Drug development process

Drug Development Process:

A drug has to pass through multiple steps before reaching in to the market. And the whole
process is called the drug development process.

● Research for a new drug begins in a laboratory,

● Then it gets tested in animals(preclinical study).
● If it is found to be safe and effective, IND approval is obtained before testing in humans.
● Then the drug gets tested in humans. (phase0,1,2,3) (clinical study)
● After phase 3, NDA approval is obtained for the drug to be released into the market
● In the market, the phase 4 studies happens(post marketing surveillance).

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PRE-CLINICAL TRIALS:

● It is the animal testing done before testing a drug on people. Researchers must find out if
it is safe and effective.
● The main goals of preclinical studies are to determine a safe starting dose to be used in
humans first and assess the potential toxicity of the product
● Preclinical studies are done in accordance with GLP(good laboratory practices)

Steps in preclinical studies includes;

a) formulation development,: Formulation development assesses the best way to prepare a
drug. considering the factors such as solubility, frequency and mode of administration, stability
of the formula, and palatability are all assessed.

b) pharmacology: The pharmacology stage assesses the pharmacodynamics and

pharmacokinetics of a drug including ADME – Absorption; Distribution; Metabolism; and
Excretion

c) safety pharmacology; Safety plays a huge part in the preclinical stage of pharmaceutical
product development.

● It identifies potential undesirable pharmacodynamic effects of the drug on physiological

function. ie, it tries to evaluate PK-PD relationship of a drugs adverse effect.
● Researchers can use computer modelling and simulations to an extent, and also uses
animals to assess safety. They will assess the pharmacodynamics of the drug on many
organ systems such as: the cardiovascular, respiratory systems, renal functionality etc

d) toxicology studies; Preclinical toxicity studies involve testing the newly screened compounds
to determine the safety of that compound in at least two different animal species

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Based on the time & duration of the study and its objectives, the preclinical toxicity studies can
be classified into

● Acute toxicity studies/Single dose study: Single high doses are given to small group of
animals and are observed for mortality for 1-3 days. The dose which kills 50% of animal
is LD50 (lethal dose 50)
● Sub-acute toxicity studies(repeated dose study); Repeated doses are given and adverse
effects following a treatment period of 2–4 weeks' duration is observed
● Sub-chronic toxicity studies; (Repeated dose study): adverse effects occurring after the
repeated or continuous administration of a test sample for up to 90 days is observed
● Chronic toxicity studies(repeated dose study): test compound is administered for more
than 90 days and is evaluated for safety on long term usage.

Based on the number of doses administered, the toxicity studies can be classified into;

● single-dose toxicity studies (acute toxicity study)

● repeated dose toxicity studies (sub-acute, sub-chronic, and chronic toxicity studies).

Similarly, based on the area of exposure of interventional drugs in animals, toxicity studies can
be divided into

● systemic toxicity studies (comprises of acute, sub-acute, chronic, sub-chronic, and

reproductive toxicity studies) and
● local toxicity studies (Dermal toxicity, Ocular toxicity studies).

CLINICAL TRIAL

Clinical trials are research studies that test a medical, surgical, or behavioral intervention in
humans. It begins only after receiving IND approval from the authorized body.

● These trials are the primary way that researchers determine if a new form of treatment or
prevention, such as a new drug, diet, or medical device (for example, a pacemaker), is
safe and effective in people
● Often, a clinical trial is designed to learn if a new treatment is more effective or has less
harmful side effects than existing treatments.

Requirements to conduct Clinical trial:

Considering the safety and risk of the participants, Clinical trials must comply with many
requirements that do not apply to other types of research.

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Drug development process

1. IND approval; physician might submit a research IND to FDA to propose studying an
unapproved drug, or an approved product for a new indication or in a new patient
population.
● There are 3 types of IND:

a) An Investigator IND is submitted by a physician who both initiates and conducts an

investigation, and under whose immediate direction the investigational drug is administered or
dispensed

b) Emergency IND: The use of a test article on a human subject in a life-threatening situation in
which no standard acceptable treatment is available and where there is not sufficient time to
obtain IRB (institutional review board) approval.

Eg: Approval of covid vaccines were of this category.

c) Treatment IND; Itis 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. It is a single subject IND. For ex; A physician is caring for an
individual patient with life threatening disease who may benefit from the use of an
investigational drug can be applied for treatment IND when no other options are available for
him.

2. Guideline; (ICH GCP, ICMR and Schedule Y)

Clinical trial must be conducted in accordance with ICH-GCP (International Council for
Harmonisation- Good Clinical Practice), ICMR and schedule Y guidelines.

