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PHARMACOTHERAPEUTICS

Pharmacotherapy relates to the use of drugs in the prevention and treatment of disease. It is
the “art and science” of applying drug-related didactic knowledge (pharmacodynamics and
pharmacokinetics) and making therapeutic decisions that are the most likely to benefit a
specific patient. Therefore, patient-related variables influence the design, implementation,
monitoring, evaluating, and adjusting of drug therapy; and the education and motivation of
patients to adhere to therapeutic recommendations.

To determine patient-related variables that will impact on the success or failure of drug
therapy, clinicians must gather patient-specific information, i.e., obtain complete and accurate
medical histories. From this information the clinician must develop a problem list and
identify the potential for drug and/or dosage related adverse effects in “at risk” individuals
such as the fetus, an infant, a child, a pregnant woman, a frail elderly, or one with liver and
kidney disease; and consider factors that may affect adherence.

“The treatment of pathologic conditions through the use of drugs”.

Clinical trial

A clinical trial is a research study that tests a new medical treatment or a new way of using an
existing treatment to see if it will be a better way to prevent and screen for diagnose or treat a
disease.

For any new drug to enter in clinical trial, it must pass preclinical studies. Preclinical studies
involve in vitro (i.e. test-tube or Laboratory) studies and trials on animal populations. Wide
range of dosages of the study drug is given to animal subjects or to an in-vitro substrate in
order to obtain preliminary efficacy, toxicity and pharmacokinetic information.

PHASES OF CLINICAL TRIAL

1. Pre-clinical studies

Pre-clinical studies involve in vitro (i.e., test tube or laboratory) studies and trials on animal
populations. Wide-ranging dosages of the study drug are given to the animal subjects or to an
in-vitro substrate in order to obtain preliminary efficacy, toxicity and pharmacokinetic
information and to assist pharmaceutical companies in deciding whether it is worthwhile to
go ahead with further testing.

2. Phase 0

 Phase 0 trials are usually the earliest trials of drugs in people

 Phase 0 studies usually only involve a small number of people and they only have a
very small dose of a drug
 less likely to have side effects

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 These studies aim to find out if a drug behaves in the way researchers expect it to
from their laboratory studies

3. Phase I

 Typically 20-80 healthy volunteers

 First in humans – normal volunteers except for oncology.
 Emphasis on drug safety
 Identify major side-effects, metabolism, routes of excretion
 Duration: about 1 year
 Sufficient information about pharmacokinetics and effects to permit design of well-
controlled Phase 2 studies
 About 70% that make it to this phase will pass
There are different kinds of Phase I trials:

1. SAD
Single Ascending Dose studies are those in which small groups of subjects are given a
single dose of the drug while they are observed and tested for a period of time. If they
do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in
line with predicted safe values, the dose is escalated, and a new group of subjects is
then given a higher dose. This is continued until pre-calculated pharmacokinetic
safety levels are reached, or intolerable side effects start showing up at which point
the drug is said to have reached the Maximum tolerated dose (MTD).

2. MAD
Multiple Ascending Dose studies are conducted to better understand the
pharmacokinetics & pharmacodynamics of multiple doses of the drug.

4. Phase II

 Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II
trials are performed on larger groups (20-300) and are designed to assess how well the
drug works, as well as to continue Phase I safety assessments in a larger group of
volunteers and patients.
 When the development process for a new drug fails, this usually occurs during Phase
II trials when the drug is discovered not to work as planned, or to have toxic effects.
 Phase II studies are sometimes divided into Phase IIA and Phase IIB.
 Phase IIA is specifically designed to assess dosing requirements (how much drug
should be given), whereas Phase IIB is specifically designed to study efficacy (how

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well the drug works at the prescribed dose(s)).Some trials combine Phase I and Phase
II, and test both efficacy and toxicity.

