Introduction to

Clinical Trials

Chew Chun Keat, AMN

RPh (No. 5793)
Dip. IT, B. Pharm (Hons), MClinResMeth,
Certara Certified NCA Analyst
Content
• Introduction
• Types
• Designs
• Phases
• Study Protocol
• Clinical Trial Sharing
• Conclusion
Definition of Clinical Trials
• Good Clinical Practice (ICH E6 R3)
• Any interventional investigation in human participants intended to discover or verify
the clinical, pharmacological and/or other pharmacodynamic effects of an
investigational product(s); and/or to identify any adverse reactions to an
investigational product(s); and/or to study absorption, distribution, metabolism and
excretion of an investigational product(s) with the object of ascertaining its safety
and/or efficacy.

• WHO
• Clinical trials are a type of research that studies new tests and treatments and
evaluates their effects on human health outcomes. People volunteer to take part in
clinical trials to test medical interventions including drugs, cells and other biological
products, surgical procedures, radiological procedures, devices, behavioural
treatments and preventive care.
Investigational product (IP)
• A pharmaceutical form of an active substance or placebo being
tested or used as a reference in a clinical trial, including products
already with a marketing authorisation but used or assembled
(formulated or packaged) in a way different from the authorised
form, or when used for an unauthorised indication, or when used to
gain further information about the authorised form
International guidelines for conducting trials
• Following famous cases such as the Nazis in WWII and black
American men in syphilis studies (1932 –1972) there followed
the declaration of Helsinki

• Agreement between countries that there needed to be a global

standard by which all trial are conducted

• This is Good Clinical Practice (GCP) protects those in a trial, but

also those who’s treatment will depend on the data

• Essentially ensures that the rights of the patient are protected

and by all those given a drug or intervention in the future based
upon that data
• GCP = Quality Data + Ethics

• Data and Reported Results are Credible, and Accurate =

quality data

• Rights, Integrity, and Confidentiality of Trial Subjects are

Protected = ethics
 What is a Clinical Trial?
A properly planned and executed clinical trial is a powerful
experimental technique for assessing the effectiveness of
an intervention

3 important points:
Specify the intended study population to which the results
Population of the study are inferred. E.g. patients with certain diseases
at certain stages or healthy human subjects

Tx can be placebo or any combination of new drug, a new

Intervention diet, a surgical procedure, a diagnostic test, a medical
device or no treatment

E.g. evaluate effectiveness and safety of the treatment,

Outcome Assess Quality of Life, pharmacogenomics, cost
effectiveness.
Important Issues Before Beginning: 3 E’s & 1 S

• Effect
• Pharmacological effects of drugs
• Efficacy
• The ability of a drug to produce a desired therapeutic
effect under controlled conditions
• RCTs
• Effectiveness
• Drug action in ‘real life’
• Of significant interest to pharmaceutical industry
• Safety
• Is the drug safe to be consumed
Why?
• Better evidence of the effect or the outcomes that cannot be
obtained with other observational method.
• Test an ‘intervention’ – be it a product, procedure or health care
sytem….in order to improve standard of care!
• Most have a comparison CONTROL group
• To show experimental treatments or trial are safe and efficacious.
• Variation is minimized and bias is controlled, more validity
• Measures effects over a period of time
• Must be done before medication is part of standard of care
Hierarchy of Study Designs
Systematic
review and meta
analysis of RCTs
RCTs

Cohort studies

Case control studies

Level of
Cross sectional studies evidence

Case studies

Ideas, expert opinions, editorials

Anecdotal
Types of trials

Treatment trials Prevention trials

Screening trials Diagnostic trials

Quality of life
trials
Types of trials
• 1. Treatment trials

• Involves an intervention such as medication, psychotherapy, new devices, or

new approaches to surgery or radiation therapy.
• The early phases aim to find out more about the safety and side effects of a
new treatments.
• Later phases aim to see if a new treatment works better than the current
treatment. Or if a new treatment works better than a placebo.
 Types of trials

2. Prevention trials 3. Screening trials

• Looks for better ways to prevent • Aims to find the best ways to detect
disorders from developing or certain disorders or health conditions.
returning. • Researchers may plan screening trials
• Different kinds of prevention research to see if new tests are reliable enough
may study medicines, vitamins, to detect particular types of cancer.
vaccines, minerals, or lifestyle • Or they may try to find out if there is
changes. an overall benefit in picking up the
cancer early.
 Types of trials

4. Diagnostic trials 5. Quality of life trials

• Refers to the practice of looking • Explores ways to improve
for better ways to identify a comfort and the quality of life for
particular disorder or condition. individuals with a chronic illness.
• Aim to determine the accuracy, • Assess the impact of an
safety and effectiveness of intervention on patient’s
diagnostic test compared to physical, emotional and social
standard methods well-being.
Study Design of Clinical Trials
Parallel
a.k.a experimental study

Crossover
Randomized
clinical trial (RCT)
Factorial

Clinical trials Adaptive

Concurrent
Non-randomized control studies
clinical trial
(Non-RCT) Historical control
studies
Randomized clinical trial
• Subjects in a population are randomly allocated into group
• Study & Control groups, to receive and or not receive an
experimental intervention/treatment
• Patients are randomly assigned to groups to avoid bias.
 Randomized clinical trial

Advantage Disadvantage
• Comparative • May need vast sample size
• Minimizes bias • May not always mimic real life
• Minimizes confounding factors situation
• Statistical reliability • Highly controlled (inclusion &
exclusion factors)
• Ethical challenges
• Cost and time
Randomized clinical trial

Parallel Crossover Factorial

• Compare 2 different • Each person tries • Studies involve 2 or

groups of people, both treatments, one more factors while
where each group after the other. (with randomizing
receives different washout period) • Able to investigate
treatments. • Helps to see how the joint effect of two
each treatment works or more factors on a
for the same person. dependent variable
 Parallel Design

https://learning.eupati.eu/mod/book/tool/print/index.php?id=340
 Crossover Design

https://learning.eupati.eu/mod/book/tool/print/index.php?id=340
Factorial Design

https://learning.eupati.eu/mod/book/tool/print/index.php?id=340
Non-randomized controlled trial
• In non-randomised controlled trials, participants are allocated into
treatment and control arms by the investigator.

• Non-randomised controlled trials have the potential to study two groups

that are not strictly comparable. However, there are different types of
controls that can be used in non-randomised trials:
• Control groups can be concurrent controls, or
• Historical controls.

• When using a historical control, all participants in the trial receive the study
medicine; the results are either compared to the patient’s history or a
previous study control group.

https://learning.eupati.eu/mod/book/view.php?id=340
Adaptive trial design
• Utilize the accumulated data to decide any modification in
accordance with prespecified rules without affecting the trial
integrity and validity
• Often more efficient, informative and ethical than fixed design,
may make better use of resources, time and money and fewer
participants

• Types of modification may include:

• Sample size changes
• Early termination due to futility or efficacy endpoint achieved
• Addition or removal of intervention arms
• Study population eligibility criteria, new subgroup
• Hypothesis (ie. superiority and non-inferiority)
• Randomization ratio
 Adaptive Trial Design

Screening Follow up
Outcome
↑ sample size New study drug

Outcome
Study drug
Study
population Outcome
Placebo / Active treatment
/ SOC
Superiority vs
Subgroup non-inferiority
Examples
WHO Solidarity Trial
• An international randomised trial of additional treatments for COVID-19 in
hospitalised patients who are all receiving the local standard of care
Population Patient infected by COVID-19
Sample size Open ended
Allocation of treatment Randomized
Treatments - Remdesivir
- Hydroxychloroquine
- Lopinavir with Ritonavir
- Lopinavir with Ritonavir plus Interferon
- Artesunate
- Infliximab
- Imatinib
- Standard of care (control)
Hypothesis testing Superiority
Outcomes - Primary: In-hospital mortality
- Secondary: In-hospital mortality subdivided by initial respiratory
support, duration of hospital stay, initiation of ventilation
Follow-up Until patients death or are discharged
Blinding
Blinding, or “masking”, is the process by which information that
has the potential to influence study results is withheld from one
or more parties involved in a research study.

Blinding bias

Blinding is used to prevent conscious or unconscious bias in the

clinical trial

design of a clinical trial and how it is carried out.

bias recruitment

This is important because bias can affect recruitment and

allocation, care, attitudes, assessments, etc.
Source of bias
• Participant knowledge of their group allocation can bias expectations,
adherence to the trial protocol, treatment-seeking behavior outside
the trial, and assessment of the effectiveness
• Differential treatment, attention, or attitudes toward subjects by a
non-blinded healthcare team or other members of the research staff
• Sources
• Trial participant
• Clinical staff administering treatment
• The doctor assessing treatment
• The team interpreting results
 Types of blinding

Unblinded or open Single blind

• No blinding is used, and all • One party, the investigator or,
parties are aware of the usually, the participants, is
allocation of participants to unaware of what medicine the
treatment groups. participant is receiving.
• However, it may not fully
eliminate bias
 Types of blinding

Double blind Triple bind

• Neither the participants nor investigators • Participants, clinicians, data collectors,
know which participants are receiving the outcome adjudicators and data analysts
experimental medicine or placebo do not have access to details of group
• Produce objective results, since the assignment.
expectations of the investigator and the • This ensures that bias for or against the
participant do not affect the outcome tested treatment is very unlikely to occur.
• Maintaining blinding can be challenging if • Requires additional resources and
noticeable differences between logistics, not feasible with small-scale
treatments or side effects. studies
Blinding Advantages / Disadvantages
• Advantages:
• Protect against performance / reporting bias
• Data collection and follow up
• Outcome assessment and reporting
• Other care received during the trial
• Interpretation of results
• Disadvantages:
• May be logistically or ethically impossible
• May not reflect clinical care practices
• Concomitant care
• Increases logistical complexity
• Increase cost
Hypothesis Testing
• Superiority
• Non-inferiority
• (Equivalence)
Superiority Design
• Primary objective of showing that the response of the intervention is
superior to a comparator
Non-Inferiority Design
• To show new treatment is at least as good as old treatment
• Hypothesis
• If new treatment is worse than old treatment, one can be rejected
(one sided)
• Detectable difference is small, but hypothesis is one-sided,
less sample size as compared to equivalence trial.
• Assume the comparator treatment has been established to
have a significant effect (against placebo)
Equivalence Design
• To show intervention response are close to control group
response
• How much should be the limit of difference be considered
equivalent
• The differences allowed should be clinically unimportant
• The difference margin should be small
• Probability of detecting difference should be large
• Therefore, large sample size is needed
 Non Equi

Equi

Equi

Equi

Non Equi

Non Equi

Non Equi

Non Equi

BE Acceptance Range
Stages of Drug Development

To develop ONE
successful
medicine, it can
take:
• Testing of 10k
drug candidates
• Over a decade
• Over 1 billion
dollars
 Phase 1 Phase 2 Phase 3 Phase 4
Objectives
• Mainly • Safety • Mainly • Real world
safety • Efficacy efficacy long term side
• Safety effect
 Phase 1 Clinical Trial

Reference: US FDA: Step 3 Clinical Research [Internet]. USA: US FDA: 2018 [updated 2018 Apr 01; cited 2021 Jul 9]. Available
from: https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
Graphics by Institute for Clinical Research (ICR), Ministry of Health Malaysia.
The Types of Phase 1 Trial Design
Examples of Phase 1 Trial Planning
FIH
MAD (Multiple
SAD (Single Ascending Dose) Ascending Dose)

30mg 15mg Food

Cohort 4
15mg 10mg 15mg
10mg Cohort 7
Cohort 3 (n=8) Cohort 5 Cohort 6
(n=8)
Cohort 8 Effect
5mg (n=8) 6A + 2P (n=8) (n=8)
6A + 2P
(n=24)
Cohort 2 6A + 2P 6A + 2P 24A Crossover
1mg (n=8) 6A + 2P
Cohort 1 6A + 2P
(n=8)
6A + 2P 15mg 15mg Drug-drug
15mg BA/BE Cohort 9a Cohort 9b
interaction
A – Active Cohort 10 (n=12) (n=12)
P – Placebo (n=24) 12A+D 12A+D
D – Other drug(s)
Phase 1 Clinical Trials in Malaysia
 Regulatory Guideline on Phase 1 Unit Accreditation

National Pharmaceutical Regulatory

Agency (NPRA) released the Malaysian
Guideline for Phase 1 Unit Inspection &
Accreditation in June 2018

Sources:
https://www.npra.gov.my/images/Guidelines_Central/Guidelines_on_Clinical_Trial/MALAYSIANGUIDELINEFORPHASEIUNITINSPECTION.pdf
Phase One Unit Inspection & Accreditation Program

