DRUG DISCOVERY

AND DEVELOPMENT
CLINICAL TRIALS
Key points
 Drug development follows a
structured sequence of different
steps ensuring safety and aiming at
therapeutic progress.
 The process is structured by the
successive conduct of phase I, II, PHASES OF CLINICAL TRIALS
and III clinical trials.
 Appropriate interpretation of I. PHASE 0: CLINICAL TRIAL
clinical trial results is paramount  Phase 0 implicates investigative,
 The forms and the methods of drug first-in-human (FIH) trials conducted
development are evolving in the era according to FDA guidelines.
of targeted agents .  Phase 0 trials besides being termed
as human microdose studies, have
Clinical Trial single sub-therapeutic doses given
 A clinical trial is a research study to 10 to 15 volunteers and give
conducted in patients, with patients, pharmacokinetic data or help with
and for patients, to answer specific imaging specific targets without
questions about their treatment, exerting pharmacological actions.
diagnosis, or follow-up.  Pharmaceutical industries perform
 Clinical trials (also called Phase 0 studies to pick which of
interventional studies) are used to their drug applicants has the
determine whether new biomedical preeminent pharmacokinetic
or behavioral interventions are both parameters in humans.
safe for patients and effective at
treating their disease II. PHASE 1: SAFETY AND DOSAGE
 Non-interventional clinical study is a  Phase I trials are the first tests of a
study where the medicinal drug with a lesser number of
product(s) if given, are prescribed healthy human volunteers.
as per current practice.  In most cases, 20 to 80 healthy
 The objectives may be to collect volunteers with the
additional data relating to the disease/condition participate in
disease or its treatment such as Phase 1.
cognitive function and long term  Patients are generally only used if
toxicity profile. the mechanism of action of a drug
 Drug development process is a indicates that it will not be tolerated
generic term for the process by in healthy people.
which an investigational drug  Phase 1 studies are closely
advances from preclinical studies to monitored and collect information
clinical trials, through to approval about Pharmacodynamics in the
for marketing after review by human body.
regulatory agencies.  Researchers adjust dosage
regimens based on animal study
data to find out what dose of a drug
can tolerate the body and what are
its acute side effects.
 As a Phase 1 trial continues,
researchers find out:
 the research mechanism of
action,
 the side effects accompanying
with increase in dosage
 information about effectiveness.
 Almost 70% of drugs travel to the
next phase
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AND DEVELOPMENT
III. PHASE 2: EFFICACY AND SIDE New Drug Application
EFFECTS  A New Drug Application (NDA)
 Phase II trials are conducted on expresses the full story of a drug
larger groups of patients (a few molecule.
hundred) and are aimed to evaluate  Its purpose is to verify that a drug is
the efficacy of the drug and to safe and effective for its proposed
endure the Phase I safety use in the people studied.
assessments.  A drug developer must include all
 These trials aren‘t sufficient to about a drug starting from
confirm whether the drug will be preclinical data to Phase 3 trial data
therapeutic. in the NDA
 Phase 2 studies provide additional  Developers must include reports on
safety data to the researchers. all studies, data, and analysis.
 Researchers use these data to:
 refine research questions Besides clinical trial outcomes,
 develop research methods developers must include:
 design new Phase 3 research  Proposed labeling
protocols  Safety updates
 Around 33% of drugs travel to the  Drug abuse information
next phase.  Patent information
 Most prominently, Phase II clinical  Institutional review board
studies aid to find therapeutic doses compliance information
for the large-scale Phase III studies.  Directions for use