5. Phase III

 Phase III studies are randomized controlled multicenter trials on large patient groups
(300–3,000 or more depending upon the disease/medical condition studied) and are
aimed at being the definitive assessment of how effective the drug is, in comparison
with current 'gold standard' treatment.
 Because of their size and comparatively long duration, Phase III trials are the most
expensive, time-consuming and difficult trials to design and run, especially in
therapies for chronic medical conditions.
 It is common practice that certain Phase III trials will continue while the regulatory
submission is pending at the appropriate regulatory agency. While not required in all
cases, it is typically expected that there be at least two successful Phase III trials,
demonstrating a drug's safety and efficacy, in order to obtain approval from the
appropriate regulatory agencies (FDA (USA), TGA (Australia), EMEA (European
Union), etc.).
 Once a drug has proved satisfactory after Phase III trials, the trial results are usually
combined into a large document containing a comprehensive description of the
methods and results of human and animal studies, manufacturing procedures,
formulation details, and shelf life. This collection of information makes up the
"regulatory submission" that is provided for review to the appropriate regulatory
authorities in different countries.
 Most drugs undergoing Phase III clinical trials can be marketed under FDA norms
with proper recommendations and guidelines, but in case of any adverse effects being
reported anywhere, the drugs need to be recalled immediately from the market. While
most pharmaceutical companies refrain from this practice, it is not abnormal to see
many drugs undergoing Phase III clinical trials in the market.

6. Phase IV

 Phase IV trials involve the safety surveillance(pharmacovigilence) and ongoing

technical support of a drug after it receives permission to be sold(after approval under
FDA accelerated approval program)
 To compare the drug with other drugs already in the market
 To monitor long term drug effectiveness
 To monitor impact on patient quality of life
 To determine the cost effectiveness of a drug therapy relative to other traditional and
new therapies
 To observe if there is a reaction between the two drug
 To observe the impact on pregnant women

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 Harmful effects discovered by Phase IV trials may result in a drug being no longer
sold, or restricted to certain uses: recent examples involve cerivastatin (brand names
Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

CLINICAL TRIAL AND DRUG DEVELOPMENT

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Role of Clinical Trial in new drug development:

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for
studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or
trials, that are done in people. As the developers design the clinical study, they will consider what
they want to accomplish for each of the different Clinical Research Phases and begin the
Investigational New Drug Process, a process they must go through before clinical research begins.
The ultimate goal of drug development is to bring a new compound with proven therapeutic effect to
the market. In this context, the transition from preclinical research to clinical stages marks a critical
turning point, as it nears the new medicinal product to the market. With the promise of marketing
authorization, though far ahead in the road, hanging on the horizon, the approval of a clinical trial
usually attracts investors and leads to a respectable rise of the company shares. However, everything
comes at a price. Clinical trials are not without risks, and while the perspective of success is
encouraging, the crude reality is that most compounds fail before reaching the market. As explained in
previous entries, despite higher R&D expenditures, attrition rates are high and, what is worse, on the
rise.
Data collected between 1990 and 2004 show that the number of unsuccessful clinical trials has been
steadily increasing during the last years: from 30% to 50% at Phase 1, from 40% to 70% at Phase 2
and from 20% to nearly 50% at Phase 3. As a result, less than 10% of the drugs that enter clinical
trials end up being approved by regulatory agencies. Clinical trials are only a small part of the
research that goes into developing a new treatment. Drugs of the future, for example, first have to be
discovered or created, purified, described, and tested in labs (in cell and animal studies) before ever
reaching human clinical trials. Of all the substances that are tested in these early stages, very few are
promising enough to be tested in humans.
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead
compound has been identified through the process of drug discovery. It includes pre-clinical research
on microorganisms and animals, filing for regulatory status, such as via the United States Food and
Drug Administration for an investigational new drug to initiate clinical trials on humans, and may

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include the step of obtaining regulatory approval with a new drug application to market the drug.
Indeed, of every 5,000 cancer molecules identified in the laboratory, about 250 will enter pre-clinical
testing. Of this 250, fewer than 10 are tested in clinical trials and on average only one will be
approved by regulatory authorities. The process of bringing a new treatment from the research stage
(laboratory) to clinic is estimated to take between 10–13 years

TYPES OF CINICALTRIAL:

Treatment trials

Test experimental treatments, new combinations of drugs, or new approaches to surgery or

radiation therapy.

Prevention trials

Look for better ways to prevent disease in people who have never had the disease or to
prevent a disease from returning. These approaches may include medicines, vitamins,
vaccines, minerals, or lifestyle changes.

Diagnostic trials

Conducted to find better tests or procedures for diagnosing a particular disease or condition.