• Accreditation program for Phase I Units conducting FIH trials was established since 2018
• All FIH trials in Malaysia must be conducted in a Phase One Unit accredited by NPRA under the program
• Purpose:
✓ To ensure that the site comply with local and international regulatory requirements
✓ To ensure that the safety and welfare of the trial participants are protected
✓ To create a safe regulatory environment for the conduct of FIH trials in Malaysia
✓ Provide assurance to Sponsor on the quality and integrity of FIH trials conducted in Malaysia
• List of accredited Phase I Units (as of May 2025):
✓ Hospital Umum Sarawak, Sarawak
✓ Hospital Ampang, Kuala Lumpur
First-in-Human (FIH) Trial Centres

•FIH trial sites accreditation

at CRC SGH and CCT
Hospital Ampang

•Conduct FIH trials in

oncology, haematology and
other therapeutics area

•Contribute to development
of new medicines, vaccines
and biologics
46
BIOANALYTICAL SITES

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

LIQUID CHROMATOGRAPHY TANDEM MASS
SPECTROPHOTOMETRY (LCMS-MS)
Phase 2 Clinical Trial
• Administer the drug to a group of patients with the disease or condition
for which the drug is being developed.
• Typically involving a few hundred patients, these studies aren't large
enough to show whether the drug will be beneficial.
• Patients of homogenous population (100-300)
• Phase 2 studies provide researchers with additional safety data.
• Dose ranging and ceiling effects
• Researchers work to determine the most effective dose
• Therapeutic exploratory
• Researchers use these data to refine research questions, develop research
methods, and design new Phase 3 research protocols.
Phase 3 Clinical Trial
• To demonstrate whether or not a product offers a treatment benefit
to a specific population.
• Sometimes known as pivotal studies, these studies involve 300 to
30,000 participants.
• Phase 3 studies provide most of the safety data.
• In previous studies, it is possible that less common side effects might
have gone undetected. Because these studies are larger and longer in
duration, the results are more likely to show long-term or rare side
effects
• Therapeutic confirmatory
 Phase 2/3 Clinical Trials in Malaysia

• 817 registered
Phase clinical trial
2, 2/3 and 3 in
clinicaltrials.gov
• 496 completed
• 116 recruiting

Sources: www.clinicaltrials.gov
 Phase 2/3 Clinical Trials in Malaysia

• 86.8% Drugs
• 8.7% Biological
• 1.4% Device
• 1.1% Dietary
• 0.5% Procedure
• 0.2% Combination
• 0.1% Radiation
• 1.2% Others

Sources: www.clinicaltrials.gov
 Clinical Trial Success Rates by Phase

Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853.
doi:10.1001/jama.2020.116655
Drug Development Cost Estimation
 Mean and Median Expected R&D Expenditure
Approved by USFDA, 2009-2018

Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853.
doi:10.1001/jama.2020.116657
Phase IV
• Phase IV studies take place after • To know rare and long-term
country approval and there is a adverse effects
need for further testing in a • Special group like children,
wide population over a longer pregnancy can be tested.
timeframe.
• Post-marketing surveillance
• Large number of patients being
treated by practicing physicians
Example: Thalidomide, 1957
• Primarily prescribed as a sedative or hypnotic
• Nausea and to alleviate morning sickness in pregnant women
• Shortly after the drug was sold, in Germany, between 5,000 - 7,000 infants were born with
phocomelia (malformation of the limbs).
Retracted Approved Drug
Clinical Trial Phases
Who is involved?
• Investigators
• Coordinators / Project managers
• Nurses, clinical officers, fieldworkers
• Pharmacists
• Data manager and entry clerks
• Monitor / QA
• Laboratory staff
And possibly….
• Data safety and monitoring board
• Clinical trial steering committee
 Clinical Trial Registration

• All clinical trials should be registered.

• The minimum information that must be registered is specified in
the WHO Trial Registration Data Set.
• The Declaration of Helsinki states that "Every clinical trial must be registered in a
publicly accessible database before recruitment of the first subject".
• The registration of all interventional trials is considered to be a
scientific, ethical and moral responsibility
 Clinical Trial Registration
• Importance
• To ensure that decisions about health care are informed by all of the available
evidence.
• Improving awareness of similar or identical trials will make it possible to avoid
unnecessary duplication.
• Describing clinical trials in progress can make it easier to identify gaps in clinical
trials research.
• Help facilitate recruitment of participants.
• Enabling researchers and health care practitioners to identify trials of interest
which could result in more effective collaboration.
• Registries checking data as part of the registration process may lead to
improvements in the quality of clinical trials by identifying potential problems
early in the research process.
Research Registration Database

National Medical Research Register

(https://www.nmrr.gov.my)
Guidelines for Clinical Trial
 National Healthy Research
Volunteer Register
https://nhrvr.crc.gov.my

• To prevent healthy volunteers from over-volunteering themselves in clinical

trials
• Enhance subject safety and trial integrity
National Healthy Research Volunteer Register
(nhrvr.crc.gov.my)
 Ethics Considerations

• Researchers use a group of experts, called an ethics review committee or

Institutional Review Board (IRB).
• They compare the study risks to the study benefits that participants or
others in the future may receive to improve their health.
• They review, approve, and monitor the clinical study's protocol.
• Their role is to protect the rights and well-being of people participating in
a study.
• Typically includes people with varying backgrounds, including a
community member, to make sure that research activities conducted are
completely and adequately reviewed.
Prior to clinical trials

Feasibility studies Pilot studies

• Designed to see if it is possible to • Small versions of the main study.
do the main study. • Pilot studies help to test that all the
• They aim to find out things such as main parts of the study work
whether patients and doctors are together.
happy to take part, and how long it • They may also help answer the
might take to collect and analyse research question.
the information.
• Sometimes information collected
• They don’t answer the main during the pilot study in the results
research question about how well of the main study.
a treatment works.
Designing Clinical Trials
• Trials follow a specific study plan, called a protocol.
• Before a clinical trial begins, researchers review prior information
about the drug to develop research questions and objectives.
• Who qualifies to participate (selection criteria)
• How many people will be part of the study
• How long the study will last
• Whether there will be a control group and other ways to limit research bias
• How the drug will be given to patients and at what dosage
• What assessments will be conducted, when, and what data will be collected
• How the data will be reviewed and analyzed
Study Protocol
• A document that describes the objective(s), design, methodology,
statistical considerations and organization of a trial.
• The protocol usually also gives the background and rationale for the
trial.
• ICH Good Clinical Practice (E6R3)
 Study Protocol
1. General Information 6. Discontinuation of trial intervention and
• Protocol title, unique protocol identifying number Participant withdrawal from trial
and date. • When and how to discontinue participants from
• Name and address of the sponsor. the trial/investigational product treatment
• Details on the criteria for study
2. Background Information discontinuation/study termination
• Describe disease/available treatments/new
treatment 7. Treatment of participants/Intervention
• Type of intervention/treatment. Dose, frequency,
3. Objectives/purpose duration
• Describe the purpose based on the phase of the
study (efficacy/safety/side effects) 8. Assessment of Efficacy
• Describe the purpose of the developed drug • Methods used to assess effectiveness/efficacy or
outcome of the intervention being studied
4. Study design
• Study design, type of trial, intervention protocol, 9. Assessment of Safety
groups • How patients will be monitored (adverse event
reporting, safety assessments)
5. Selection, Inclusion & Exclusion criteria
• How participants are recruited
• Criteria to include and exclude participants based
on the study conducted
 Study Protocol
10. Statistics/ Data analysis 13. Ethics
• Statistical methods and analysis planned to • Addresses ethical considerations and
analyze the data collection, sample size compliance with regulatory requirements,
calculation etc. including approval from institutional review
boards and informed consent procedures.
11. Direct Access to source records • Discuss the ethical principles guiding the
• Investigator permits access to source conduct of the trial, including informed
records consent, participant confidentiality
12. Quality Control and Assurance 14. Data handling & Recordkeeping
• Summary of the monitoring approaches that • Outlines procedures for data collection,
are part of the quality control process for management, and storage to ensure
the clinical trial. accuracy, confidentiality, and integrity of the
study data.
15. Financing and Insurance
16. Publication policy
Selection, Inclusion & Exclusion Criteria
of Participants
• Researchers look for people who fit a certain
description, called eligibility criteria.
• People of a certain age or gender
• People who do or do not have a certain
illness, disease, or health condition
• People with or without a certain health
history, such as a prior treatment
• People who are exposed to or are in
contact with something that affects their
health
• To keep participants safe and enroll the right
participants to collect the data they need to answer the
research question.
Example
 SARS-CoV-2 Vaccine Trials In Malaysia

Protocol ID Study Title Sponsor

Randomized, Double -Blinded, Placebo Controlled Phase III Clinical Trial for the Evaluation of ÏMBCAMS
20200404 Efficacy and Safety of SARS-CoV-2 Vaccine, Inactivated (Vero Cell) in Healthy Population Aged
18 Years and Above in Malaysia
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Clinical Trial to Sinovac Biotech Ltd
Evaluate the Efficacy, Immunogenicity and Safety of COVID-19 Vaccine (Vero Cell),
PRO-nCOV-3002
Inactivated (CoronaVac®) in Children and Adolescents Aged 6 months to 17 Years
A multi-national, randomized, double-blind, placebo-controlled Phase III clinical study to Shenzen Kangtai
evaluate the efficacy, safety and immunogenicity of SARS-CoV-2 Vaccine (Vero Cells),
2021L001
Inactivated for the Prevention of COVID-19 in healthy adults Aged 18 years and Older
A Global, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Livzon Mabpharm
Study to Evaluate the Efficacy, Safety, and Immunogenicity of Sequential Immunization of Inc.
TG2102V01 Recombinant SARS-CoV-2 Fusion Protein Vaccine (V-01) Against COVID-19 in Healthy Adults
Aged 18 Years and Older after the Vaccination of 2 Doses of Inactivated Vaccines
Immunogenicity, Efficacy and Safety of Inhaled (IH) viral vectored vaccine (Convidecia, Cansino Bio
CT 2022-01 CanSino) as second booster dose against emerging Variants of Concern (VOC) of SARS-CoV-
2 to prevent breakthrough infections. A randomized observer-blind controlled trial.
Randomized, Double-Blinded, Placebo Controlled Phase III Clinical Trial for the
Evaluation of Efficacy and Safety of SARS-CoV-2 Vaccine, Inactivated (Vero
Cell) in Healthy Population Aged 18 Years and Above in Malaysia

• Name of Investigational Product: SARS-CoV-2 Vaccine, Inactivated (Vero Cell)

• Sponsor: Institute of Medical Biology Chinese Academy of Medical Sciences (IMBCAMS)

• Prof Dr Che Yan Chun, Head of R&D, IMBCAMS, China
• Tatiana, Global Project Manager, Brazil
• Local Sponsor Representative: TOP Pharma
• Coordinating PI: Dr Yasmin Mohamed Gani
• Project Lead: Mr Chew CK
• 9 hospitals under coordination by Institute for Clinical Research
• IMR performing immunogenicity test and genomic sequencing of SARS-CoV-2 virus
No Study Sites
1 Hospital Ampang
2 Hospital Umum Sarawak
3 Hospital Pulau Pinang
4 Hospital Seberang Jaya
5 Hospital Sultanah Bahiyah
6 Hospital Raja Permaisuri Bainun
7 Hospital Taiping
8 Hospital Sungai Buloh
9 Hospital Sultan Abdul Halim
Trial Registration in NMRR and
ClinicalTrial.gov
National Medical Research Register:
• https://v1.nmrr.gov.my/fwbPage.jsp?fwbPageId=PublicDirectoryOfMedicalResearchForm&fwbAction=View&
pager.offset=0&pk.uuid=713ae7896878f6d7b21073a95d7908e5&uk.uuid=713ae7896878f6d7b21073a95d7
908e5

Clinicaltrials.gov
• https://clinicaltrials.gov/ct2/show/NCT04659239?cond=vero+cell&cntry=MY&draw=2&rank=1
Randomized, Double -Blinded, Placebo Controlled Phase III Clinical Trial for
the Evaluation of Efficacy and Safety of SARS-CoV-2 Vaccine, Inactivated
(Vero Cell) in Healthy Population Aged 18 Years and Above in Malaysia
Trial Design Diagram
Screening Follow up (12 months)

Outcome
Study Vaccine

3000
(10% - ≥60 years)
Placebo
Outcome
 Intervention of the Trial
Arm Intervention/treatment
Experimental: Biological:
Investigational Vaccine Inactivated SARS-CoV-2 Vaccine (Vero cell)

Participants will receive 2 doses of the inactivated The inactivated SARS-CoV-2 vaccine (vero cell) was
SARS-CoV-2 vaccine (Vero cell) according to the manufactured by IMBCAMS. Each dose of 0.5ml is
immunization schedule of D0, D14. for per person per time use.