IV. PHASE 3: EFFICACY AND ADVERSE FDA Review

DRUG REACTIONS MONITORING  Once FDA obtains a complete NDA
 Researchers plan Phase 3 studies the FDA team of review may require
to prove whether a product deals an about 6 to 10 months to take a
action benefit to a specific people pronouncement on whether to
or not. approve the NDA.
 Sometimes known as pivotal studies,  If Once FDA obtains a incomplete
these studies comprise 300 to 3,000 NDA then FDA team of review will
volunteers. refuse the NDA.
 Phase 3 studies deliver most of the  If the FDA governs that a drug has
safety data. been revealed to be safe and
 The previous study might not be effective for its proposed use, it is
able to detect less common side then essential to work with the
effects. However phase 3 studies developer to upgrade prescribing
are conducted on a large number of information.
volunteers and longer in duration,  This is denoted as “labeling”
so the results are more probable to  Labeling precisely defines the basis
detect long-term or uncommon side for approval and direction on how to
effects. use the drug.
 Around 25-30% of drugs travel to  However, the remaining issues
the next phase of clinical research. require to be fixed before the drug
 If a drug developer has data from its to be approved for marketing. In
previous tests, preclinical and other cases, FDA needs additional
clinical trials that a drug is safe and studies.
effective for its intended use, then  At this situation, the developer can
the industry can file an application choose whether to continue further
to market the medicine. development or not.
 The FDA review team  If a developer distresses with an
comprehensively inspects all FDA decision, there are tools for
submitted data on the drug and official appeal.
makes a conclusion to approve or
not to approve it.
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V.
AND DEVELOPMENT
PHASE 4: POST-MARKET DRUG The Code, issued in 1947,
SAFETY MONITORING drafted some central ethical
 Phase 4 trials are conducted when unquestioned principles that were
the drug or device has been reinforced afterward in subsequent
approved by FDA. declarations and laws, such as the
 These trials are also recognized as principle of autonomy, which was
post-marketing surveillance brilliantly crystalized at the first
involving pharmacovigilance and statement of the Code:
continuing technical support after
approval. "The voluntary consent of the human
 There are numerous observational subject is essential. This means that the
strategies and assessment patterns person involved should have legal
used in Phase 4 trials: capacity to give consent, should be so
 to evaluate the efficacy situated as to be able to exercise free
 cost-effectiveness power of choice, without the
 safety of involvement in real- intervention of any element of force,
world settings fraud, deceit, duress, overreaching, or
 Phase IV studies may be required other ulterior form of constraint or
by regulatory authorities (e.g. coercion; and should have sufficient
change in labeling, risk knowledge and comprehension of the
management/minimization action elements of the subject matter involved
plan) or may be undertaken by the as to enable him to make an
sponsoring company for understanding and enlightened
competitive purposes or other decision."
reasons.
 Therefore, the true illustration of a The Declaration of Helsinki is a
drug‘s safety essentially requires critical document in medical research
months and even years that mark up ethics, adopted in 1964 by the World
a drug‘s lifespan in the market. Medical Association (WMA) in response
 FDA reviews reports of to the ethical failings of past research,
complications with prescription and including those revealed during the
OTC drugs, and can decide to add Nuremberg Trials.
precautions to the dosage or
practice information, as well as Institutional Review Boards
other events for more serious (IRBs) are critical bodies established to
adverse drug reactions. review and oversee research involving
human subjects to ensure ethical
INFORMED CONSENT standards and participant protections.
Informed consent is a process in Created in response to past unethical
which a participant in any clinical research practices, IRBs are now legally
investigation is informed about the required in many countries, especially
details of the study and any potential for studies funded by government
risks and benefits. agencies or conducted within
institutions like universities and
It is an ethical and legal hospitals.
requirement for any research involving
human participants. Purpose:
 to protect the rights, safety, and
The Nuremberg Code, developed welfare of participants in research,
after World War II in response to the ensuring compliance with both
Nazi medical experiments, established ethical and regulatory guidelines.
for the first time the principle that  Informed consent is one of the most
informed consent is essential for ethical important aspects of research
medical research. ethics.
 Regulations requiring informed
consent have been promulgated to
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AND DEVELOPMENT
protect the human subjects For ethical and valid consent, the
participating in clinical research. subject's decision has to be a voluntary
 The basic ethical principle behind one.
informed consent legalities is to The voluntarism of an individual
protect the autonomy of human may be affected by various factors such
subjects which states that welfare as:
and interests of a subject  intellectual and emotional maturity
participating into clinical research to make a complex decision
are always above the society's  illness-related considerations such
interests and welfare. as:
 Medical research directed towards  psychological effects of
treatment advances for society's dreaded or incurable diseases
benefit and betterment can never or severe mental disorders
be built on sacrificing the rights and  religious and cultural values and
health of research participants. beliefs such as:
 catholic beliefs regarding moral
There are two distinct stages to a action at the beginning and end
standard consent process for of life
competent adults:
The voluntarism of an individual
 Stage 1 (giving information): the may be affected by various factors such
person reflects on the information as:
given; they are under no pressure to  relationship with caregiver
respond to the researcher including economic and care
immediately. burden.
 undue influence or coercion for
 Stage 2 (obtaining consent): the research participation.
researcher reiterates the terms of
the research, often as separate II. INFORMATION DISCLOSURE
bullet points or clauses; the person Information disclosure refers to
agrees to each term (giving explicit providing information that is necessary
consent) before agreeing to take for a patient to make an informed
part in the project as a whole. decision and is one of the essential
Consent has been obtained. elements of valid informed consent.