Screening trials

Test the best way to detect certain diseases or health conditions.

Quality of Life

Trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for
individuals with a chronic illness.

MONITORING CLINICAL TRIALS:

The purposes of trial monitoring are to verify that:

[Link] rights and well being of human subjects are protected.

[Link] reported trial data are protected.

[Link] conduct of the trial is in compliance with the currently approved

protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

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ROLE OF PHARMACISTS IN CLINICAL TRIALS

• Pharmacists have an active role to play in research and clinical trials first of all, we
provide the necessary facilities required for proper storage of the investigational
medicinal products (IMPs), either in the fridge or at controlled room temperature.
Regular temperature monitoring is ensured and recorded.
• It is also the pharmacist’s duty to ensure there is constant supply of IMPs at all times,
and that they are dispensed to patients accordingly. Patients are counselled on the
correct use of the IMPs in addition to any written information that is provided, such
as, Informed Consent Form or the Patient Information Leaflet.
• Besides managing clinical trials, oncology pharmacists often run research projects
that are aimed at improving outcomes in patients who receive medications, such as
chemotherapy or other supportive drugs like anti-emetics, blood growth factor
injections, etc.
• Drug Utilization Evaluations (DUEs) are research projects that are commonly
conducted by pharmacists. These projects aim to facilitate rational use of drugs
within our patients.
• In addition, pharmacists also conduct observational surveys that are aimed at
investigating patients’ or physicians’ perspectives and attitudes towards medications.

REGULARLY AFFAIRS IN CLINICAL TRIALS

IND (Investigational New Drug Application)

 FDA's role in the development of a new drug begins when the drug's sponsor has
screened the new molecule for pharmacological activity and acute toxicity potential in
animals, wants to test its diagnostic or therapeutic potential in humans
 The molecule changes in legal status under the Federal Food, Drug, and Cosmetic
Act and becomes a new drug subject to specific requirements of the drug regulatory
system
 Drug is to be the subjected to an approved marketing application before it is
transported or distributed across state lines
 IND- notice of claimed investigational exemption for a new drug must be filed with
regulatory body.

TYPES OF IND

 Investigator IND

 Submitted by a physician who both initiates and conducts an investigation, and under
whose immediate direction the investigational drug is administered or dispensed.
 Physician might submit a research IND to propose studying an unapproved drug, or
an approved product for a new indication or in a new patient population

 Emergency Use IND

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 Allows FDA to authorize use of an experimental drug in an emergency situation

 Does not allow time for submission of an IND in accordance with 21CFR , Sec.
312.23 or Sec. 312.34

 Treatment IND

 Submitted for experimental drugs showing promise in clinical testing for serious or
immediately life-threatening conditions while the final clinical work is conducted and
the FDA review takes place

Content of IND

In three broad areas:

 Animal Pharmacology and Toxicology Studies –

 An assessment as to whether the product is reasonably safe for initial testing in

humans
 Any previous experience with the drug in humans

 Manufacturing Information

 composition, manufacturer, stability, and controls used for manufacturing

the drug.

 Clinical Protocols and Investigator Information

 Commitments to obtain informed consent from the research subjects, to obtain review
of the study by an institutional review board (IRB), and to adhere to the
investigational new drug regulations.

Once the IND is submitted, the sponsor must wait 30 days before initiating any clinical trials.
During this time, FDA has an opportunity to review the IND for safety to assure that research
subjects will not be subjected to unreasonable risk.

Format of IND

 Cover sheet (Form FDA-1571)

 Name, address, telephone of sponsor

 Identification of phases
 Commitment not to begin CT until IND approval
 Commitment by IRB- Form 56
 Commitment for conducting CT- accordance with regulations
 Name, title – Monitor

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 Name, title – person(s) for reviewing

 Name, Address of CRO, if any
 Signature of sponsor

B. Table of contents
C. Introductory statement & general investigational plan
D. Investigators brochure
E. Study protocol
F. Investigator facilities & IRB data
G. Chemistry manufacturing & control data
H. Pharmacology & toxicology data
I. Previous human experience.

IND REVIEW PROCESS

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NDA (NEW DRUG APPLICATION)

The vehicle through which drug sponsors formally propose that the regulatory body approve
a new pharmaceutical for sale and marketing.
The data gathered during the animal studies and human clinical trials of an Investigational
new product become part of the NDA.