Placebo Comparator: Placebo Biological: Placebo

Participants will receive 2 doses of the placebo The placebo was manufactured by IMBCAMS. Each
according to the immunization schedule of D0, D14. dose of 0.5ml is for per person per time use.
 Study Objective and Outcome Measures
Primary outcome measure(s)
• The efficacy of the investigational vaccine against symptomatic and laboratory-
confirmed COVID-19 starting from Day 14 after the second dose.
• The incidence of solicited AEs at the inoculation site (local) and solicited AEs at the non-
inoculation site (systemic) within 7 days after each dose.
Secondary outcome measure(s)
• The efficacy of investigational vaccine for symptomatic and laboratory-confirmed
COVID-19 cases after at least one dose of immunization.
• The incidence of AEs from the first dose to 28 days after whole-course immunization.
• The incidence of SAEs from the first dose to at least 12 months after whole-course
immunization.
• The investigation of ADE/VED that probably related to the laboratory-confirmed COVID-
19 from 14 days after the second dose till the end of trial.
• GMT of IgG and neutralizing antibody
• Specific T cells with ELISPOT
 Inclusion Criteria:
1.Adults aged 18 years and above (including boundary values), both female and
male.
2.Legal identification of the participants shall be provided.
3.Participants shall understand the content in the Informed Consent Form (ICF) and
the vaccine for administration, sign the ICF voluntarily and are capable of using
thermometers and rulers, and filling in diary cards and contact cards as per the
requirements.
4.Subject shall be able to communicate well with investigators, understand and
comply with the requirements of this study.
5.Participants with oral temperature ≤ 37.9 ℃.
6.Female participants of childbearing potential (defined as any female who has
experienced menarche and who is NOT surgically sterile [i.e., hysterectomy,
bilateral tubal ligation, or bilateral oophorectomy] or postmenopausal [defined as
amenorrhea at least 12 consecutive months]) must agree to be heterosexually
inactive OR consistently use any of the acceptable methods of contraception.
 Exclusion Criteria:
1.Contraindications to commonly used vaccines;
2.History of allergy to any vaccines or drug;
3.Received any vaccine within 1 month before the first dose of vaccination；
4.Serious diseases required to be excluded, including but not limited to
history of diseases in nervous system, cardiovascular system, blood and
lymphatic system, immune system, kidney, liver, gastrointestinal tract,
respiratory system, metabolism, bones and other systems, and a history of
malignant tumors;
5.Before immunizing the first dose of investigational vaccine, those who
developed acute disease within 2 weeks, or had symptoms of fever or
upper respiratory tract infection within 7 days;
6.Those who have a hereditary bleeding tendency or blood coagulation
dysfunction, or a history of thrombosis or hemorrhagic disease；
7.Surgical removal of whole or part of spleen for any reason；
 Exclusion Criteria:
8. Those who have undergone surgery within 3 months before signing the ICF or those who plan to
undergo surgery during or within 3 months after completion of the trial (including plastic surgery,
dental and oral surgery);
9. Those who donated or lost blood (≥400 mL) in the past 3 months, who received blood
transfusion or use of blood products, or who plan blood donation during the trial;
10.Those who received other investigational or unregistered products (drugs, vaccines, biological
product or devices) in the past 3 months before signing the ICF, or plan to use them during the
study.
11.Those who received immunosuppressant therapy within 6 months before signing the ICF, such
as long-term systemic glucocorticoid treatment (with systemic glucocorticoid therapy for more
than 2 consecutive weeks within 6 months, such as prednisone or similar drugs), but local
administration is permitted (such as ointment, eye drops, inhalants, or nasal spray). The local
administration should not exceed the recommended dose in the package insert or have any signs
of systemic exposure;
12.Participants cannot meet the criteria through the comprehensive physical examination, mainly
including:
1. Abnormal vital signs with clinical significance (awakening heart rate <55 beats/min or >100 beats/min,
systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg);
2. Those who tested positive for type 1 or type 2 human immunodeficiency virus (HIV-1/2) antibody, or SARS-
CoV-2 nucleic acid;
 Exclusion Criteria:
13.History of COVID-19;
14.Participants who have a positive pregnancy test, or are
breastfeeding, or planning pregnancy, or plan to donate sperm or
eggs within 12 months from the screening period to the whole-
course immunization;
15.Participants who are considered as inappropriate for the trial by
investigators.
16.Suspected or known current alcohol or drug dependency.
17.Investigator site personnel directly related to this study and/or their
immediate families; immediate family is defined as a spouse, parent,
child, or sibling, whether biological or legally adopted.
Timeline and Trial Status
• IMBCAMS approached MOH via local representative, TOP Pharma,
around Sep-Oct 2020
• 13 Dec 2020 - obtained approval from MREC
• 8 Jan 2021 - obtained NPRA approval
• 23 Jan 2021 - IP arrived at KLIA
• 27 Jan 2021 - Official launch of the trial by former YBMK
Timeline and Trial Status
• IMBCAMS approached MOH via local representative, TOP Pharma,
around Sep-Oct 2020
• 13 Dec 2020 - obtained approval from MREC
• 8 Jan 2021 - obtained NPRA approval
• 23 Jan 2021 - IP arrived at KLIA
• 27 Jan 2021 - Official launch of the trial by former YBMK
• 30 Jan 2021 - First subject recruited
• 21 Apr 2021 - Recruited 3000 subjects
• 4 May 2021 - Last participants inoculated
Peak of the COVID-19 Pandemic
 Randomized, Double -Blinded, Placebo Controlled Phase III Clinical Trial for
the Evaluation of Efficacy and Safety of SARS-CoV-2 Vaccine, Inactivated
(Vero Cell) in Healthy Population Aged 18 Years and Above in Malaysia
Trial Design Diagram
Screening Follow up (6 months) Follow up (12 months)

Outcome
Study Vaccine Study Vaccine x 2

3000
(10% - ≥60 years)
Outcome
Placebo Study Vaccine + Placebo
Timeline and Trial Status
• IMBCAMS approached MOH via local representative, TOP Pharma, around Sep-Oct 2020
• 13 Dec 2020 - obtained approval from MREC
• 8 Jan 2021 - obtained NPRA approval
• 23 Jan 2021 - IP arrived at KLIA
• 27 Jan 2021 - Official launch of the trial by former YBMK
• 30 Jan 2021 - First subject recruited
• 21 Apr 2021 - Recruited 3000 subjects
• 4 May 2021 - Last participants inoculated
• August 2021 - Early statistical results found favourable vaccine efficacy, and proposed
crossover design
• 18 August 2021 - Obtained approval from MREC and NPRA for crossover design
• 10 Oct 2021 - All consented trial participants received the 4th dose
 Study Title:

Immunogenicity, Efficacy and Safety of Inhaled (IH)

viral vectored vaccine (Convidecia, CanSino) as
second booster dose against emerging Variants of
Concern (VOC) of SARS-CoV-2 to prevent
breakthrough infections.
A randomized observer-blind controlled trial.
Protocol #: CT 2022-01
 Study Sites

∙ Centre for Clinical Trial, Hospital Ampang

∙ Department of Nephrology Transplant, Hospital Kuala Lumpur
∙ Department of Rheumatology, Hospital Selayang

96
Study Protocol: CT2022-01
Study objective To determine the immunogenicity, efficacy and safety of IH Convidecia
(CanSino), as a second booster vaccination against Omicron and other emerging
VOCs to prevent breakthrough infections.

Study design This will be a randomized single-blind controlled trial.

These subjects will be randomized in a ratio of 1:1 to receive a second
booster dose of IH Convidecia vaccine (treatment arm), or a second
booster dose of mRNA vaccine BNT162b2 (Pfizer).

Study Population A total of 540 subjects age 18 or older who have completed a course of primary
and first booster vaccination at least 16 weeks before, and who have sub-optimal
antibody response to the first booster dose, will be enrolled into this study.

Estimated duration of Each participant will participate in the study for approximately 6.5 months from
the study the time the participant is enrolled through to final contact.

97
Study Treatment

Vaccine IH Convidecia mRNA vaccine (Pfizer)

Type Recombinant Novel Coronavirus BNT162b2
Vaccine, Adenovirus Type 5 Vector
Manufacturer CanSino Biologics Inc. China/ Solution Pfizer and BioNTech
Biologics Bhd Malaysia
Dosage form Liquid solution Liquid solution
Unit Dose 0.1 ml/dose 0.3 ml/dose
Strength(s)
Route of Inhalation (IH) of aerosol droplets Intramuscular injection
Administration for generated from the liquid solution of
IH Convidecia the vaccine using a nebulizer
Dosage Level(s) IH dose: 0.1 ml containing > 0.8 × 1010 0.3 ml/dose
viral particles
Delivery system for Nebulizer (Aerogen) Micro needle syringe
inhalational route
98
Participant
Disposition
flow chart

99
Baseline characteristics of analysis population

100
101
Solicited and unsolicited ADRs (0-28 Days post
booster vaccination)
103
Non-inferiority analysis of geometric mean
concentration and seroconversion rate of
anti-spike RBD IgG (wild-type)

104
Immune responses
elicited by the
second booster
vaccination
105
Cumulative risk of breakthrough Covid19 infection (14th day post vaccination)

106
107
Pharmacokinetic Study
• A Phase 1 Bioequivalence Study of a Test Tablet Formulation of
Ravidasvir With the Reference Tablet Formulation of Ravidasvir Study
• Ravidasvir formulation produced by Doppel (T) vs Ravidasvir
formulation produced by EEPI (R)
• Sample size = 36
• Study design = A Phase 1, Open-Label, Four-Period, Two-Sequence,
Two-Treatment, Single Dose, Randomized, Crossover Bioequivalence
Study
 A Phase 1, Open-Label, Four-Period, Two-Sequence, Two-Treatment,
Single Dose, Randomized, Crossover Bioequivalence Study

Ravidasvir

Post Study Safety

Randomization

(Doppel)

Assessment
200 mg Period 1 Period 2 Period 3 Period 4
n = 36
Ravidasvir
(EEPI)
Fasting Period 1 Period 2 Period 3 Period 4

Washout Washout Washout

Period Period Period
7 days 7 days 7 days
Solidarity Plus Trial
I-TECH Study
Unsung Hero to Advancement of Medical
Sciences
• Trial volunteers
• Altruistic
• Thorough understanding
• High commitment

• Data generated by trial volunteers today will help to advance

medical sciences.
Guidance from the newly launched
Guidance for Best Practices for Clinical Trials
• Joint use of resources and sharing of expertise
by making optimal use of pre-existing
resources and facilities associated with
routine health care practice while not unduly
hampering such routine care
• sustained approach to funding and a shift
away from “project-by-project” clinical trials
infrastructure
• extending trial sites from large national
centres to smaller local centres or indeed
patients’ homes
 Conclusions &
Take Home Message

• Clinical trials are the stepping stone for medicines

• Clinical trials often yield important results that affect health and well
being

• Quality of data, safety, well being and rights of subject must be uphold
 THANK YOU FOR
YOUR ATTENTION

[email protected]
 Ethics of Human and
Animal Experimentation

Dr Janet Tan Sui Ling

Department of Pharmaceutical Technology
Faculty of Pharmacy
Universiti Malaya

www.um.edu.my
Learning Outcomes
▪ CLO 4: Explain the safety evaluations, ethics of
human and animal experimentation, intellectual
property and commercial considerations in drug
development.
» Explain the principles related to human and
animal experimentation ethics.

2
Definition

▪ Principles and guidelines that govern the conduct of

studies involving animal and human subjects to ensure
their welfare, rights, and dignity are respected.

Animal Research Ethics Human Research Ethics

3
 Animal Research Ethics - Introduction
▪ A term used to describe human-animal relationships and how animals
ought to be managed and treated
▪ The subject matter includes:
» animal rights (should use or not)
» animal welfare (QoL, minimize suffering)
» animal law (animal welfare act 2015)
» animal cognition (mental capacity)
» wildlife conservation (Wildlife conservation act 2010)
» the moral status of nonhuman animals,
» And the history of animal use

4
Animal Research Ethics - Introduction

▪ The general opinion is that animals have a moral status, and that
our treatment of them should be subject to ethical considerations.
▪ Such views are reflected in the following positions:
» Animals have an intrinsic value which must be respected.
» Animals are sentient creatures with the capacity to feel pain,
and the interests of animals must therefore be taken into
consideration.
» Our treatment of animals, including the use of animals in
research, is an expression of our attitudes

5
Animal Research Ethics – Use of Animals

▪ Animals are used in research or experimentation in place

of human subjects for various reasons
» Disease Treatment
» Prevention
» Treatment of Injuries
» Basic Medical Testing
» Medical Diagnosis

6
Principles for Ethical Care and Use of
Animals

Societal
benefit

Respect
for life

7
Principles for Ethical Care and Use of
Animals – Respect for Life
▪ Living creatures deserve respect.
▪ Animals used in research should be of an appropriate
species and health status and should involve the minimum
number required to obtain valid scientific results.
▪ It also recognizes that the use of different species may raise
different ethical concerns.
▪ Selection of appropriate species should consider cognitive
capacity and other morally relevant factors.
▪ Alternative methods such as mathematical modes,
computer simulation, and in vitro systems should be
considered and used whenever possible.
8
Principles for Ethical Care and Use of
Animals – Societal benefit

▪ The advancement of biological knowledge and improvements

in the protection of the health and well-being of both humans
and other animals provide strong justification for biomedical and
behavioral research.
▪ Where animals are used, the assessment of the overall ethical
value of such use should include consideration of the full range
of potential societal goods, the populations affected, and the
burdens that are expected to be borne by the subjects of the
research.

