Abstract

Today, drug safety data collection in India is both manual and electronic with
reporting of potential overlapping and duplicate data, which is likely incomplete
for further review and analysis. Furthermore, standardized data collection and
timelines are not aligned with international standards. Complete coverage of safety
data from all sources throughout the life of the drug cannot be ensured. Efforts
toward the early detection of drug safety issues are minimal. There is no mandate
to publicly disclose drug safety findings.
Periodic safety data reporting in clinical trials, proactive safety data collection
related to potential safety concerns, electronic medical records, electronic
expedited reporting, collection of targeted data from stakeholders, and standardized
and harmonized data collection aligned to the International Council for
Harmonization guidelines are required. The Central Drugs Standard Control
Organization should implement requirements to submit Development Safety
Update Reports, Periodic Benefit-Risk Evaluation Reports, and Risk Management
Plans.

Keywords: Adverse drug reaction, clinical trial, drug safety, India,

pharmacovigilance

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 Contents
• Introduction
• Collection of Safety Data
• Pharmacovigilance in Clinical Trial
• Why do we need Pharmacovigilance
• Adverse Drug Reaction
• Adverse Event
• Serious Drug Event
• Serious vs Severe event
• Common Practices in Safety Monitoring
• Conclusion

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 Safety Data Generation: Clinical Phase

Introduction
The practice of pharmacovigilance, the science and activities relating to detection,
assessment, understanding, and prevention of adverse effects or any other drug-
related problem is growing rapidly in India.
Since clinical trials are experiments in humans, they need to be conducted
following established standards so as to guard the safety, rights and well-being of
the participants. These regulation include the International Conference on
Harmonization Good Clinical Practice (ICH-GCP) Guidelines, International
Ethical Guidelines for Biomedical Research Involving Human Subjects issued by
the Council for International Organizations of Medical Sciences (CIOMS) and
therefore the ethical principles set forth within the Declaration of Helsinki. GCP is
that the “standard for the conducting, performance, planning, monitoring,
recording, auditing, analyses and reporting of clinical trials that gives assurance
that the info and reported results are believable and accurate which rights,
integrity and confidentiality of trial subjects are protected”.
Clinical trials give the evidential base for regulatory approvals of safe and effective
medicines. With long development cycles and ever-increasing costs in conducting
clinical trials, both the pharmaceutical industry and regulators are making attempts
to be much active in safety evaluations. Early safety detection not only results in
better patient protection, but also possible to save lots of development cost. Safety
evaluation may be a central component altogether stages of the drug development
life-cycle.

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Collection of Safety Data
 There is a mix of manual and electronic safety data collation methods
followed for different purposes in clinical trials and postmarketing settings.
Clinical trial sponsors collect safety data using the electronic case record
forms (eCRFs).
 The Central Drugs Standard Control Organization (CDSCO) collects the
safety data in clinical trials in paper-based forms (physical format).
 The mode of data collection for the purpose of expedited reporting of serious
adverse events (SAE) in clinical trials is also done manually and in physical
format as investigators and sponsors are expected to complete prescreening
checklist for the submission of SAE and submit SAE using paper form to the
regulatory authority.
 In the recently established Pharmacovigilance Programme of India (PvPI),
the post marketing data collection at adverse reaction monitoring centers is
manual, further the data are transferred electronically to the World Health
Organization Vigiflow database. There are no electronic reporting forms for
health-care professionals (HCPs) and industries such as MedWatch in the
USA.
 Sponsors, investigators, and Ethics Committees are well focused on the
collection of safety data to ensure safety and well-being of trial participants
and protect the rights of the patients.
 Regulatory authority is yet to achieve 100% coverage from all types of
safety information such as special situations, special population, overdose,
abuse, off-label use, misuse, medication error, occupational exposure, and
all sources of information such as all possible solicited and unsolicited
sources of information, literature, digital and social media, non-
interventional studies, compassionate use, and named patient use.

Pharmacovigilance in clinical trials

Pharmacovigilance may be a process of continuous monitoring and evaluation
of all adverse events during drug development process, to make sure the
security of the participants and a continuing assessment of the risk and the
benefit.

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There are four distinct phases of a drug’s clinical trial cycle after animal studies
have been completed.
 Phase I

Phase I trials are concerned primarily with establishing a new drug's safety
and dose range in about 20-100 healthy volunteers. How a drug is absorbed,
distributed, metabolized and excreted by the human body is called
Pharmacokinetics. This is determined through frequent blood draws (usually
in an inpatient environment) to check for the level of drug in the blood
plasma.