Features

• Once the application is submitted, the FDA has 60 days to conduct a preliminary
review which will assess whether the NDA is "sufficiently complete to permit a
substantive review”
• If everything is found to be acceptable, the FDA will decide if the NDA will get a
standard or accelerated review and communicate the acceptance of the application and
their review choice in another communication known as the 74-day letter
• A standard review implies an FDA decision within about 10 months

Goal of NDA

Provide enough information to permit FDA reviewers to establish the following:

 Safety & effectiveness of drug?

 Benefits overweigh risks?
 Is the drug’s proposed labelling (package insert) appropriate, and what should it
contain?
 Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the
drug and the controls used to maintain the drug’s quality adequate to preserve the
drug’s identity, strength, quality, and purity?

Classification of drugs in NDA

• Center of drug evaluation and Research(CDER) classifies new drug applications according
to the type of drug being submitted and its intended use:

1. New molecular entity

2. New salt of previously approved drug
3. New formulation of previously approved drug
4. New combination of two or more drugs
5. Already marketed drug product- Duplication (i.e., new manufacturer)
6. New indication (claim) for already marketed drug (includes switching
marketing status from prescription to OTC)
7. Already marketed drug product ( no previous approved NDA)

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 In US following 4 types of applications are submitted for approval of drug for marketing
depending upon the type and nature of the drug:

1. New Drug Application (NDA)

2. Biological License Application (BLA)
3. Application u/s 505(b)(2)-Paper NDA
4. Supplemental New Drug Application (SNDA)

NDA contents

1. Introduction
 Brief description of the drug and the therapeutic class to which it belongs
2. Chemical and pharmaceutical information
3. Animal Pharmacology
4. Animal Toxicology
5. Human/Clinical Pharmacology phase I
6. Therapeutic exploratory trials (Phase II)
7. Therapeutic confirmatory trials (Phase III)
8. Special Studies
o Geriatrics, pediatrics, pregnant or nursing women
9. Regulatory status in other countries
10. Prescribing information
11. Samples and Testing Protocol/s

General requirements for filing an NDA

The new (present) NDA regulations require that an application be submitted in two copies :

(A) Review copy.

 Summary
 The safety update reports

(B) archival copy.

 Chemistry,
 Manufacturing and controls.
 Nonclinical pharmacology andtoxicologyhuman pharmacokinetics and bioavailibility
microbiology
 clinical data
 Statistics
 Labeling
 Patent information

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NDA Regulations

1. Review Time Frames (21 CFR 314.100):

Within 180 days of receipt of an application, the FDA will review and issue an approval,
approvable, or not approvable letter. This 180-day period is called the review-clock” During
the review period an applicant may withdraw an application (21 CFR 314-65) and later
resubmit it.

2. Filing Time Frames (21 CFR 314.101):

 Within 60 days after the FDA receives an application, a determination will be made
whether the application may be filed.

 If FDA files the application, the applicant will be notified in written. The date of
filing will be the date 60 days after the FDA received the application.

 The date of filing begins the 180-days period of the review. If FDA refuses to file the
application, the sponsor will be given the opportunity to meet with FDA to discuss the
reasons why the application is not file able.

NDA review process

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ABBREVIATED NEW DRUG APPLICATION (A.N.D.A)

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An Abbreviated New Drug Application (ANDA) contains data submitted to FDA's Center for
Drug Evaluation and Research, Office of Generic Drugs, for review and ultimate approval of
a generic drug product.