9
Principles for Ethical Care and Use of
Animals – Nonmaleficence

▪ Vertebrate animals are sentient.

▪ The minimization of distress, pain and suffering is a
moral imperative.
▪ Procedures that cause pain or distress in humans may
cause pain or distress in other sentient animals.

10
5 Freedom of Animal Welfare

▪ The welfare of an animal includes its physical and

mental state
▪ Good animal welfare implies both fitness and a sense
of well-being.
▪ Any animal kept by man, must at least, be protected
from unnecessary suffering.

11
5 Freedom of Animal Welfare

12
Institutional Animal Care and Use
Committee (IACUC)

▪ Required by federal regulations for most institutions

that use animals in research, teaching, and testing.
▪ Responsible for oversight of the animal care and use
▪ Review and approval of animal use activities, and
inspection of animal facilities.

13
Animal Experimentation

▪ 85 % of the animals used in research are rodents - rats and

mice that have been bred for laboratory use
▪ Most laboratory tests on animals are simple single type
tests - change in diet, drawing a simple blood sample,
administering a drug
▪ Animals are given anesthetics if a procedure is going to be
invasive in any way
▪ Dogs, cats and non-human primates account for only 3 out
of 1000 subjects in experimentation
▪ Humans are still the largest group that is used for research
and experimentation and beats out all other lab animals
when it comes to testing.

14
Animal Experimentation
Acceptable Unacceptable
Suffering is minimized in all experiments It causes suffering to animals.
Human benefits are gained which could The benefits to human beings are not
not be obtained by using other methods proven.

Any benefits to human beings that

animal testing does provide could be
produced in other ways.

15
The 3 Rs Concept

VS

16
Reduce

▪ Means minimizing the number of animals needed to

perform an experiment.
▪ The IACUC will determine if thoughtful experimental
design was employed to minimize overall animal use.

17
Ways to Reduce

Improving experimental Improving techniques of Sharing information with

techniques data analysis other researchers

Consulting with a Minimizing variables Performing literature

statistician to use only such as disease, stress, searches and consulting
the numbers of animals diet, genetics, etc., that with colleagues to
required to achieve may affect experimental ensure that experiment
significance. results. not duplicated.

Using the appropriate

species of animal so that
useful data is collected.

18
Refine

▪ Refining experimental protocols to minimize pain or

distress
▪ Examples of refinement include:
• Identifying pain and distress and try to prevent or relieve it.
• Using less invasive techniques
• Better medical care
• Better living conditions
» Receiving adequate training prior to performing a procedure.
» Using proper handling techniques for animals.

19
Replace

▪ Replacing 'higher' animals with 'lower' animals

▪ Replacing experiments on animals with alternative
techniques such as:
» Experimenting on cell cultures instead of whole animals
» Using computer models
» Studying human volunteers
» Using epidemiological studies
▪ Alternative method should not require animal-derived
biological material, if use some, considered as
incomplete replacement

20
5 Minutes Break!

21
Human Research Ethics - Objectives

to protect human participants.

to ensure that research is conducted in a

way that serves interests of individuals,
groups and/or society as a whole.

to examine specific research activities and

projects for their ethical soundness

22
Human Research Ethics – General
Guidelines
Every proposal for medical research on human subjects must be reviewed and
approved by an independent ethics committee before it can proceed

Medical research involving human subjects must be justifiable on scientific ground

If the risk is entirely unknown, then the researcher should not proceed with the
project until some reliable data are available

The voluntary consent of the human subject is absolutely essential.

Research subjects have a right to privacy with regard to their personal health
information.
23
Ethical Principles

• Nuremberg code -1947

1

• Belmont Report- 1979

2

• Declaration of Helsinki -
3 1964

24
Ethical Principles: Nuremberg Code -1947

▪ Voluntary informed consent

▪ Fruitful result for the good of society
▪ Prior experimentation on animals and prior knowledge of the
problem
▪ Avoidance of unnecessary physical or mental injury
▪ Banning of known lethal or disabling procedures
▪ Degree of risks should not exceed benefits
▪ Proper preparation and facilities to prevent injury or death
▪ Performance of experiments only by scientifically qualified
people
▪ Participants may freely end the experiment
▪ The experiment must stop if it proves too dangerous
25
Ethical Principles: Belmont Report- 1979

▪ The Belmont Report was written by the National

Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research
▪ identifies basic ethical principles and guidelines that
address ethical issues arising from the conduct of
research with human subjects.

26
Ethical Principles: Belmont Report- 1979

Justice
Beneficence • Efforts to describe
the risks and benefits
• Efforts must be made equally
Respect for Persons to maximize the
benefits of research • To disseminate any
• Have the right to research findings,
decide for themselves and to minimize any
potential risks. both bad and good
whether they want to
• Inform all subjects • Subjects and
participate, or to
about these potential participants must be
withdraw
risks treated fairly and
equally

27
Belmont Report Application

Informed Consent

Assessment of Risk & Benefit

Selection of Subject

28
Belmont Report Application : Informed
Consent

▪ Information
» Disclosure of information to subjects
▪ Comprehension
» The manner and context in which information is conveyed is
as important as the information itself
▪ Voluntariness
» Considered valid only if voluntarily given

29
Ethical Principles: Declaration of Helsinki -1964

▪ Developed by The World Medical Association (WMA)

▪ Statement of ethical principles for medical research
involving human subjects, including research on
identifiable human material and data.

30
Declaration of Helsinki -1964

General Principle

• The patient’s best interest is above everything else.

• Minimizes possible harm to the environment.

Risks, Burden and Benefits

• May only be conducted if the importance of the

objective outweighs the risks and burdens
• Measures to minimize the risks must be implemented.
The risks must be continuously monitored, assessed
and documented by the researcher.

31
Declaration of Helsinki -1964

Vulnerable Groups & Individuals

• All vulnerable groups and individuals should receive

protection.
• research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of
this group

Scientific Requirements and Research

Protocols
• design and performance of each research study involving
human subjects must be clearly described and justified in
a research protocol.
32
Declaration of Helsinki -1964

Research Ethics Committee

• Submitted, approved, monitor, amendment approval, final report.

Privacy & Confidentiality

• Protect privacy of research subjects and confidentiality of their

personal information

Informed Consent

• Participation by individuals capable of giving informed consent as

subjects in medical research must be voluntary.
• Incapable of giving informed consent, the physician must seek
informed consent from the legally authorised representative
33
Declaration of Helsinki -1964
Use of Placebo

• Must test new intervention against best intervention, unless don’t exist – placebo / no
intervention

Post-Trial Provision

• People in charge (sponsors, researchers, and the host country government) need to plan
how participants can continue to get any helpful treatment after the trial ends. –shared with
subject when getting consent

Research Registration & Publication & Dissemination of Results

• Registered in publicly accessed database, Results must be publicly available (accurate,

negative, positive inconclusive data etc)

Unproven Interventions

• May use an unproven intervention if in the physician’s judgement it offers hope of saving life,
re-establishing health or alleviating suffering.

34
Informed Consent

Process in which a health care provider educates a patient about the

risks, benefits, and alternatives of a given procedure or intervention.

The patient must be competent to make a voluntary decision about

whether to undergo the procedure or intervention.

Informed consent is both an ethical and legal obligation of medical

practitioners which originates from the patient's right to direct what
happens to their body.

35
 Required Elements of Informed Consent

(5) assessment
of the patient's
(4) risks and understanding
benefits of of elements 1
alternatives, through 4.
(3) reasonable
alternatives,
(2) the risks and
benefits and the
(1) the nature of procedure,
the procedure,

36
Principles of Informed Consent Form

Competence
• To understand and decide

Voluntariness
• In deciding

Disclosure
• Of material information

Understanding
• Of information given

Consent
• Decision and authorization in favor of chosen plan
37
Informed Consent Form

1. Purpose of study
2. Subject selection criteria
3. Study procedures
» Chronological order, how long, how often.
4. Potential risks and discomfort
» Psychological, social, legal, and financial
5. Potential benefits
» Expected benefits to participants, society science
6. Cost and compensation
» Cost of time/money, and compensation that will be offered

38
Informed Consent Form

7. Future use of data

» Will be further used, not distributed, published
8. Confidentiality
» Procedure to safeguard data, where, who, how, when
9. Participation and withdrawal
» Voluntary, may refuse or withdraw anytime, no penalty
10. Contact Information
11. Subject Consent
» Agree to join with signature of subject and investigator

39
Informed Consent Form

40
Ethics Application in Malaysia

41
 National Medical Research Register
(NMRR)
▪ Center for research application for a study related to MOH.
▪ A database for all clinical trials that are conducted in Malaysia
(Research directory)
▪ Streamlines the application, review and approval process to conduct
research in the MOH
▪ Investigators to submit relevant documents to be reviewed by the
respective authorities such as
» Jawatankuasa Penilaian Penyelidikan (JPP) , the ethical approval
application by the Medical Research & Ethics Committee (MREC),
MOH,
» the MOH Research Grant (MRG) application and
» Publication& Presentation Approval by the Director General of
Health

42
Medical Research and Ethics
Committee (MREC)

▪ Under Ministry of Health (MOH)

▪ Provide independent guidance, advice and decision on
ethical issues of health research involving human
subjects conducted by staff of the MOH or conducted
by non- MOH researchers using facilities of the MOH

43
Conclusion

▪ In summary, while human and animal experimentation

is important in scientific discovery, it must be
conducted with ethical rigour to respect the dignity and
welfare of all subjects involved.
▪ Through continued vigilance and ethical innovation, we
can advance science responsibly and humanely.

44
 Thank you

www.um.edu.my universityofmalaya unimalaya uniofmalaya

 PRECLINICAL TOXICOLOGY : IN
VITRO AND IN VIVO MODELS
Ts Dr Muhammad Luqman Bin Nordin
Department of Pharmaceutical Technology
Faculty of Pharmacy
Universiti Malaya

www.um.edu.my
By the end of this topic

1. Explain the principles and purposes of in vitro and in vivo

toxicological testing in the context of preclinical drug
development.
2. Differentiate between in vitro and in vivo experiments to
assess the safety and toxicity profile of pharmaceutical
compounds.
3. Demonstrate awareness of ethical, legal and regulatory
considerations in the use of animal models in preclinical
toxicology.
2
Toxicology
What is toxicology?
- Study of effect toxicants/poisons to the body, how to diagnose and
treat toxicosis.
- Toxin is term used to describe toxicants/poisons originating
from biological processes.
- Toxic is term used to describe the effects of a toxicant/poison
on biological systems.
- Toxicosis, poisoning, and intoxication are synonymous terms for the
disease produced by a toxicant.
- Xenobiotic can be define as any foreign substances which the body
does not recognize such as drugs or any chemicals.
3
 Common terminology
▪ Toxin :
Toxic substances that are produced naturally (nature origin).

▪ Toxicants :
Any chemical that can injure or kills human, animal or plant –poison.

▪ Hazard
The biological effects produced by substances (i.e., toxicity). Hazards pose risks
only if the exposure is sufficiently high.

▪ Toxicity testing :
Involves the use of living systems to estimate toxic effects.

▪ Toxicology pathology :
Is the branch of pathology that deals with the effects of toxic agents manifested as
changes in subcellular, cellular, tissue or organ morphology.
4
▪ Metabolism
The sum of the processes by which a particular substance is handled in the living body.

Metabolite
▪ a product of metabolism.

Dose
▪ Is an actual amount of substance/drug consumed/taken at a time.

Dosage
▪ Prescribed regimen for administering a medication or substance, encompassing the amount,
frequency, and duration of use.

▪ Preclinical development/study
Stage of research that begins before clinical trials which important feasibility, testing and drug
safety data are collected, typically in laboratory animals.

5
 GENERAL OVERVIEW OF POISONOUS SUBSTANCE EXPOSURE
Emission Exposure via Distribution and exposure
e nvironment
Air

Source(s)

sludge
effluent Water Agric ultural soil Treated soil

terrestrial
aquatic ec osystem
Sewage
ec osystem
treatment plant
Sediment Groundwater

consumer products man food produc ts

milk crops meat fish drinking air

water

4
HOUSEHOLD PRODUCTS - exposure
 Source of toxicology
Medications and Drugs:
• Certain prescription medications, over-the-counter drugs, and recreational drugs can cause toxicity when
misused, taken in large amounts, or interact with other substances.

