Teaching &
for (ASU&H) Drugs. Research in Ayurveda,
Jamnagar
• National Institute of Unani
Intermediary Pharmacovigilance Centres (IPvCs) Medicine, Bengaluru
• National Institute of Siddha,
Chennai
• National Institute of
Peripheral Pharmacovigilance Centres (PPvCs) Homoeopathy, Kolkata
various AYUSH institutions across the country
 Who Can report ?
• Ayurveda/Siddha/Unani physicians

• Pharmacists, nurses, researchers

• Patients and caregivers

• Academic institutions, hospitals, and industry

stakeholders
 SAE Reporting for AYUSH drugs
AyushSuraksha website:
allows online submission of suspected
ADR reports.

Contacting NPvCC: The National

Pharmacovigilance Coordination Centre
(NPvCC) can be contacted

(011 26950401/402)

[email protected]

Reporting Forms: Specific ADR

reporting forms are available for
Ayurveda drugs.
 ADR Reporting Process
• Go to: https://ayushsuraksha.com

• Register/Login (for healthcare professionals or institutions)

• Select appropriate reporting form:

For Healthcare Professionals (simplified forms)
For Patients/Consumers

• Fill out details:

Patient demographics
Details of ASU drug used
Description of ADR
Outcome

• Submit online or download the form and send it to

the nearest monitoring center.
AE/ADR Reporting Form
 Key Features of Ayushsuraksha
Feature Description
Allows registered users (doctors,
pharmacists, patients) to report
ADR Reporting
suspected adverse events.

Easy-to-fill digital forms for ADR

Online Form Submission reporting (similar to CDSCO's forms).

Provides pharmacovigilance SOPs,

Guidelines & SOPs reporting formats, and FAQs.

Downloadable materials and training

Access to PvPI Resources tools for sensitizing stakeholders.
 Benefits of Using Ayusuraksha
• Ensures active pharmacovigilance in the AYUSH sector.

• Helps regulators and manufacturers improve product

safety.

• Encourages rational use of ASU medicines.

• Aligns with WHO guidelines on traditional medicine

safety monitoring.
Safety Monitoring
in Clinical Trial
 Why it matters ?
 To protect rights, Safety & wellbeing of participants
by identifying & managing potential risks

Verifying ethical conduct of the trial

 Identifying AE/ADR Timely Intervention

Minimizing potential Harm

Ensuring Data Accuracy & Integrity

Compliance with regulatory guidelines

The science and practice of monitoring the safety of medicines, with
the goal of identifying, assessing, and preventing adverse effects or
drug-related problems.

 Detection: Identifying potential safety issues associated with

medicines, including adverse drug reactions (ADRs).

Assessment: Evaluating the severity, frequency, and nature of

adverse effects.

Understanding: Investigating the mechanisms and causes of

adverse effects.

 Prevention: Taking measures to reduce the risk of adverse

effects, including better labeling, patient education, and
regulatory actions.
 Guidelines for Safety Monitoring
 The International Conference on Harmonization Good
Clinical Practice (ICH-GCP) Guidelines

 International Ethical Guidelines for Biomedical

Research involving Human subjects issued by Council
for International Organizations of Medical Sciences
(CIOMS)

 Declaration of Helsinki

 New Drugs & Clinical trial Rules, 2019 (India) CDSCO

3rd Schedule (Rule No. 8,10,11, 25,35, 42 & 49) Page 142
Key Stakeholders in Safety Monitoring
 Responsibilities of Key Stakeholders
Sponsor overseeing the entire safety monitoring process.
PI Conduct of the trial & reporting ofIsafety events
IRB Reviews & approves trial protocol, monitors safety & compliance
DSCO
E &thical
DSMB Provide independent oversight review Committee
of safety data
C
CRO Data Management & Reporting

DCGI / CDSCO Regulatory Authority

 Safety Monitoring Activities
Adverse Event Reporting:
All adverse events (side effects) that occur during the trial
must be reported to the sponsor and other relevant
parties.

Data Quality Assurance:

Ensuring the accuracy and completeness of data collected
throughout the trial.

Protocol Adherence:
Monitoring that the study is being conducted in
accordance with the approved protocol.
 Safety Monitoring Activities
Periodic Safety Reviews:
Regular review of safety data by the sponsor, DSMB, or
other designated bodies.

Interim Analyses:
Statistical analyses performed during the trial to assess
the safety and efficacy of the treatment.

Regulatory Reporting:
Reporting safety information to regulatory authorities as
required.
 Tools & Techniques for Safety Monitoring
Clinical Trial Protocol:
Outlines the procedures for safety monitoring, including reporting
requirements and data review processes.

Case Report Forms (CRFs):

To collect and document data on adverse events and other safety-related
information.

Periodic Safety Update Reports (PSURs):

Regular reports submitted to regulatory authorities that summarize the
safety data collected during the trial.

Statistical Analyses:
Statistical methods are used to assess the risk of adverse events and to
identify potential safety signals.
 Tools & Techniques for Safety Monitoring
Development Safety Update Report :
Comprehensive annual report prepared during clinical development of
drug. Provides yearly update on safety profile of investigational product.