 Once ANDA is approved, an applicant may manufacture and market the generic drug
product to provide a safe, effective, low cost alternative to the public.
 A generic drug product is the one that is comparable to an innovator drug product in
dosage form, strength, route of administration, quality, performance characteristics
and intended use.
All approved products, both innovator and generic, are listed in FDA's Approved Drug
Products with Therapeutic Equivalence Evaluations(Orange Book).
 Generic drug applications are termed "abbreviated" because they are generally not
required to include preclinical (animal) and clinical (human) data to establish safety
and effectiveness. Instead, generic applicants must scientifically demonstrate that
their product is bioequivalent (i.e., performs in the same manner as the innovator
drug).One of the ways that scientists use to demonstrate bioequivalence is to measure
the time taken by the generic drug to reach the bloodstream in 24 to 36 healthy
volunteers. This will gives them the rate of absorption or bioavailability of the generic
drug, which they can then compare to that of the innovator drug. The generic version
must deliver the same amount of active ingredients into a patient's bloodstream in the
same amount of time as the innovator drug.
 Use of bioequivalence as the base for approving generic drug products was
established by the "Drug Price Competition and Patent Term Restoration Act of
1984," also known as the WAXMAN-HATCH ACT. It is because of this Act that
there is the availability of less costly generic drugs into the market without conducting
costly and duplicative clinical trials. At the same time, the brand-name companies
(innovators) can apply for up to five additional years longer patent protection for the
new medicines that they developed to make up the time lost while their products were
going through FDA's approval process.
 Brand-name drugs are subject to the same bioequivalence tests as generics upon
reformulation.

Laws, Regulations, Policies and Procedures Code of Federal Regulations (CFR):

The following regulations apply to the ANDA process:

21CFR Part 314: Applications for FDA Approval to Market a New Drug or and Antibiotic
Drug.
21CFR Part 320: Bioavailability and Bioequivalence Requirements.
21CFR Part 310: New Drugs.

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Format & content

[Link] summary
[Link], Manufacturing and controls section
[Link] clinical pharmacology and toxicology section
[Link] pharmacokinetics & bioavailability section
[Link] and statically section
[Link] section

Difference between submission of NDA and ANDA

 A New Drug Application (NDA) requires the submission of :

[Link]-controlled clinical studies to demonstrate effectiveness

[Link] and clinical data to show safety
[Link] descriptions of manufacturing and packaging procedures
[Link] annotated labeling referencing all studies from which statements contained in the
package insert has been derived.

 In contrast to NDA, ANDA requires the submission of :

[Link] descriptions of the components

[Link], controls, packaging, and labeling (which can be in final, printed form), data
sufficient to assure the bioavailability or bioequivalence of the drug to be marketed. The
labeling should be prepared in accordance with that specified in DESI (Drug efficacy study
implementation)Notice or other Federal Register Notice. The manufacturing and controls
information to be provided are the same as required for a New Drug Application.

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Resources for ANDA Submissions

The following resources have been gathered to provide the legal requirements of an ANDA
application, assistance from CDER to help meet those requirements, and internal ANDA
review principles, policies and procedures.

Guidance Documents for ANDAs

The FDA has numerous guidances that relate to ANDA content and format issues.
Below is a list of some recent Guidances of interest.
Guidance documents to help prepare ANDAs are listed together in the following

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categories:
 Generics :

o Generics (Draft - Distributed for comment purposes only).

o Procedural Draft: Applications Covered by Section 505(b)(2). This provision permits
FDA to rely, for approval of an NDA, on data not developed by the applicant.

 Biopharmaceutics:

o Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -

General Considerations. This guidance should be useful for applicants planning to
conduct bioavailability (BA) and bioequivalence (BE) studies during the IND period
for an NDA, BE studies intended for submission in an ANDA, and BE studies
conducted in the postapproval period for certain changes in both NDAs and ANDAs.

 Drug Master Files: A Drug Master File (DMF) is a submission to the FDA that
may be used to provide confidential detailed information about facilities,
processes, or articles used in the manufacturing, processing, packaging, and
storing of one or more human drugs.
 Guidance for Industry: Changes to an Approved NDA or ANDA
 Refusal to Receive: Clarifies CDER's decisions to refuse to receive an
incomplete application.
 Inactive Ingredient Database: This database contains all inactive ingredients
present in approved drug products or conditionally approved drug products
currently marketed for human use.