ELEMENTS OF INFORMED CONSENT For a valid consent, information

provided to a research subject should
For ethically valid and real include, but not limited to:
informed consent, these critical  health condition for which the
elements are required to be essentially research is proposed
employed and adequately present while  nature and purpose/reason of the
informed consent is expressly sought study
from a research subject:  study treatment or intervention and
I. Voluntarism experimental procedures
II. Information disclosure  probable risks and benefits
III. Decision-making capacity associated with research
participation
I. VOLUNTARISM  nature of illness and possible
is defined as the ability of an outcome if the condition is left
individual to judge, freely, independently, untreated
and in the absence of coercion, what is  availability, risks, and benefits of
good, right, and best subjected to alternative treatments
his/her situation, values, and prior  right to withdraw at any time
history.  any other information seems
necessary for an informed decision
to be taken by the patient
 DRUG DISCOVERY
AND DEVELOPMENT  appreciate his/her situation
The forgoing information realistically
disclosure is aimed at enabling the  appreciate his/her health condition
patients to make an informed, rational,  consequences if left untreated
and logical decision in the light of their  that the purpose of study is
cultural, psychological, and social research and not the treatment
values and beliefs.  consequences of participation in
research study
III. DECISION-MAKING CAPACITY
The ability to understand and Competency or competence, a
appreciate the nature and related notion, should not be confused
consequences of health decisions and with decisional capacity; however, both
to formulate and communicate decisions describe an individual's ability to make
concerning health care. decisions.
The decisional capacity of an Competency is an individual's
individual depends on his/her cognitive legal standing to make healthcare
abilities and voluntarism and is decisions or it is a legal determination
adversely affected by cognitive made by a court of law.
impairment or compromised voluntarism. For example, a 15-year-old
patient may possess the capacity of
Decisional capacity comprises making decision for him- or herself, but
four elements or abilities: may remain incompetent from legal
 understanding the information point of view.
 appreciation of the situation
 rational manipulation of the OBTAINING INFORMED CONSENT
information Regulations and guidelines
 communicating or evidencing a governing clinical research have
choice provided guidance on how and in what
manner the informed consent has to be
A capable individual must be obtained from study subjects in those
able to have a factual understanding of various situations.
the information provided to him/her;
however, there is much less clarity on: OBTAINING INFORMED CONSENT
 what degree or extent of
understanding is required to be
capable.
 how much information, as a
threshold value, must be
understood by the individual to be
considered as 'enough' factual
understanding.

Researchers are advised to

ensure that the patient has:
 at least, understood the purpose of
the research
 risks associated with the research
intervention
 obligations and consequences of
research participation
 his/her right to withdraw consent
any time during the study

For a subject to be considered

capable of making healthcare decisions,
he/she must be able to:
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AND DEVELOPMENT
INFORMED CONSENT INITIATION 3. Collection of valid scientific
evidence is necessary to determine
the safety and effectiveness of the
intervention;
4. Obtaining informed consent is not
feasible because the subjects are
not able to give their informed
consent as a result of their medical
condition,
5. The intervention must be
administered before consent can be
obtained from the subject's legally
authorized representative;
6. 6. There is no reasonable way to
identify prospectively individuals
likely to become eligible for
participation;
7. Participation in the research holds
out the prospect of direct benefit to
the subjects; and
8. The clinical investigation could not
practicably be carried out without
the waiver.

Medical emergency refers to

circumstances where a patient is in life-
threatening situation requiring urgent
medical treatment, and where the time
required for information disclosure may
cause potential harm to the patient.
EXCEPTIONS TO INFORMED CONSENT
As a rule of thumb, informed
Emergency research involves
consent has to be obtained from each
the most vulnerable subject population,
study subject, before they participate in
i.e. subjects with no capacity to control
the research.
what happens to them and no capacity
to consent, in a setting where the
However, there are certain
emergency circumstances require
situations, such as emergency research
prompt action, and generally provide
and therapeutic privilege, which are
insufficient time and opportunity to
exceptions to this general rule wherein
locate and obtain consent from subject's
information disclosure to the subject
LAR.
may be shortened appropriately in part
or full.
Therapeutic privilege refers to a
It is noteworthy that in these
situation or practice whereby an
conditions patients still retain the right
investigator or a physician may not
to refuse to participate in the research.
reveal, usually a part of, medical
information to a patient related to the
According to this guidance, all of
diagnosis or treatment of the disease
the following conditions must be present
condition when they believe that
for a study to qualify to be conducted as
disclosure of such information would
emergency research:
cause a potential harm to physical,
1. The human subjects are in a life-
mental, or social well-being of the
threatening situation that
patient, and the harm is as serious as is
necessitates urgent intervention;
medically contraindicated.
2. Available treatments are unproven
or unsatisfactory;
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AND DEVELOPMENT
WRITTEN INFORMED CONSENT
PROCESS

A written process is used where:

 Reading and signing forms is not
problematic.
 The research is complex or has
multiple stages.
 First access to the research
participants is by providing written
information.

*see attached document

ORAL INFORMED CONSENT PROCESS

An oral consent process is

where the researcher and participant
have a conversation to give information
and obtain consent. There is no paper
form to sign.

It is normally used:
 where literacy is a problem
 where there are cultural or political
concerns with signing contract-like
documents
 where either the researcher and/or
the participant could be put at risk
by the existence of a paper record
 where time for consent is limited,
e.g. a chance interaction between
researcher and participant
(although you should not use an oral
process merely to correct poor
planning of research)
 for research conducted via remote
video conferencing software

When obtaining oral consent,

please ensure you are recording the
consent process either using a
recording device (for example audio
recorder if you are conducting an
interview that needs to be recorded) or,
if participants do not agree to audio
recording or if using or keeping audio
records is unsafe, by using a researcher
record of oral consent template or
completing a written consent form on
their behalf.