Heavy Metals:
• Lead, Mercury, Cadmium, and Arsenic are common environmental toxins that can accumulate in the body over
time, leading to neurological damage, kidney damage, and other serious health issues.

Chemicals and Pesticides:

• Exposure to harmful chemicals in cleaning products, personal care products, paints, and industrial chemicals can
lead to toxicity. These chemicals can be absorbed through the skin, inhaled, or ingested.

Environmental Toxins:
• Air Pollution: Chemicals like carbon monoxide, sulfur dioxide, nitrogen oxides, and particulate matter can affect
the respiratory and cardiovascular systems.
• Water Pollution: Contaminants like heavy metals (e.g., lead, mercury), pesticides, and industrial chemicals in
water can lead to poisoning and organ damage.
• Soil Contamination: Toxins from industrial waste, agricultural runoff (pesticides, herbicides), and heavy metals 7
can enter the body through food or direct contact.
Alcohol and Tobacco:
• Excessive consumption of alcohol can lead to liver damage, brain dysfunction,
and other harmful effects.
• Smoking exposes the body to toxic substances like nicotine, tar, carbon
monoxide, and formaldehyde, which can cause lung and cardiovascular damage.

Microbial Toxins:
• Some bacteria, fungi, and molds produce toxins (mycotoxins, endotoxins) that
can lead to food poisoning or systemic illness if ingested, inhaled, or absorbed.

Food Contaminants:
• Pesticides and Herbicides used in food production can leave residues on fruits
and vegetables.
• Heavy Metals in fish, particularly mercury in large fish like tuna, can pose risks to
the nervous system.
• Food Additives or artificial chemicals may cause toxicity if consumed in large
amounts over time.
8
 Classification of toxic effects
• Effect of toxicant/poison are often defined according to dose, frequency , routes and
duration of exposure with extreme levels (very high dose) of exposure most agents can
produce adverse effects.
• The response may occur :

1.Acute : effects during the first 24-hr period

▪ often single type of poison with high dose of exposure.

2.Sub-acute : toxic effect occur between 30-90 days exposure.

▪ the toxic effect apparent over a period of several days or weeks.

3.Chronic- effects produced by prolonged exposure (≥3 months)

▪ often multiple exposure of poison.
9
Factors that affect toxic response

1. Dose
▪ Too much of a good thing can be bad. Highly toxic chemicals
can be life saving when given in appropriate doses. (Poisons are
not harmful at a sufficiently low dose).

▪ LD50 is the dose that is lethal to 50% of a test sample. It is an

estimator of lethality and the most common expression used to rate
the potency of toxicants.
10
2. Frequency
• Single or repeated dose of certain toxic compounds may
considerately affect the toxic response within the body. (eg:
acute or chronic).

3. Duration
• How long the exposure with high or low amount of
certain toxic compounds.

11
6. Chemical nature
• Influences absorption. Lipid-soluble substances
tend to be more readily absorbed.

7. General state of health

• Disease and debilitated body are more susceptible to
the toxic action of poisons- impaired metabolism.

12
 Preclinical Studies and its methods
Preclinical Studies

In-vitro In-Vivo

➢Receptor Pharmacological Toxicological

Characterization Studies Study
➢Receptor binding assay
➢Enzyme inhibition
➢Cytotoxic activity Efficacy Safety

Determination of
Starting Dose
Preclinical toxicology
The aims of preclinical toxicology are :

(a) to reduce to a minimum the risk to the healthy

volunteers and the patients to whom the drug will be
given in clinical trials.

(a) to ensure that the risk in patients treated with the drug
once it is on the market is commensurate with the
benefits. The latter is also a major concern during
clinical development.
14
In vitro and in vivo studies

▪ In vitro studies are performed with microorganisms, cells, or

biological molecules outside their normal biological context.
Colloquially called "test-tube experiments", these studies in
biology and its sub disciplines are traditionally done in lab ware
such as test tubes, flasks, Petri dishes, and microliters plates.

▪ In vivo are those in which the effects of various biological entities

are tested on whole, living organisms, usually animals, including
humans, and plants, as opposed to a tissue extract or dead
organism.
15
▪ in vitro toxicology consists of using cells or tissues
maintained or grown in controlled laboratory conditions to
examine the toxic properties of compounds and mixtures.

▪ This allows the toxicity of xenobiotics to be examined at the

fundamental level of the cell without the interplay of complex
physiological systemic effects that are often observed in
whole organisms.

▪ However, specific cellular functions could be examined with

primary cultures of cells from specific tissues such as the
liver for xenobiotic biotransformation, kidney for ionic
homeostasis, and the nerve cells for neurotransmitter
signaling effects.
16
▪ In vitro systems are considered as alternative testing methods to
reduce the use of animals in toxicity studies, refine toxicity evaluations
(i.e., to go beyond general growth or survival data), and replace in
vivo studies—the so-called 3 Rs of alternative tests.

▪ Cell or tissue-based approaches represent a more direct way to

determine the mode of action of xenobiotics at the fundamental level.

▪ In this respect, in vitro test systems could represent a powerful tool for
toxicity screening and understanding the fundamental mode of action
of chemicals provided that the data are related to the whole organism
in some way.

▪ In this respect, in vitro tests could be validated with the corresponding

in vivo model or whole organism with a suite of model toxicants. 17
 In vitro study
Advantage: Disadvantage:
◻ Studies can be completed in short period of time. ◻ May not represent the target
◻ Reduces risk in post clinical trials. organism accurately because
◻ Reduction of animal sacrifice during toxicity screening they are simplified to such an
of various chemicals. extent that they lose one or
more vital characteristics of the
◻ More controlled exposure conditions (hormonal and
organism
cofactor make-up of the exposure media).
◻ Conducted within a
◻ Increased precision of the response (less biological
limited time period,
variation than with in vivo systems).
rather than continuously
◻ High bioanalytical throughput for rapid screening
monitored.
investigations. The mean caveats of in vitro systems
are as follows: (1) relevance to in vivo or whole-
animal effects (i.e., does a cellular toxicity effect
correspond to an effect toward the whole organism?),
and (2) loss of systemic effects (e.g., gender- or age-
18
related effects).
Example of the assay
Bioassay Biomarker
▪ A bioassay is an analytical method to determine the ▪ Biomarkers reflect the biological response to the
potency or effect of a substance by its effect on living treatment or a pharmacological activity in response to
animals or plants, or on living cells or tissues treatment or identify safety problems (toxicity) related
(biological system). to treatment
▪ Role of bioassays in drug discovery is to help scientist
find potential drugs for a particular disease. ▪ Examples of biomarkers

▪ Bioassay can also be used to measure the changes ▪ Cardiovascular disease; Blood pressure, Cholesterol levels
in biomarkers following treatment to determine ▪ Diabetes; Hemoglobin A 1 c, Insulin, Glucose levels
o Efficacy & Potency ▪ Toxicity (Adverse Effects); Liver, Kidney functions,
o Adverse effects Mutagenesis etc

19
▪ A dose-response relationship refers to the relationship
between the dose or concentration of a substance and
the biological response it produces. 20
 Other in vitro bioassays
These assays provide valuable information about the toxic effects of substances without the need for whole
organisms. Here are some common types of in vitro toxicological bioassays:

▪ 1. Cytotoxicity Assays:
o Measure the ability of a substance to cause cell death. Examples include the MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide) assay and the lactate dehydrogenase (LDH) release assay.
▪ 2. Genotoxicity Assays:
o Assess the potential of a substance to cause damage to genetic material. Common genotoxicity assays include
the Ames test, micronucleus assay, and comet assay.
▪ 3. Mutagenicity Assays:
o Specifically focus on the ability of a substance to induce mutations in DNA. The Ames test is a well-known
example.
▪ 4. Reproductive Toxicity Assays
o Evaluate the impact of a substance on reproductive processes. This can include tests like the in vitro
mammalian cell micronucleus test for assessing chromosome damage.

▪ 5. Embryotoxicity Assays:
o Examine the effects of a substance on embryonic development. The embryonic stem cell test (EST) is an
example. 21
 ▪ 6. Neurotoxicity Assays:
o Investigate the toxic effects of substances on the nervous system. Examples include assays using neuronal cell lines or primary neuronal
cultures.
▪ 7. Hepatotoxicity Assays:
o Assess the toxic effects of substances on liver cells. Hepatocytes or liver cell lines are commonly used in such assays.
▪ 8. Nephrotoxicity Assays:
o Evaluate the toxic effects on kidney cells. Kidney cell cultures or specific assays for renal toxicity may be employed.
▪ 9. Endocrine Disruption Assays:
o Investigate the ability of a substance to interfere with the endocrine system. Cell-based assays using hormone-responsive cell lines are
commonly used.
▪ 10. Cell Proliferation Assays:
o Measure the impact of a substance on the growth and proliferation of cells. Examples include the bromodeoxyuridine (BrdU)
incorporation assay.
▪ 11. Enzyme Inhibition Assays:
o Assess the ability of a substance to inhibit specific enzymes, providing insights into potential metabolic disruptions.
▪ 12. Oxidative Stress Assays:
Measure the generation of reactive oxygen species (ROS) or the antioxidant capacity of cells in response to a substance.
◻ 13. Immunotoxicity Assays:
Examine the effects of substances on the immune system, including assays for cytokine production or immune cell function. 22
 In vivo studies
▪ in vivo are those in which the effects of various biological
entities are tested on whole, living organisms or cells, usually
Animal models animals, including humans, and plants, as opposed to a
of Disease States tissue extract or dead organism.
▪ The study of the hazardous effects of chemical substances
on a living organism, such as a laboratory animal, is known
Behavioural Studies as in vivo toxicology.

• Gives information about :

Functional Imaging
• Metabolic profile
• Toxicology
Ex-Vivo Studies
• Drug interaction
Some more ?
 In vivo study

Advantages:

▪ As essential tools for preclinical drug screening, serving as primary in vivo

models for assessing pharmacokinetic parameters such as drug efficacy, safety
and toxicity (Mukherjee et al. 2022).
▪ Allow the identification of behavioural changes; many disease models (eg :
Alzheimer's and Parkinson's disease (Domínguez-Oliva et al. 2023).
▪ Providing novel therapeutic approaches, diagnostics techniques and surgical
procedures (before advancing to clinical trials) (Doke and Dhawale 2015).
▪ The discovery of vaccines and, more recently, the significant advances in
worldwide diseases (such as COVID-19 or cancer) were made possible thanks to
the usage of animal species (Domínguez-Oliva et al. 2023; Mukherjee et al. 2022).
24
 Animal models of disease states
• Test conditions involving induced disease or injury similar to
human conditions.
Animal models
of Disease States • Must be equivalent in mechanism of cause.
• Can predict human toxicity in 71% of the cases.
Behavioural Studies

• Example :
Functional Imaging
✓ NOD/SCID (Non-obese diabetic/severe combined
immunodeficiency) mouse use for human cancer
xenografts/hematologic malignancies.
Ex-Vivo Studies ✓ BALB/c mouse : Syngeneic tumor models (eg;4T1 breast
cancer).
✓ Sprague Dawley : Toxicity study.
 Behavioural Studies
• Tools to investigate abnormal behavior that is caused by
Animal models agent chemicals, drugs or synthetic, which is the final
of Disease States
integrated expression of nervous function in the intact
animal.
Behavioural Studies
• Behavior is integrated outcome of nervous system. Thus,
it is connection between nervous toxicity and behavior.
Functional Imaging
• Used to observe depression and mental disorders.
Ex-Vivo Studies
• Example:
• Pain assessment
• Anxiety Based
• Presynaptic & postsynaptic inhibition (synaptic
inhibition)
-stop signaling/neurons communication

27
 Behavioral changes – Example pain analysis
Pain analysis
▪ According to Langford et al., (2010), pain can be identified through facial expression.

▪ To measure the pain level experiences by nonhuman species, a mouse grimace scale
(MGS) was developed. MGS can be defined as a standardized behavioral coding system
which assess the facial expression of pain. It was highly accurate and reliable (Langford et
al., 2010).

▪ MGS was determined through basic five features as shown in Figure 1 and each feature
consist of scale from 1 which indicated absence of pain to 3 which indicated severe pain.

▪ The features that were assessed are orbital tightening, nose bulge, cheek bulge, ear
position and whisker change. 28
Pain analysis

Figure 1 : MGS scale to assess the pain level suffer

by mice model (Langford et al., 2010) 29
In vivo toxicology
▪ It’s crucial to use the right animal model for
the right test.
▪ We use animal models which are closely related to
human physiology for the endpoint of interest
▪ We have very strict animal guidelines for the care and
use of animals
▪ An error, like the one used to study thalidomide can
lead to catastrophic failure

30
 In vivo toxicology

▪ Thalidomide tragedy (1961-1962).