Report Type When Required Submitted To Submission

Timeline
DSUR During clinical trials DCGI, EC Annually (within 60
days)
PSUR Post-marketing DCGI Every 6 months (first 2
years), then annually
SAE Any SAE during DCGI, EC, 24h (initial), 14d
trials Institution Head (detailed)
 Timeline
for SAE
Reporting

23 April 2025 Dr. Rashmi Gurao 39

Responsibility of SAE Reporting
Investigator C DSCO
• Immediate Reporting within • Processing & Review of
24 hours – Sponsors, Ethical SAE Reports.
Committee, DCGI
• Detailed Reporting – within • Database Management
14 days
SAE
Reporting

S ponsor Ethical Committee

Immediate Reporting within 14
days – DCGI, Ethical Committee, 7 • Review & Report to DCGI with 30
days in case of death calender days.
Compensation– for trial related
death or injury
Managing Adverse Events
in
Ayurveda Studies
 Ayurveda – No ADR, Really ??
Björnsson HK, Björnsson ES, Avula B, Khan IA, Jonasson JG, Ghabril M, Hayashi PH,
Navarro V. Ashwagandha-induced liver injury: A case series from Iceland and the US
Drug-Induced Liver Injury Network. Liver Int. 2020 Apr;40(4):825-829. doi:
10.1111/liv.14393. Epub 2020 Feb 11. PMID: 31991029; PMCID: PMC8041491.

Kales SN. Ayurvedic lead poisoning: An under recognized, international problem.

Indian J Med Sci. 2009;63:379–81.

Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augustine P. Comprehensive

review of hepatotoxicity associated with traditional Indian Ayurvedic herbs. World J
Hepatol. 2020 Sep 27;12(9):574-595. doi: 10.4254/wjh.v12.i9.574. PMID: 33033566;
PMCID: PMC7522561.

Philips CA, Paramaguru R, Joy AK, Antony KL, Augustine P. Clinical outcomes,
histopathological patterns, and chemical analysis of Ayurveda and herbal medicine
associated with severe liver injury-A single-center experience from southern India.
Indian J Gastroenterol. 2018;37:9–17. -
Ayurveda – No ADR ??

Ajanal MN, Nayak SU,

Kadam AP, Prasad BS.
Pharmacovigilance study
of Ayurvedic medicine in
Ayurvedic Teaching
Hospital: A prospective
survey study. Ayu. 2015
Apr-Jun;36(2):130-7. doi:
10.4103/074-
8520.175539.
PMID: 27011712; PMCID:
PMC4784121.
 Ayurveda – No ADR ??
In this prospective study, ADR monitoring was done in KLE Ayurveda Secondary Care
Hospital, Belgaum, Karnataka, India by spontaneous and intensive monitoring
technique for a span of 1-year (June 2010 to May 2011)

In a span of one year,

84 adverse drug events were reported out of which 52 confirmed as ADR.

The overall incidence of ADR in the patient population was 1.14%, out of which
 23 (44.23%) were related to Panchakarma (detoxification process),
 13 (25.00%) related to the herbal formulations and
 06 (11.53%) were of Rasa Aushadhi (mineral or herbo-mineral
formulations).

The commonly affected organ systems were gastrointestinal system 24 (46.15%)

and skin 15 (28.84%). The majority of the reactions were moderate 30 (57.69%) to
mild 20 (38.46%) in severity. Most patients recovered from the incidence.
 Challenges for Reporting AE in Ayurveda
Perception of “Natural means Safe” Variation in Prakriti

Lack of Standardization Limited patient follow up

Complex multi-herb Formulas Limited Practitioner Awareness

Rasaushadhi & Documentation Issues

Use of Over the counter (OTC) & Self Medication Lack of Regulatory Framework or Enforcement
Protocol Development:
• Define clear AE definitions (including Ayurveda-specific symptoms).
• Include AE monitoring and reporting procedures.
• Risk Assessment: Identify potential AEs based on the herbs,
formulations, or procedures being used by reviewing classical
Ayurvedic texts, modern pharmacology, and pilot data.

Informed Consent:
Clearly inform participants about potential risks, known AEs, and
emergency procedures.
 Planning Phase
Ethics Approval:
• Ensure protocol includes AE monitoring and reporting plans,
and is approved by an Institutional Ethics Committee (IEC).
• If using Rasaushadhis (herbo-mineral drugs) or proprietary
formulations, seek regulatory clearance (AYUSH/CDSCO).

Investigator Training
• Recognizing AEs specific to Ayurveda (e.g. ama formation, vata
prakopa, detox reactions).
• Causality and severity grading.
• Reporting timelines and documentation standards.
 AE Monitoring During the Study
Training:
Investigators and study staff should be trained to recognize,
document, and report AEs — including subtle or delayed
effects that might be unique to Ayurveda interventions.