Pharmacokinetic trials are usually considered Phase I trials regardless of

when they are conducted during a drug's development. Dosage range of a
new drug is determined by administering increasingly larger doses to one or
more groups of subjects, who are closely monitored for harmful side effects.
The goal is to learn the maximum tolerated dose that does not produce
unacceptable side effects.

Phase I studies may involve risks even though an investigational drug has
passed the Preclinical phase of testing. Although usually conducted with
healthy volunteers, Phase I trials are sometimes conducted with severely or
terminally ill patients, for example those with AIDS or cancer.

A Phase I trial takes several months to complete. About 70 percent of

experimental drugs pass this initial phase of testing.

 Phase II

Phase II studies determine the effectiveness of an experimental drug on a

particular disease or condition in approximately 100 to 300 volunteers. This
phase may last from several months to two years.
Most Phase II studies are randomized, which means that subjects are
assigned randomly (by chance not by choice) to receive either the
experimental drug, a standard treatment or a placebo (harmless, inactive
substance). Those who receive the standard treatment or placebo are called a
control group.

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 Randomized Phase II studies are often double-blind, which means that both
subject and physician don't know which treatment is being used. Blinding
prevents any unscientific influence on the study results that could be caused
by knowledge of the treatment. In a single-blind study, only the subject is
unaware of the treatment used.

Since larger numbers of patients receive a treatment in Phase II studies than

in phase I studies, there is a greater chance to observe and compile side
effect information. Subjects in a Phase II trial may benefit from their
participation if they receive an active treatment. Approximately 33 percent
of experimental drugs which pass Phases I and II will go on to Phase III.

 Phase III

Phase III studies are conducted at multiple centers with several hundred to
several thousand patients for whom the drug is intended. Massive testing of
a drug provides continued generation of data on a drug's safety and efficacy.
As in Phase II, most Phase III studies are randomized and blinded.

Phase III trials provide the bulk of information needed for the package insert
and labeling of a medicine, after it has been FDA approved.

A drug in this phase can be studied for several years and may be one of 25-
30 percent that pass Phases I, II and III. Once a Phase III study is completed,
a pharmaceutical company can request FDA approval to market the drug.
This is called a New Drug Application (NDA). The NDA contains all the
scientific data that the company has gathered throughout the phases in all
trials.

 Phase IV

After successful completion of Phase III clinical trials and authorization for
marketing, the pharmaceutical company may conduct phase IV trials in
order to continue to monitor the drug on a much larger scale and in a less
controlled real world environment.

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Need of Pharmacovigilance
Pharmacovigilance analyzes which adverse events cross the line of drug’s efficacy.
Or in other words we can say it determines which side effects are worth the
risk to patients compared with how effective they are at treating a disease.
Incomplete information collected during the pre-marketing phase of drug ADRs
are leading cause of morbidity and mortality in both developing and developed
world. ADRs were 4th-6th commonest cause of death in the US in 1994 It has been
suggested that ADRs may cause 5700 deaths per year in UK 30-70% ADRs are
preventable. They increase cost of patient care and loss of patient confidence in
health care system.

⚫ Humanitarian concern: Animal toxicology is often not

⚫ Humanitarian concern: Animal toxicology is often not a good predictor for
human effects-Evidence of safety from clinical trials insufficient due to some
limitations (phase 1-3): limited size, narrow population (age &sex specific),
narrow indications (only specific disease), short duration
⚫ Safe use of medicine: It has been suggested that ADRs may cause 5700 deaths
per year in UK.
⚫ Adverse drug reactions are expensive
⚫ Promoting rational use of medicine
⚫ Ensuring public confidence
⚫ Ethical concern: Not reporting is serious reaction is unethical.

Adverse drug reaction

A response which is noxious and unintended and which occurs at doses normally
used in human for the prophylaxis, diagnosis or therapy of diseases or for
modification of physiological function .The role of pharmacovigilance is to
determine which adverse events cross the line of a drug’s efficacy.

Adverse event
ICH E6: An Adverse event is any undesirable medical event in a patient or clinical
investigation subject administered a pharmaceutical product and that does not have
any relationship with this treatment. An Adverse event can also states as an
unfavorable and unintended reaction (including an abnormal laboratory finding).
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Serious drug event
SAE is defined as an Adverse Event or Adverse Drug Reaction that is associated
with death, inpatient hospitalization (in case the study was being conducted on
out-patients), prolongation of hospitalization (in case the study was being
conducted on in-patients), persistent or significant disability or incapacity, a
congenital anomaly or birth defect, or is otherwise life threatening.
 Death
 Life threatening
 Result in hospitalization/ prolongs existing hospitalization
 Persistent or significant disability or incapacity
 Congenital abnormality or birth defect
 Medically significant

Serious, unexpected, suspected adverse reaction

 Serious
 Not included in product core safety data sheet
 Suspected link to the drug

Serious vs. severe

Severe is mostly used to account the intensiveness (severity) of a specific
event (as in mild, moderate, or severe pain) the event itself, however, may
be of comparatively minor medical significance (such as severe headache).