● Schedule Y is a schedule in the Drugs and Cosmetics Act of India that provides
guidelines for the conduct of clinical trials of new drugs in India.
● The ICMR National Ethical Guidelines document sets the standards for the ethical
requirements to be followed in biomedical research in India. It is expected that all
biomedical and health research in the country should follow this guidance which will go a
long way towards improving the quality and outcomes of research
● Good Clinical Practice (GCP) is an international ethical and scientific quality standard for
the design, conduct, performance, monitoring, auditing, recording, analyses and reporting
of clinical trials. It also serves to protect the rights, integrity and confidentiality of trial
subjects.

ICH-GCP PRINCIPLES:

There are 13 core principles of ICH-GCP and they are as follows:

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1. Clinical trials should be conducted in accordance with ethical principles that have their origin
in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory
requirements.

2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
anticipated benefit for the individual trial subject and society. A trial should be initiated and
continued only if the anticipated benefits justify the risks.

3. The rights, safety and well-being of the trial subjects are the most important considerations
and should prevail over interest of science and society.

4. The available non-clinical and clinical information on an investigational product should be

adequate to support the proposed clinical trial.

5. Clinical trials should be scientifically sound, and described in clear, detailed protocol.

6. A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/ independent ethics committee (IEC) approval/favorable
opinion.

7. The medical care given to, and medical decisions made on behalf of subjects should always be
the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective tasks.

9. Freely given informed consent should be obtained from every subject prior to clinical trial
participation.

10. All clinical trial information should be recorded, handled, and stored in a way that allows its
accurate reporting, interpretation and verification.

11. The confidentiality of records that could identify subjects should be protected, respecting the
privacy and confidentiality rules in accordance with the applicable regulatory requirements.

12. Investigational products should be manufactured, handled and stored in accordance with
applicable Good Manufacturing Practice (GMP). They should be used in accordance with the
approved protocol.

13. Systems with procedures that assure the quality of every aspect of the trial should be
implemented.

3. Institutional Review Board (IRB) or Independent Ethics Committee

(IEC); It is an independent body with medical, scientific, and non-scientific members, whose
responsibility is to ensure the protection of the rights, safety and well-being of human subjects

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involved in a trial by reviewing, approving, and providing continuing review of trial protocol and
amendments and of the methods and material to be used in obtaining and documenting informed
consent of the trial subjects. Clinical trials can be done only after receiving approval from IEC.

4. Registration of Clinical trial in clinical trial registry.

5. Protocol:

This is a document which describes every step of a clinical trial. (like a detailed cooking recipe
enlisting each step of cooking). Protocol must be in accordance with GCP guidelines which are
accepted internationallyu and are published by the International Council for Harmonisation
(ICH). It basically includes;

● the types of patients who may enter the study

● the schedules of tests and procedures
● the drugs involved
● the dosages, or amount of the drug
● the length of the study
● what the researchers hope to learn from the study.
● How are they going to use the collected datas
● Reasons why the clinical trial may be stopped
● etc

According to the ICH Good Clinical Practice guidelines, a protocol should include the following
topics:

● Title Page (General Information)

● Background Information
● Objectives/Purpose
● Study Design
● Inclusion and Exclusion of Subjects
● Treatment of Subjects
● Assessment of Efficacy
● Assessment of Safety
● Adverse Events
● Discontinuation of the Study
● Statistics
● Quality Control and Assurance
● Ethics
● Data handling and Recordkeeping
● Publication Policy
● Project Timetable/Flowchart
● References
● Supplements/Appendices

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Drug development process

Phases of Clinical trial;

1. Phase 0: Microdose study

● Not a mandatory phase

● Study of a drug at very low doses(1/100th of actual dose) given for a short
duration(<7days) is given to identify preliminary Pharmacokinetic information and the
precise dose to be used in phase 1 study is called Microdose study.
● 10-15 healhy volunteer

2. Phase 1: Safety and tolerance

● Assess safety, tolerability, PK and PD

● No blinding and is open labelled
● Dose escalation studies are done and Safe clinical dosage in human is fixed at this stage.
● Maximum tolerance dose(MTD) is found at this stage by escalating the treatment dose
until the dose limiting toxicity(DLT) is reached.
● 25-100 healthy volunteers: subject receive no therapeutic benefit by participation.
● Duration- 6-12 months

3. Phase 2: Therapeutic exploratory trial

● Safety, efficacy and drug interaction is mainly studied.