ETHICAL ISSUES IN CLINICAL TRIALS

Core Principles of Clinical Trial Ethics

Three basic principles

• Justice
• Respect for Persons
• Beneficence and non-malaficence
- maximize benefits
- minimize harms and wrongs
- do no harm

PRINCIPALS OF ETHICAL RESEARCH

Essential Elements of Ethical Research

 Balance of Risks and Benefits

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• Minimize risks to subjects

• Maximize benefits to individual subjects and to society
• Benefits should be proportional to or outweigh risks.
 Non-maleficence and Beneficence

 Non-Exploitation

 Provide remuneration to test subjects

 Inform subjects about all potential side effects and risks
 Ensure ample compensation for accidental injury
 Insurance, Rehabilitation, Life-long support

 Privacy & Confidentiality

 Inform subjects about the extent to which personal info would be disclosed
 Do not divulge identity and records of test subjects as far as possible
 Do not Provide information which will allow identity to be guessed

 Precaution

 Design the study such that risks to the subjects is minimized

 Ensure there are no adverse side effects

 Balancing principles

• Balancing the need for a rigorous design with the obligation to maximize benefits and
minimize harms
– Equipoise
– Randomization
– Choice of control
– Example: Randomized Controlled Trials

 Clinical Equipoise

“Genuine uncertainty within the scientific community...” about the

comparative merits of intervention ‘A’ and ‘B’

 Competence

 Professional Competence
 All personnel involved in trials should be trained and qualified
 A strong sense of ethics essential for personnel

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 Transparency & Accountability

 No aspect of the study should be hidden, Except for privacy reasons

 Prior disclosure of all conflicts of interest
 Maintain permanent records of all research data and notes
 Fix responsibility for the study and its outcomes
 Burden of Proof is always with those who conduct the trial

 Patient rights

 Use in the country after approval

- drug is marketed only in the affluent countries
- insist on drug would be released at a price that is reasonable

 Vulnerability of patients in a trial

i. Money paid
ii. Health care to the family
iii. Free medicines at the hospital
iv. Free diagnostic tests
v. Counter to the cardinal principle of autonomy
vi. Not be compelled or unfairly enticed to participate
vii. Truly a free choice?

INFORMED CONSENT

 Subjects should consent to participate in the study

 Subjects should be fully informed about the objectives of the study
 Subjects have the right to withdraw at any point during study

No refund of remuneration should be demanded on early withdrawal

Informed Consent Form (ICF)

• A well-documented informed consent is the hallmark of any ethical research work.

• It is the responsibility of the investigator/researcher to obtain the informed consent of the
prospective participant or in the case of an individual who is not capable of giving informed
consent, the consent of a legal guardian.
• Informed consent respects individual's autonomy to participate or not to participate in
research.
• Adequate information about the research is given in a simple and easily understandable
vernacular language in a document known as the ‘Participant/Patient Information Sheet’
attached along with the ‘Informed Consent Form (ICF)’.

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ETHICS COMMITTEE

Independent review of clinical research ensures the public that investigator biases have not
distorted the approach, that ethical requirements have been fulfilled, and that subjects will not
be exploited.

 Minimize conflict of interest

 Public Accountability

Members of Ethics committee (E.C)

1. Chair person, preferably from outside the institution

2. 1-2 basic medical scientists
3. 1-2 clinicians from various institutes
4. One legal expert or retired judge
5. One social scientist
6. One philosopher or ethicist
7. One lay person from community
8. Member secretary

Responsibilities of EC

• Review of proposed research before the commencement of the research

• Independent, competent and timely review of all ethical aspects of the project proposals
received.
• Safeguard the dignity, rights, safety and wellbeing of all actual or potential research
participants
• The appropriateness of the study design in relation to the objectives of the study.
• The statistical methodology (including sample size calculation).
• The potential for reaching sound conclusions with the smallest number of research
participants should be assessed.
• The EC should also look into matters like Informed consent process.
• Qualifications of Principal investigator and supporting staff, adequacy of infrastructure and
facilities,
• Risk benefit ratio, plans to maintain confidentiality and plans for post trial access and
compensations.
• They also need to ensure that there is regular evaluation of the ongoing studies.
• EC is the most important check point for promoting ethical research in the country.