Serious is based on patient / event action or outcome criteria commonly

associated with events that pose to patient’s life threatening or functioning.

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Common practice in Safety Monitoring
Stakeholders in safety monitoring

Sponsor:

Clinical trial sponsors, normally pharmaceutical companies, are obligated for

development of the clinical trial protocol. Sponsor has designed Case Report
Forms (CRFs) as data collection tools. These tools are gradually based on
electronic data capture modules through the internet rather than the traditional
paper-based way. With access to all accumulating data, sponsors are authorized to
report key safety information to all stakeholders in a timely fashion.

Subjects:

Subjects are patients or healthy volunteers who agree to participate in a clinical

trial and have signed the Informed Consent Form. with else information, the
ICF gives important safety info so the subjects can take an informed decision on
whether to participate in the trial. The informed consent must be given
freely, without compulsion and must be based on a clear-cut understanding of
what participation concern involves. By giving consent, subjects give permission
to the investigators to collect health information and body measurements as
per the protocol. In a phase 1 clinical trial, when the drug is first used in healthy
humans, healthy volunteers are paid for their time and willingness to be exposed to
unknown risks.
Later phase trials are generally conducted in patients with the disease of interest,
and payments to these subjects for participation are disputatious.

Investigators:

Investigators are qualified individuals who are skilled and experienced to give
medical care to subjects registered in the trial. Investigators determine potential
subjects and educate them about the trial participation to see that if they can make
an informed decision. While the trial is ongoing, investigators are supposed to
follow up to the protocol treatment plan in delivering care.

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Institutional review board/ Ethics committee:

The Institutional Review Board (IRB), also well known as the ethics committee,
is charged with protecting the rights and welfare of human subjects enlisted to
participate in research protocols conducted under the endorsement of the
institution to which the IRB is affiliated.
The IRB reviews all clinical trial protocols concern human subjects that the
particular institution is involved with and has the authority to approve, disapprove
or require modifications to the protocols.

Data and Safety Monitoring Board:

The Data and Safety Monitoring Board (DSMB), also called data monitoring
committee (DMC), is an expert committee, independent of the sponsor, chartered
for one or more clinical trials. The mandate of the DSMB is to review on a regular
basis the accumulating data from the clinical trial to ensure the continuing safety of
current participants and those yet to be enrolled.

⚫ Safe use of medicine: It has be

⚫ Adverse drug reactions are
expensive
⚫ Promoting rational use of
medicine
⚫ Ensuring public confidence
⚫ Ethical concern: Not report
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Regulatory Authorities:

In the US, prior to the initiation of a first in human clinical trial, pharmaceutical
sponsors must submit an Investigational New Drug (IND) application to the FDA
as required by law. The FDA reviews the IND (typically within 30 calendar days)
for safety to ensure that research subjects will not be subjected to unreasonable
risk. The agency has several scientific committees that carry out the evaluation of
applications from pharmaceutical companies. In other parts of the world,
regulatory authorities will have similar mandates, but may operate under different
local laws and regulations.

Medical Community and Patients:

Clinical trials generate data that contribute to the body of knowledge about the
treatment and the disease that benefit the broader medical community and,
ultimately, the patients. Safety information of one product may be informative to
other practitioners using a similar class of agents.

Conclusion
The information to assess the safety profile of drug is given by pharmacovigilance.
Participation of professionals of health care country wide to report adverse drug
reaction or adverse events plays a major role in the success of
pharmacovigilance. Current progress in Pharmacovigilance is well-marked by
increase in use of databases to make the process more proactive and organized. It
must be in everyone’s priority to develop safe and effective medicines to patients.
During clinical trials monitoring patient safety is a critical component throughout
the drug development life- cycle. To ensure a systematic approach of safety
monitoring pharmaceutical sponsor must work proactively and collaboratively
with all stakeholders. For risk management plans, risk evaluation and
minimization strategies. There will be greater demand for more comprehensive
and innovative approaches that apply quantitative methods to collecting data
from all sources, ranging from the discovery and preclinical through with
clinical and post-approval stages, As the industry transitions from passive to

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active safety surveillance activities. The globalization of clinical trials has posed

extra challenges.

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