● Dose response determination is done
● Determine dose regimen, frequencies and dosage forms.
● 100-300 patients who are sick are included in the study.
● Duration: 6 months to several years

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Drug development process

● phase 2 is divided into 2:

a) phase 2a: Designed to assess dosing requirements

b) Phase 2b: Designed to study efficacy.

4. Phase 3: Therapeutic confirmatory trial

● It is done to establish efficacy of a drug against existing therapy in large number of

patients, method of usage and to collect safety data.
● Determine optimal dose regimen to be used in general population
● large scale, multicentered, randomised controlled trial.
● 100-3000 patients who are sick are included in the study
● Duration: >5years
● it is divided into 2:

a) Phase 3a; Prior to NDA and generates data on safety and efficacy

b) Phase 3b; After obtaining NDA but before it reaches in the market.

5. Phase 4 study: Post marketing surveillance

● After phase 3, NDA approval is obtained from DCGI to release drug into the market.
Phase 4 studies are carried out in general population when the drug is in market.
● Studies continues to collect datas of drugs safety and efficacy and side effects in a larger
general population who takes this drug when the doctor prescribed. Doctor follow up
with the patient and collects data which is shared with the manufacturer.
● Helps to detect rare ADRs and drug interactions, and identification of new indications
● It has no fixed duration and is conducted in variety of populations.
● These are observational and non experimental in nature.
● Periodic safety update reports(PSUR) has to be submitted by the manufacturer every 6
months for 2 years, then annually for next 2 years during phase 4(ie,after marketing
approval)

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Drug development process

● Harmful effects discovered at this stage may result ina drug being no longer sold or
restricted to certain uses

DEFINITIONS:

1. Inclusion criteria; It specify the characteristics required for a person to include him in the
study, such as stage of disease or specific pathophysiological characteristic
2. Exclusion criteria; It specify characteristics that disqualify patients from participation

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3. Placebo: A placebo is an inactive pill, liquid or powder that looks exactly like the
experimental treatment but has no effect on the body. In some clinical trials, experimental
treatments are compared with placebos to evaluate the effectiveness of the experimental
treatment.
4. Control group: A control group consists of participants who receive either standard
treatment or a placebo and serves as a comparison group to measure the effectiveness of
the experimental treatment other participants are receiving. ie, It is the standard with
comparisons are made

Eg; In a pharmaceutical study to determine the effectiveness of a new drug on the treatment of
migraines, the experimental group will be administered the new drug and the control group will
be administered a placebo (a drug that is inert, or assumed to have no effect)

5. Double blind study: A double blind study is a clinical trial in which both the participant
and clinical trial team DONOT know which participants are receiving the experimental
treatment and which are receiving a placebo or standard treatment.
6. Single blind study: A participant in a single-blind study does not know which drug they
are receiving( experimental drug or placebo), but the study doctor knows.
7. U.S. Food and Drug Administration (FDA): The Food and Drug Administration (FDA) is
a government regulatory agency responsible for ensuring the safety and effectiveness of
all medications, vaccines, medical equipment used for prevention, diagnosis, and
treatment
8. Bias; Bias in research is any deviation from the truth which can cause wrong results and
wrong conclusions. Bias happens in every research. The methods have to be adapted to
reduce it.

Types of bias:

● Information bias: error in measurement or data collection

● Recall bias; When patients cannot recall past events and give unclear or wrong
information. This is importsnt in retrospectiv studies
● Publication bias;
● Interviewer bias; It is from the person conducting the research study. It can result from
the way the interviewer ask questions or react to responses, but also from any aspect of
their identity, such as their sex, ethnicity, social class, or perceived attractiveness.
● Observer bias; It is the tendency of research participants to see what they expect or want
to see, rather than what is actually occurring.
● The Hawthorne effect refers to people’s tendency to behave differently when they
become aware that they are being observed. As a result, what is observed may not
represent “normal” behavior, threatening the validity of your research
● Researcher bias; Researcher bias occurs when the researcher’s beliefs or expectations
influence the research design or data collection process. eg: if researcher already knows

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Drug development process

that alcohol causes liver disease, his questions and data recording will always be in such a
way that the final result always says alcohol is the reason for his liver disease.
● Response bias: It is a general term used to describe a number of different situations where
respondents tend to provide inaccurate or false answers to self-report questions, such as
those asked on surveys
● Attrition bias: Attrition bias is the selective dropout of some participants who
systematically differ from those who remain in the study

eg: In an intervention study of diet in people with depression, those with more severe depression
might find it harder to adhere to the diet regimen and therefore more likely to leave the study. So
the people remaining in the study will be more of people with low grade depresion resulting in
bias in the result.

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