▪ Introduced as safe and effective during
pregnancy to treat nausea.
▪ Potent human teratogen, caused major
birth defects in ~10,000 children.
▪ Very short or missing arms and legs,
missing parts of the ears, and
deafness

31
In vivo toxicology
▪ Considerations to select animals:
1. Selection of relevant animal species.
2. Suitable age.
3. Physiological state.
4. The manner of delivery (dose, ROA, treatment regime).
5. Stability of the test material under the condition of use.
6. Gender.
7. Number of animals to use.

32
The Principles of Humane Animal Experimentation

33
▪ These principles serve to guide in vivo researchers to achieve
the highest degree of animal welfare during the experimental
process.

▪ It was Originally outlined in 1959 by Russell and Burch, laid

the foundation for the basis of animal welfare in research that
we still use today.

▪ In vivo research is critical to the development of new

therapeutics, but steps can be taken to reduce the burden
placed on research animals.

34
Creation of the 3 R’s- Reduction, Refinement, and Replacement (not to be confused with 35
Reduce, Reuse, Recycle).
Contribution of animal models translation to humans

Yagihashi, S. (2023) 36
More details definition of preclinical study
▪ Preclinical studies refer to the testing of a drug, procedure or
other medical treatment in animals before trials may be carried
out in humans. During preclinical drug development, the drug’s
toxic and pharmacological effects need to be evaluated through
in vitro and in vivo laboratory animal testing. The FDA requires
sponsoring companies to develop a pharmacological profile,
determine toxicity in at least two species of animals and conduct
short-term toxicity studies.

▪ Various preclinical requirements exist for different kinds of

laboratory animals. Information gathered in preclinical studies are
used as evidence and support in FDA applications for the
approval of new drugs and medical procedures.
37
Importance of Preclinical trials

38
Preclinical stages
▪ At pre-clinical stage ,the regulatory bodies will generally
request :

I. Pharmacological profile of drug involving

pharmacokinetics and pharmacodynamics.
II. Determine the acute toxicity of the drugs in at least two
species of animals.
III. Conduct a short-term toxicity studies ranging from 2
weeks to 3 months, depending on the proposed duration
of use of the substance in the clinical studies. 39
 The range of major tests undertaken on a potential
new drug during preclinical trials.

➢Pharmacokinetic profile
➢Pharmacodynamic profile
➢Bioequivalence and bioavailability
➢Acute toxicity
➢Chronic toxicity
➢Reproductive toxicity and teratogenicity
➢Mutagenicity
➢Carcinogenicity
➢Immunotoxicity
40
 Specific Drug approved
compounds
Compounds synthesized and
by FDA almost 15
Compound
initially tested in preclinical s enter years after synthesis
screened in vitro & clinical and more than
in vivo assays testing $ 1 billion invested

Average time to market = 15 years

Figure 2 : Drug Development Pathway (Moller, 2012).

41
 Extrapolation of Preclinical Data
▪ Preclinical in vivo and in vitro studies are fundamental to the safe and
effective development of new drugs. Preclinical research is essential to a
better understanding of the pharmacological and toxicological activities of
drugs and their metabolites. Data generated by animal models and
alternative methods can be used and extrapolated to improve clinical trials,
particularly those for anticancer drugs.

▪ Estimation the first human dose is the first step in clinical trial or clinical
development of the drug molecule; it has to go through the successfully
through all of the hurdles of preclinical studies.

▪ A dose response curve must be obtained to check the therapeutic dose

and the toxic dose.
▪ Adverse drug response must be estimated to nullify the consequences.
42
Importance of preclinical trials
▪ To determine dose, toxic dose and pharmacological action and safety
profile.

▪ It is the requirement of regulatory body for performing clinical trials.

▪ As ethical view point, it is necessary to check safety of drug on animals

before starting to check on human being.

▪ To check the pharmacokinetic profile of drug & based on it, select the
route of administration in human for clinical trials.

▪ Regulatory authority approval to commence clinical trials is based largely

upon preclinical pharmacological and toxicological assessment of the
potential new drug in animals. 43
Toxicity testing
▪ Toxicology studies will be carried out both in vitro and on animal species.

▪ Toxicology and safety testing determine the potential risk a compound pose to
man and the environment.

▪ Dosage levels are explored initially at the stage of animal testing in efficacy and
safety models.

▪ Most substances are toxic if given at high enough doses: aims of early drug
development are to characterize the toxicity of a compound and to find the
balance between desired activity and tolerable toxicity.

44
 Types of toxicological investigations
Acute toxicity 2 weeks studies in minimum 2 species to
determine maximum tolerated dose.
Sub-acute toxicity 6 months studies in 2 species

Chronic toxicity ❑ Up to 12 months studies in rats and non-

rodent to determine if adverse effects
occur with repeated daily dosing.
❑ Oncology studies
o At least 18 months in mice
o 2 years in rat
➢ Earlier studies demanded calculation of an LD50 value (i.e. the quantity of the drug required to cause death
of 50 per cent of the test animals). Such studies required large quantities of animals, were expensive, and
attracted much attention from animal welfare groups.
➢ Nowadays, in most world regions, calculation of the approximate lethal dose is sufficient.
45
 Reproductive toxicity and teratogenicity
➢ Fertility studies aim to assess the nature of any effect of the
substance on male or female reproductive function.

➢ The drug is administered to males for at least 60 days (one full

spermatogenesis cycle).

➢ Females are dosed for at least 14 days before they are mated.

➢ These reproductive toxicity studies complement teratogenicity

studies, which aim to assess whether the drug promotes any
developmental abnormalities in the foetus (usually rats and rabbits).

➢ Evaluates effects on reproductive function and ability to produce

birth defects.

46
 Mutagenicity, carcinogenicity tests
❖ Mutagenicity tests aim to determine whether the proposed drug is capable of
inducing DNA damage, either by inducing alterations in chromosomal
structure or by promoting changes in nucleotide base sequence.

❖ Mutagenicity tests are usually carried out in vitro and in vivo 18-24 month,
often using both prokaryotic and eukaryotic organisms.

❖ Longer-term carcinogenicity tests are undertaken, particularly if

(a) the product’s likely therapeutic indication will necessitate its administration over prolonged
periods few weeks or more .
(b) if there is any reason to suspect that the active ingredient or other constituents could be
carcinogenic.
47
Acceptable toxicity
➢ Nowadays, extensive toxicological studies ensure that drugs causing
serious toxicity do not reach the market, unless of course the agent
concerned has potentially life saving role in treating a diseases.

➢ And where no other more suitable drugs are available.

➢ Even though the HIV drugs is considered toxic to human body.

However at present, HIV infection represents such a serious threat to
life therefore it is considered acceptable to use the drugs to treat it.

48
ROUTE OF EXPOSURE OF TOXICANTS

1. Skin & mucous membrane.

2. Lung (Inhalation).
3. Ingestion.

49
Skin & mucous membrane

▪ First line defense system.

▪ Chemicals that can penetrate
healthy intact skin (eg: hydrogen
cyanide).
▪ Absorption through skin from the
chemical that absorbed through
clothing is far worse.
50
 Lung (Inhalation)

▪ Depends on
• Size
Larger molecule (>10 micrometer) → lodge in
bronchioles/bronchi.
Insoluble particles (asbestos) → macrophage
tried to engulf but damaged → hydrolytic
enzyme leak →local tissue damage
• Rate of physical work (tidal volume increase
by exertion)

51
Ingestion

▪ Mostly can be avoided.

▪ Unexposed to poisonous materials.

52
CONCLUSION
▪ Preclinical toxicology are essential elements of the drug
discovery and development process and are critical in
enabling the translation of findings from the laboratory
to the clinical trials.
▪ No drug is completely non-toxic or safe. Adverse effects
can range from minor reactions such as dizziness or
skin reactions to serious and even fatal effects such as
anaphylactic shock.
▪ Remember : Quality, safety and efficacy are matters.
53
 THANK YOU

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 Pre-formulation
concept as a whole
SSSO
Content
Introduction
Optimization
Physicochemical Characterization
◦ Organoleptic
◦ Bulk Characterization
◦ Solubility Analysis
◦ Stability Analysis
 Introduction
“Pre-formulation study is a phase which works on study of physical, chemical, analytical, pharmacokinetic,
and pharmacodynamic properties of new chemical entity and utilize the obtained results to design and
develop an effective, stable, and a safer dosage form.”
Toxicology Formulation into
Preformulation
studies dosage form
Objective
1. To lay down foundation for transforming a drug into a pharmaceutical formulation in such a way that it
can be administered in a right way, in right amount, and at the right target.
2. To provide longer stability to the formulation by proper designing and protecting drug component
from environmental condition and to evaluate performance of developed formulation.
3. To generate information useful to the formulator in developing stable and bioavailable dosage forms
which can be mass-produced.
 Pre-formulation study outline
Pre-formulation is a group of
studies that focus on the
physicochemical properties of a
new drug candidate that could
affect
◦ drug performance and
◦ development of a dosage form.
•This could provide important
information for
◦ formulation design
◦ molecular modification.
Continue
Continue
 Optimization of an active molecular
entity
The optimization of molecule is
needed to ensure
1. stability of molecule under normal
environmental condition
2. to enhancing the performance of
that molecule (bioavailability and
stability)
 Efforts made to optimize a molecule
is to form salts, solvates, polymorphs,
and more importantly prodrug.
Salts
Converting a molecule into a salt form is
widely used to significantly enhance the
performance of a molecule.
This improvement can be made in area such
as follows:
◦ Improved stability (hydrolytic and thermal
stability)
◦ Better organoleptic properties (taste masking)
◦ Increased patient compliance (decreased side
effects)
◦ Modified release dosage forms
 Salts
Factors to be considered while selecting appropriate salt form.
1. Type of formulation to be developed
◦ For tablet, oral solution, or injectable; sodium and hydrochloride salt
leads to enhanced solubility and better bioavailability.
◦ For suspension; insoluble salt forms like tosylate, estylate, and embonate
are preferred.
◦ Example
◦ the propionic acid derivative naproxen exists in free acid form and has lower
water solubility and hence less bioavailability.
◦ When it is converted to sodium salt, its water solubility is increased by several
fold and hence better bioavailability.
Salts
2. Therapeutic indication
◦ if drug is indicated in the treatment of hypertension, need to consider the suitability ofusing
sodium or potassium salt
3. Meet regulatory requirement
◦ must be free from toxicity. For example, use of lithium salt is strictly prohibited.
4. Type of release
◦ For immediate release formulations, sodium or hydrochloride salts are preferred as they
show better solubility.
◦ For delayed release formulation, one can prefer low solubility salt form such as tosylate,
estylate, and embonate
5. Patient compliance
◦ Reduce pain
◦ Taste masking
Prodrug
Prodrug is the chemically modified inactive derivative of
active form with optimized properties and better in vivo
performance.
Prodrug can be defined as inactive form that undergoes
biotransformation and converted to active form to elicit its
pharmacological effect
There are two main broad classes of prodrug that are
carrier-linked prodrug and
bioprecursor prodrug
 Prodrug (Goals)
Improving unfavorable physical properties: Improving unfavorable pharmacokinetic
properties:
Improvement in water
solubility. Improving bioavailability.

Improvement in Improving penetration

lipophilicity. power through membrane.

Improvement in chemical Reduce first-pass

stability. metabolism.

Improvement in Target-specific drug

organoleptic characteristic. delivery.
 Prodrug
CARRIER-LINKED PRODRUG

Drug is linked to a carrier moiety by a

temporary covalent linkage
Carrier molecule or functional group can be
easily removed in vivo, usually by hydrolytic
cleavage

BIO PRECURSOR PRODRUG

Results from a molecular modification of the

active principle
In vivo transformation of drug generates a
new metabolite (metabolic transformation)
 Target-specific drug delivery

• selective metastatic colon cancer is capecitabine

which is prodrug of 5-fluorouracil. Capecitabine
requires triple-phase transformation to be
converted to its active form 5-fluorouracil.

Examples Improve the lipophilicity

• terbutaline is orally active beta-2-agonist and is

indicated in bronchial asthma. It requires
significantly higher dose due to lower
lipophilicity. Its prodrug bambuterol has
improved lipophilicity as well as chemical
stability and thus requires considerably lower
dose than terbutaline
Physicochemical Characterizations
Organoleptic Bulk Solubility Stability
properties characterization analysis analysis
Crystallinity and Drug-excipient
Odour Polymorphism Partition coefficient compatibility
(LogP)
Hygroscopicity
Colour Stability in various
Fine particle Dissociation constant conditions
characterization (pKa) • Hydrolysis
Appearance • Oxidation
Density • Photolysis
• Racemization
Solubility study • Stability as
Etc: texture, taste Flow properties solid/solution
Importance of Physicochemical CCC
Understanding Physicochemical Properties:
◦ Provide essential insights into the physicochemical properties of drug substances, including solubility,
stability, polymorphism, and compatibility with excipients.
◦ Crucial for selecting the most appropriate formulation approach and excipients to ensure the drug's
stability, bioavailability, and efficacy.