Regular Assessments:
Schedule frequent check-ins with participants to proactively
identify symptoms.
 AE Monitoring During the Study
Daily Logs: Maintain detailed records of:
• New symptoms (e.g., rash, loose stools,
dizziness).Exacerbation of existing conditions.
• Laboratory values, if applicable (especially for
rasaushadhis).
• Agnimandya (digestive weakness)
• Ama lakshanas (toxicity signs)
• Dosha vriddhi symptoms
• Allergic reactions (e.g. urticaria from herbs like
Ashwagandha or Shatavari)
• Onset and duration
• Severity (mild/moderate/severe)
• Relationship to the intervention
(unrelated/possible/probable/definite)
• Action taken (e.g., dosage reduced, treatment paused)
 AE Severity Gradings (CTCAE)
Grade Severity Symptoms
I Mild • Asymptomatic or mild symptoms
• Clinical or diagnostic observations only
• Intervention not indicated.

II Moderate • Minimal, local or noninvasive intervention indicated

• Limiting age-appropriate instrumental ADL*. (preparing
meals, shopping, etc.)
III Severe • Medically significant but not immediately life-threatening
hospitalization or prolongation of hospitalization indicated
• Disabling; limiting self care ADL**. (refer to bathing,
dressing and undressing, feeding self, and not bed ridden)
IV Life- • Urgent intervention indicated.
threatening
consequences
V Death related to AE
 AE Monitoring During the Study
Severity Grading (Example for Ayurveda Trials)

Grade Severity Symptoms Action

I Mild self-limiting nausea Continue with observation
II Moderate mild diarrhoea Pause or adjust dose
III Severe hepatitis, severe allergic Stop treatment; provide
reaction urgent care
IV Life- Withdraw subject;
threatening immediate medical care
consequences
V Death Report to IEC & regulatory
within 24 hours

Use a modified CTCAE (Common Terminology Criteria for Adverse

Events) format for consistency.
 Causality Assessment
Use standard tools like:

• WHO-UMC Causality Assessment or

• Naranjo Algorithm, adjusted for Ayurveda contexts.

Example: A gastrointestinal AE may be considered "probable" if it started after

administering a Tikta rasa (bitter) formulation known to increase Vata.
 Dechallenging vs Rechallenging in Pharmacovigilance
Dechallenging Rechallenging
Definition stopping of the drug, restarting of the same drug
usually after an adverse after having stopped it,
event (AE) or at the end of usually for an AE.
a planned treatment

May be complete or partial May be complete or partial

Inference If the AE goes away after If the AE returns upon
stopping the drug, it reintroducing the drug, this
suggests a possible link strengthens the causal
between the drug and the relationship between the
event. drug and the AE.

Positive AE improves or resolves AE reappears after

after stopping the drug restarting the drug

Negative AE does not improve after AE does not reappear after

stopping the drug restarting the drug
 Documentation
Use an AE/SAE reporting form that includes:
•Patient ID
•Onset date and resolution
•Symptoms
•Suspected cause
•Ayurvedic interpretation (if any)
•Action taken
•Outcome
•Reporter’s signature

Forms should be sent to: Principal Investigator, Ethics

Committee, Regulatory authorities (if SAE)

SAEs must be reported within 24 hours, per ICMR/GCP

guidelines.
 Reponse & Mitigation
Immediate Care:
• Stop or modify intervention
• Provide necessary allopathic or Ayurvedic treatment as per the
severity.

Modify Protocol if Needed: Dose adjustments, withdrawal of a

particular drug, or even halting the study arm.

Participant Withdrawal: Allow withdrawal if safety is

compromised, and ensure follow-up for resolution.

Informed Decisions:
• Modify dosage
• Withdraw suspect drug
• Consider rechallenge only under strict conditions (rare)
 Post Study Analysis
Evaluate AE Patterns:
• Are they linked to specific herbs, dosages, prakriti or dosha types?
• Were they predictable(e.g. detox reactions)

Evaluate Risk-benefit ratio

Reformulation or Reconsideration: Adjust compositions based

on observed safety signals.

Documentation: Publish safety data along with efficacy results to

build transparent evidence. (publication & regulatory dossier)
Individualized Treatments: AE management must
consider prakriti, agni, vikriti, etc.

Detox Protocols (Panchakarma): May cause temporary

symptoms that mimic AEs — need proper
differentiation.

Herb-Mineral Formulations (Rasaushadhi): Higher risk

of toxicity if not prepared properly — require stricter
monitoring
Concern Action

Detox reactions (e.g., mild Distinguish from pathological AE

diarrhea during virechana) — document as expected effect

Herbo-mineral toxicity Mandatory lab monitoring (LFTs,

RFTs)

Prakriti-based responses Stratify AE data by prakriti to see

variability
Compound polyherbal drugs Try to isolate responsible
component(s) in case of AE
 AE reporting in Ayurveda clinical trials is mandatory and regulated,
especially for new formulations or off-label indications.

 All AEs must be documented, whether or not they’re related to

the study drug. SAEs must be reported immediately.

 Investigators must maintain accurate, complete, and timely

records. Sponsors are responsible for ensuring regulatory
submissions and global safety tracking.

 All reports must be comprehensive, timely, and accurate. Use the

AYUSH GCP Guidelines (2013) for documentation standards.

 Always involve Ethics Committees and report to CDSCO if required.

Assess
Don’t Guess

Thank
23 April 2025 Dr. Rashmi Gurao
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