NUREMBERG TRIALS

• Nazi experiments

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– Experimental starvation
- Induced gangrene
– Low barometric pressure
– Induced hypothermia
– Induced burns and wounds

Characteristics

– Conducted without consent of participants

– Caused unnecessary pain, suffering and death
– Absence of benefits for the participants
– Lack of adequate scientific rationale

Nuremberg Code

• The Nuremberg Code is a set of research ethics principles for human experimentation set as
a result of the Subsequent Nuremberg Trials at the end of the Second World War.
• The ten points of the Nuremberg Code
The ten points of the Nuremberg Code
[Link] voluntary consent of the human subject is absolutely essential.
[Link] experiment should be such as to yield fruitful results for the good of society,
unprocurable by other methods or means of study, and not random and unnecessary in
nature.
[Link] experiment should be so designed and based on the results of animal experimentation
and a knowledge of the natural history of the disease or other problem under study that
the anticipated results will justify the performance of the experiment.
[Link] experiment should be so conducted as to avoid all unnecessary physical and mental
suffering and injury.
[Link] experiment should be conducted where there is an a priori reason to believe that death
or disabling injury will occur; except, perhaps, in those experiments where the
experimental physicians also serve as subjects.
[Link] degree of risk to be taken should never exceed that determined by the humanitarian
importance of the problem to be solved by the experiment..
[Link] preparations should be made and adequate facilities provided to protect the
experimental subject against even remote possibilities of injury, disability, or death.
[Link] experiment should be conducted only by scientifically qualified persons. The highest
degree of skill and care should be required through all stages of the experiment of those
who conduct or engage in the experiment.
[Link] the course of the experiment the human subject should be at liberty to bring the
experiment to an end if he has reached the physical or mental state where continuation of
the experiment seems to him to be impossible.
[Link] the course of the experiment the scientist in charge must be prepared to terminate
the experiment at any stage, if he has probable cause to believe, in the exercise of the

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good faith, superior skill and careful judgment required of him that a continuation of the
experiment is likely to result in injury, disability, or death to the experimental subject

• "The voluntary consent of the human subject is absolutely essential"

THE DECLARATION OF HELSINKI

• 1964 - Adopted by the 18th World Medical Assembly (latest version 2008)
• A notable change from the Nuremberg Code was a relaxation of the conditions of consent
• Obtain consent 'if at all possible‘
• Introduced the concept of oversight by an 'independent committee” Or ethics committees
• "All protocols must be submitted to an ethics committee for review, which must be
independent of the investigator, the sponsor or any other kind of undue influence".

BELMONT REPORT

• National Research Act/Belmont Report 1979

• The report established three tenents of ethical research,
• respect for persons,
• beneficence and
• justice

The three fundamental ethical principles for using any human subjects for research are:
1. Respect for persons: protecting the autonomy of all people and treating them with
courtesy and respect and allowing for informed consent. Researchers must be truthful
and conduct no deception;
2. Beneficence: The philosophy of "Do no harm" while maximizing benefits for the
research project and minimizing risks to the research subjects; and
3. Justice: ensuring reasonable, non-exploitative, and well-considered procedures are
administered fairly — the fair distribution of costs and benefits to potential research
participants — and equally.

Tuskegee Syphilis Study

• "399 black men thought to have syphilis were recruited and followed to determine the
course of the disease (what would happen to them).
• Penicillin was known to be an effective treatment for syphilis by about 1947.
• The subjects were not informed of what was being studied or of the treatment alternatives
available.

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No Question Marks

1. Define Pharmacotherapeutics. 2

2. What is clinical trial and preclinical study? 2

3. What are the types of Phase I trial? 2

4. Describe about the role of clinical trial in drug development 2/3

5. Pen down the types of cinical trial 2

6. Write down the role of pharmacists in clinical trials 2

7. How will you monitor clinical trial? 2

8. Write down the types of IND 2

9. What are the key features and goals of NDA? 2/3

10. Describe about the general requirements for filing an NDA. 2/3

11. Write a short note on NDA regulation. 3

12. Enlist the format & content of ANDA 2

13. Write down the difference between submission of NDA and ANDA 2

14. Illustrate investigational new drug application with details process. 5

15. Briefly describe about the phases of clinical trial. 5

16. Write a short note on new drug application 4

17. Demonstrate the process of ANDA regulation 5

18. What are the resources for ANDA Submissions? 4

19. What types of ethical issues are necessary in clinical trials? 5

20. Write down the features of Informed Consent Form (ICF) 3

21. Who are the members and what are the Responsibilities of EC? 4

22. Write a short note on Nuremberg Code, Declaration of helsinki, belmont 7

report.

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Introduction To Clinical Trial