Optimizing Formulation Development:

◦ By identifying and addressing potential challenges or limitations early in the drug development process,
◦ This optimization includes selecting suitable dosage forms, determining the optimal drug-excipient
ratios, and optimizing manufacturing processes.
◦ Overall, help streamline the formulation development process, reduce development time and costs,
and improve the chances of success for pharmaceutical products
Organoleptic
properties Organoleptic Properties
Refer to the sensory characteristics or qualities of a substance
Odour
that can be perceived by the human senses, particularly taste,
smell, sight, touch, and sometimes, hearing.
Depending on the type of product, the properties should be
Colour appealing or acceptable to end-consumers
Eg;
◦ Paracetamol (taste-masking)
Appearance ◦ Retinoic acid (colour)
◦ Antibiotics (odour)

Etc: texture, taste

 Bulk
characterization Bulk Characterization
Crystallinity, and
Polymorphism The process of understanding and describing the overall or
collective properties of a substance, typically in its larger
quantity or bulk form.
Hygroscopicity
Investigates how a material behaves as a whole, considering
factors that apply to the entire mass rather than individual
particles.
Fine particle characterization
The goal is to ensure that the material's bulk properties are
suitable for its intended use, taking into account factors that
Density
affect its stability, performance, and compatibility in different
conditions.

Flow properties
 Crystallinity and Polymorphism

Solids can be classified into 2 main categories which are 1) Crystalline and 2) Amorphous
While polymorphism is a type of crystal form.

Crystalline Amorphous Polymorphism

•A solid material in which the atoms, •lack a long-range order in their •refers to the ability of a substance
ions, or molecules are arranged in a atomic or molecular structure. In to exist in different crystal
highly ordered, repeating pattern other words, they do not have a structures or arrangements while
extending in all three spatial well-defined, repeating pattern at maintaining the same chemical
dimensions. the atomic level. composition.
•Characteristics: •Characteristics: •Characteristics:
• well-defined and repeating • disordered or random • have different crystal structures
geometric structure. arrangement of atoms. but the same chemical formula.
• exhibit sharp, well-defined • lack sharp faces and edges and • Each polymorph has its own set
faces and edges. may appear more like a random of physical and sometimes
• have a distinct melting point. network. chemical properties depend on
• may not have a distinct melting solvent, temperature & time
point; instead, they may soften • can impact the stability,
gradually over a range of solubility, and bioavailability of
temperatures. a substance.
 Crystallinity and Polymorphism

Polymorphism
Advantage:
Formulation flexibility
and better bioavailability.
Crystalline Amorphous
Advantage: Disadvantage:
Advantage: manufacturing & stability
Higher solubility hence issues d/t unpredictable
Impeccable stability higher dissolution rate,
improve bioavailability transformation
Disadvantage:
Disadvantage:
Low water solubility Reduced stability in
comparison to crystalline
Examples, antibiotics
For example, Penicillin G as sodium or potassium salt in crystalline
Crystalline form has the better stability and hence stable and better
therapeutic response in comparison to amorphous form.
For example, novobiocin when administered in crystalline form
showed no therapeutic activity, while amorphous form showed
Amorphous better absorption from gastrointestinal tract with significant
therapeutic response
Similarly, chloramphenicol palmitate exists in three different
polymorphic forms, namely, A, B, and C. Form B has higher
Polymorph solubility and better dissolution profile, while form A is more stable
one but low serum concentration was observed.
 Hygroscopicity

The capacity of a compound to absorb In European pharmacopeia, hygroscopicity is described by

atmospheric moisture. four different classes after being stored at 25°C at relative
depends on atmospheric conditions and humidity of 80% for 24 hours.
surface area.
absorbs moisture to a greater extent and Table 1: : Categorization/classification as per Ph. Eur. method
liquefies itself: Deliquescent substance
Material Category Criteria as per Ph.Eur
changes in the moisture level can Non-hygroscopic 0-0.0012% w/w
influence chemical stability, flowability,
and compressibility to a greater extent. Slightly hygroscopic 0.2-2% w/w
Moderately hygroscopic 2-15% w/w
Very hygroscopic More than 15% w/w
Fine Particle Characterization

Surface Size
area

Shape
 • improve the solubility by
reducing the particle size
(increased surface area).
Surface Size solubility • Settling, agglomeration,
area coalescence, Ostwald
ripening, increased
viscosity

Shape
• Eg suspension; too small,
Particle charged particle, unstable
stability system
Particle size greatly affects a size • Too large,
number of quality parameters caking/sedimentation
like
 dissolution rate,
 solubility,
 bioavailability,
 content uniformity, • Particle size distribution –
 grittiness. Content polydispersity index
uniformity • Risk associated with potent
drugs – burst release
 Particle shape may influence
Surface Size
area  surface area,
 flow properties,
 and compaction force.
Shape May exist in different forms like spherical,
angular, acicular, needle, oval, or rough.
Spherical particle has the minimum area and
uniform flow property.
 The maximum surface area ensures the
better solubility.
Surface Size and Surface area are inversely related to
Size each other
area
Smaller drug particle, greater surface area
Maximum surface are, better solubility
Shape
Better solubility >>>> better dissolution
Better dissolution >>>>> better bioavailability
Better bioavailability >>>> better efficacy and
overall therapeutic effect
 Density

ratio of mass of a substance to its volume, which greatly depends on particle size distribution
and shape.
Various densities are proposed to consider presence of different types of void volume in a bulk
volume

True density Bulk density Tapped density

total volume of solids total volume occupied by entire determined by placing
powder mass +space/void graduated cylinder containing
excluding all space
It can be determined by placing known weight of sample on
greater than molecule previously sieved powder bulk tapped density apparatus and
diameter. into a graduated cylinder and is operated for the fixed
measuring the volume in number of taps until a
milliliters.
constant volume is attained.
Examples
•With drugs having low density, the bulk becomes more and
hence capsule formulation is quite difficult to formulate as
capsule can incorporate limited volume.
•In development of tablet formulation, low-density drug
creates difficulties as they are having low compressibility
and hardness in tablet is difficult to achieve.
•If the difference of density is more between drug substances
and excipients, homogeneity in the formulation is difficult to
achieve
 Flow Properties

Flow property of material can be affected by a number of factors including

Frictional forces, surface tension forces, electric forces, and van der Waals
forces.
Efficient flow of drug substance powder is needed for effective tablet
formulation (hopper), Liquid formulation, important for determination of
packaging
Linkage with other physical parameters like hygroscopicity and particle size
and shape.
• In case of hygroscopic material, flow property of drug tends to deteriorate as the
presence of absorbed moisture increases cohesiveness. (hygroscopic)
• Irregular particle size and nonuniform shape can also disturb normal flow property
of drug. (shape)
• Smaller particle size, usually has better flow property (size)
 Flow Properties

How to measure flow properties

Liquid & Semisolid

Rheology, Thixotrophy

Solid
Angle of repose Hausner’s ratio Carr’s compressibility Index
Resistance to the movement of Ability of powder to decrease in
particle Number that is correlated to volume under pressure
the flowability of powder &
granules [(Tapped density−Bulk
density)/Tapped density] x100.
It is the maximum angle that can
be obtained between height of Tapped density/Bulk density
pile and a horizontal plane
Solubility analysis
Solubility Analysis
Preformulation solubility studies focus on
Partition coefficient (LogP)
drug-solvent systems that could occur
during the delivery of drug
Understanding drug solubility profile and
Dissociation constant (pKa) possible solubilization mechanism provide
a basis for formulation work

Solubility study
 Partition coefficient

◦ Ratio of concentration of solute in two LogP=(Coil/Cwater)equilibrium

immiscible or slightly miscible liquids.
◦ It measures how hydrophilic or hydrophobic
a drug is If the value of Log P is 0, it indicated that
◦ Importance drug has equal distribution in water and
◦ Estimates distribution of drug in the body
partition solvent.
◦ gives the idea about drug’s ability to cross the Value of Log P less than 1 is indicative of
lipidic membrane. higher water solubility and value greater than
◦ Lipophilic/hydrophilic balance is one of the 1 is indicative of higher lipidic solubility.
most important contributing factors for
optimum drug absorption and delivery. For optimum solubility and absorption, a
proper hydrophilic-lipophilic balance is
necessary.
 Partition coefficient

oHighly used method is to determine LogP is shake flask method

that utilizes octanol-water system to determine drug’s partitioning
behaviors.
oThere are several reasons behind selection of octanol as
partitioning solvent, which can be explained as follows:
o mimic the lipoidal character of biological membrane as it contains polar
head and nonpolar tail.
o immiscible with water;
o Solubility parameter for most of the drugs resembles with that of
octanol.
 Dissociation Constant

dissociation constant (pKa) is the property that determines the

solubility in pH-dependent environment and extent of ionization

extent of ionization that determines the absorption as unionized

form can be absorbed more readily across biological membranes

Weakly acidic drugs having pKa value around 4 are best

pKa value determination gives absorbed from stomach

idea about site of absorption. Basic drugs having pKa value of around 8 are best
absorbed from intestine
 Solubility Study

Backbone study of preformulation stage that determines the performance of developed

formulation.
Solubility and permeability forms the scientific basis of biopharmaceutics classification system
(BCS), which can provide framework for designing type of drug delivery system
 Solubility Study

The solubility of a drug is the amount of the drug that dissolves in a

given solvent to produce a saturated solution at constant temperature
and pressure
not an independent parameter but it relies on several properties like
crystal characteristics, temperature, pH, complexation, and
molecular structure.
several techniques, which are available to improve the solubility of
drug candidate, which are as follows:
Chemical modification of drug
Addition of cosolvent or surfactant
Particle size reduction
Hydrotropy
Complexation
Stability analysis
Stability Analysis
Drug-excipient
compatibility To identify the conditions in which molecule
is susceptible to deteriorate and to
determine degradation pathway.
Stability in various
conditions The mechanism of degradation and
• Hydrolysis condition provides the idea about proper
• Oxidation
• Photolysis designing of formulation, suitable molecular
• Racemization
• Stability as solid/solution
modification, appropriate storage condition,
and selection of proper packaging material.
 Drug-excipient compatibility

Most excipients have a role in administration, mediating the

release of the active component, and providing stability
against degradation.
Inappropriate excipients can also give rise to unintended
effects, which can affect the chemical nature, the stability,
and the bioavailability of the API, and consequently, their
therapeutic efficacy and safety.
This study can provide idea about type of incompatibility
and the justification behind the inactive ingredient selection
Methods in drug-excipient compatibility
study
-Fourier-transform infrared (FTIR) spectroscopy:
◦ Used to identify chemical interactions and changes in functional groups.
-Differential scanning calorimetry (DSC):
◦ Determines changes in thermal properties, such as melting point and crystallinity.
-X-ray diffraction (XRD):
◦ Analyzes changes in crystal structure and polymorphism.
-High-performance liquid chromatography (HPLC):
◦ Quantifies degradation products and assesses chemical stability.
-Compatibility testing:
◦ Involves physical mixing of drug and excipient followed by observation of any changes in
appearance, color, odor, or pH.
DSC
FT-IR
 Drug-excipient compatibility

Drug-excipient incompatibility may result in change in physical, chemical,

microbiological, or therapeutic properties of formulation.
Change in organoleptic properties of formulation.
Changes in in vivo performance of formulation, that is, dissolution.
Decreased potency of active ingredient.
Generation of toxic degradation product.
Change in physical appearance of formulation, that is, color, phase conversion.
Physical incompatibility
Active pharmaceutical ingredient and excipients interact
without undergoing chemical changes
The resulting drug product changes take place such as
alteration in physical properties
change in color, odor, flow properties, and sedimentation
rate.
Example:
tetracycline and calcium carbonate.
It results in formation of insoluble complex with calcium
carbonate, leading to slower dissolution and decreased
absorption in the gastrointestinal tract
Chemical incompatibility
There is interaction of active pharmaceutical ingredient and
excipient through chemical degradation pathway.
Involves bond breakage or new bond formation to produce
an unstable chemical entity.
Chemical reaction may take place as hydrolysis, oxidation
racemization, and Maillard reactions.
The resulting changes are more deleterious than physical
incompatibility.
Eg; certain amine drugs (paracetamol) react with lactose
(diluent) in the presence of Magnesium stearate to form
brown color compound. Cause darkening of the tablets and
the integrity of the tablet maybe loss.
Therapeutic
incompatibility
interaction will take place once the formulation is
administered into the body
referred to as biopharmaceutical interaction, interaction
between excipient, active component, and physiological
fluid
 examples
interaction of enteric coated polymers, when administered
along with antacids.
they dissolve prematurely and release the drug that is liable
to acid degradation or may cause adverse effect in GI, that is,
gastric bleeding associated with NSAIDs
 Stability in various conditions

The major mechanisms by which a molecule undergoes degradation are

Hydrolysis Oxidation

Photolysis Racemization
 Stability in various conditions

HYDROLYSIS
Hydrolysis involves reaction of a molecule with water resulting in cleavage of a chemical bond.
Effectiveness of molecule therefore depends on hydrolytic stability of molecule.
•For example, lidocaine is amide derivative of procaine, which is ester derivative used as local
anesthetic. As ester derivative is more readily hydrolyzed; its duration of action is short while
amide derivative is more stable and hence used as long-acting local anesthetic.
•Beta-lactam antibiotics are susceptible to hydrolysis and hence they are supplied as dry powder
injection where they are reconstituted before intravenous administration.
 Stability in various conditions

OXIDATION
Oxidative degradation, involves exposure of molecule to
atmospheric oxygen or autoxidation by free radicals.
Can be initiated in presence of light or elevated temperature.
So degree of oxidation can be controlled by avoiding exposure to
lights and storage at controlled temperatures.
Even the extent of oxidation can be controlled by addition of
antioxidants.
Eg: Retinoic acid contains several conjugated double bonds in its
chemical structure. These double bonds are very vulnerable to attack
by oxygen (especially in the presence of light, heat)
 Stability in various conditions

PHOTOLYSIS
Refers to decomposition of a molecule by absorption of energy when exposed to
light.
Exposure to light not only brings photodegradation but may trigger oxidation.
For example, riboflavin and vitamin B12 are susceptible to photodegradation directly
and oxidation induced by light.
So to avoid the decomposition, the formulation containing vitamin B12 and riboflavin
is stored in amber color vials.
Amber color bottles do not allow the ultraviolet radiation to pass through, which is the
main factor for photodegradation.
 Stability in various conditions

RACEMIZATION
It is an event where optically active molecule becomes inactive without any change in molecular
composition.
Racemization leads to either loss of pharmacological action or toxic effect may be enhanced by
severalfold.
 Racemization is mostly affected by the conditions like pH, type of solvents, presence of light, and
temperature.
 Stability in various conditions

Chirality
Many molecular entities exist in racemic form, but only
one form gives the desirable pharmacological activity.
Other present isomer may be devoid of pharmacological
activity or may exhibit deleterious side effects
Thalidomide exists as racemic form. It was introduced as
a sedative agent. The S-enantiomer of thalidomide was a
teratogenic agent, while R-enantiomer was effective as a
sedative agent. Lack of knowledge about chiral selectivity
leads to disastrous consequence.
Examples
Thank you
[email protected]
 INTELLECTUAL PROPERTY IN
DRUG DEVELOPMENT
Ts Dr Muhammad Luqman Bin Nordin
Department of Pharmaceutical Technology
Faculty of Pharmacy
Universiti Malaya

www.um.edu.my
By the end of this topic, you will be able to :

▪ Identify type of intellectual property available in Malaysia

and global.
▪ Explain the basic principles of intellectual property,
including patents, copyrights, trademarks, industrial
designs.
▪ Describe the role and importance of IP protection in the
pharmaceutical industry.
▪ Discuss ethical considerations around IP rights and
access to essential medicines.
2
 INTELLECTUAL PROPERTY
▪ Intellectual property (IP)
may be protected at law in
the same of any other form
of property.

▪ Intellectual property laws

vary from jurisdiction to
jurisdiction.

3
 Tangible
• Land
• Houses,
• Car, etc

PROPERTY

Intangible
IP

4
 TYPE OF IP

Trade Industrial Geographical

Patent Copyright Trademarks secret Design Indications

5
THE LAW FOR INTELLECTUAL PROPERTY
PROTECTION

• Copyright Act 1987

• Trademarks Act 1976
• Patent Act 1983
• Industrial Design Act 1996
• Geographical Indications Act 2000
• Law of Tort (Civil Law)
- Confidential information

6
PATENT
▪ A patent is an exclusive right granted for an invention, which
is a product or a process that provides a new way of doing
something, o offers a new technical solution to a problem.
▪ An invention is a product or a process that provides a new way
of doing something, or offer a new technical solution to a
problem.
▪ They usually give the creator an exclusive right over the use
of his/her creations for a certain period of time in written
document that describes what is his/her creations.
7
 PATENT
Definition of utility innovation :
A utility innovation is an exclusive right granted for a “minor” invention which does not require to satisfy the test of
inventiveness as required of a patent.

Definition of Patentable inventions :

▪ New, which means that the invention has not been publicly disclosed in any form, anywhere in the world;
▪ Involve an inventive step, that is to say the invention must not be obvious to someone with knowledge and
experience in the technological field of the invention; and
▪ Industrially applicable, meaning it can be mass produced.

Definition of Non-patentable inventions :

▪ Discoveries, scientific theories and mathematical methods;

▪ Plant or animal varieties or essentially biological processes for the production of plants or animals, other than
man-made living micro- organisms, micro-biological processes and the products of such micro-biological
processes;
▪ Schemes, rules or methods for doing business, performing purely mental acts or playing games;
▪ Methods for the treatment of human or animal body by surgery or therapy, and diagnostic methods practiced on 8
the human or animal body.
9
DURATION OF PATENT

▪ A patent is protected 20 years from the date of filing.

10
DURATION OF UTILITY INNOVATION

▪ A utility innovation is protected 10 + 5 + 5 years from

the date of filing subject to use.

11
CRITERIA FOR PATENT

• New or novelty
• Appropriate Subject Matter
• Applicable/Enablement

12
NEW OR NOVELTY

• Means “New and Never Done Before”

• Only applies to what you claim is your invention (described in the
claims)
• How to check if your idea is “Novel”
» Patents search
» Magazines & Scientific/Engineering Journals
» Existing products for sale

13
APPROPRIATE SUBJECT MATTER
1. Appropriate Subject Matter
» “Anything under the sun made by man”
» Machines / Mechanical apparatus
» Processes
• Methods to make something
• Methods to use something
» Composition of Matter
» Improvements on existing technology
» Not appropriate:
» Naturally occurring objects
» Living organisms
» Natural discoveries
» Perpetual Motion Machine
14
APPLICABLE/ENABLEMENT

▪ Idea must be developed enough that you can describe

it in sufficient detail to enable somebody with technical
skill to make and use the invention.
▪ Requires detailed written description, and usually
drawings.
▪ Don’t need to actually make your invention, or have a
prototype built.
15
Example
Claim 1: A chair comprising:
a triangular seat;
three legs attached to said seat;
a back attached to the rear of the seat; and
one armrest.

16
WHO MAY APPLY?
▪ Any person may make an application for a patent either alone or
jointly with another person. The word "person" is not limited to
natural persons and thus also includes, for example, a company;

▪ The rights to a patent shall belong to the inventor. Where two or

more persons have jointly made an invention, the rights to a
patent shall belong to them jointly. If two or more persons have
separately and independently made the same invention, and
each of them has made an application for a patent, the right to a
patent for that invention shall belong to the person whose
application has the earliest priority date.
17
 PATENT APPLICATION PROCESS
UMCIE submit an application to
Application Form (Online) via e-
Form Reviewed by UMCIE a patent agent for status search
Register IPR in UM Portal
(Novelty Search)

UMCIE will submit evaluation UMCIE will send a copy of the

UMCIE will record and file
report KJPHIUM for approval completed application
documents
and centification documents to the applicants

UMCIE will send a notice of

Received completed application
agreement to the patent agent
documents registered on
and applicant for a discussion
MyIPO from a patent agent
of the draft property 18
Patent Application Process (International)

19
20
 What is Copyright?
▪ The exclusive right to control
creative works created by
the author, copyright owner
and performer for a specific
period governed by the
Copyright Act 1987.

21
 COPYRIGHT CRITERIA
Creative works eligible for copyright :

1. literary works;
2. musical works;
3. artistic works;
4. films;
5. sound recordings;
6. broadcasts (only for broadcaster);
7. published editions; and
8. derivative works.

Sufficient effort has been expended to make the work original in character
The work has been written down, recorded or reduced to material form.
▪ Copyright protection shall not extend to any idea, procedure, method of operation or mathematical concept
22
Benefit of filling of copyright

• Public notice of your ownership and rights

• Legal evidence of ownerships
• Validity
• Maximization of damages
• Ability to bring an infringement suit

23
 Duration of copyright
1. Literary, musical or artistic works
Copyright protection will be in effect for the duration of the author's life and
will last for fifty years following his passing. When a work is co-authored, the
fifty years start after the last author's death.

2. Films, sound recordings, broadcasts, published editions or works of

Government or international bodies
The fifty-year duration was calculated starting from the first day of the
calendar year after the date on which the work was created or published.

3. Performers’ rights or equitable remuneration

The fifty-year duration was calculated starting from the first day of the
calendar year after the date on which the performance was fixed in a sound
recording or the sound recording is published.
24
Criteria for Assistance

▪ The work created should be an expression of idea rather

than a mere idea.
▪ The work must be original.
▪ The work need to be set in the form of materials.
▪ The creator is a worthy, qualified person and permanent
resident of Malaysia.
▪ The work was originally published and under control of
Universiti Malaya.
25
 The legal rights
1. The Authors
The owner of the copyright may be the author, who has both moral and exclusive rights. Usually, the author's
moral rights are retained while the exclusive right is transferred to the new copyright owner. These moral rights
are limited to the right to be identified or protest any act that affects their work or reputation.

2. The Copyright owner

The Copyright Act of 1987 gives the owner of the copyright the rights to prevent unauthorized use, reproduction
or any acts of their works. A civil or criminal court may charge person responsible for any copyright infringement
if they perform any act related to the works without the license, authority, or consent of the copyright owner.

3. The Performers

The performers have the right to stop any acts that are connected to their fixation of performance, including
unlawful use and reproduction. If someone violates their rights without permission, they could face legal action
in a civil or criminal court. They also have the same moral rights as authors, which include the right to recognize
and object any actions that harm their reputation.
26
Actions and remedies
If someone uses their work or performance without permission,
the copyright owner or performers may file a lawsuit against
them by:
• In a civil litigation, the court may issue an order for statutory
damages, an account of profits, an injunction, damages, or
any other order it thinks appropriate; or
• Criminal action by reporting the offender to the Ministry of
Domestic Trade and Cost of Living's Enforcement Division or
the Royal Malaysian Police, which could result in a fine, jail
imprisonment, or both.
27
Example Process of Copyright Application at UM

28
Procedure of Copyright Application

29
TRADEMARK
▪ Any sign that can be represented graphically and that is capable of distinguishing
the goods or services of one business from those of other businesses.

▪ A trademark includes any letter, word, name, signature, numeral, device, brand,
heading, label, ticket, shape of goods or their packaging, color, sound, scent,
hologram, positioning, sequence of motion or any combination thereof may be
trademarked.

30
SYMBOLS

mean that the trademark is registered & protected under trade mark law.

merely gives and indication that trademark is used by the company.

31
 DEFINITIONS OF TRADEMARK
▪ Trademark means any sign capable of being represented graphically which is capable of
distinguishing goods or services of one undertaking from those of other undertakings.

▪ Sign – any letter, word, name, signature, numeral, device, brand, heading, label, ticket,
shape of goods or their packaging, color, sound, scent, hologram, positioning, sequence
of motion or any combination thereof.

▪ Collective Mark – A collective mark shall be a sign distinguishing the goods or services of
members of the association which is the proprietor of the collective mark from those of
other undertakings.

▪ Certification Mark – A certification mark shall be a sign indicating that the goods or
services in connection with which it shall be used are certified by the proprietor of the
mark in respect of origin, material, mode of manufacture of goods or performance of
services, quality, accuracy or other characteristics.

32
FUNCTIONS OF TRADE MARK
▪ Origin – A trade mark helps to identify the source and those
linked for the products and services trade in the market.
▪ Choice – A trade mark assists consumers to choose goods
and services with ease.
▪ Quality – Consumers define a certain trade mark for its
known quality.
▪ Marketing – Trade mark play a significant role in promoting.
It’s common for consumers to make purchases based on
continuous effect of advertising.
▪ Economic – Recognized trade mark is a valuable asset.
Trade marks may be licensed or franchised.
33
NON-REGISTRABLE TRADE MARK

1. Prohibited Marks
If the use of which is likely to confuse or deceive the public or contrary to law.

2. Scandalous or Offensive Matter

If it contains or comprises any scandalous or offensive matter or would not otherwise
be entitled to protection in any court of law.

3. Prejudicial to the Interest or Security of the Nation

Registrar bears the responsibility of determining the trade mark, whether it might be
prejudicial to the interest or security of the nation. It may be that a mark contains an
inflammatory statement or words.
34
 FUNCTION OF TRADEMARKS
1. Origin
A trade mark helps to identify the source and those linked for the products and services trade in
the market.

2. Choice
A trade mark assists consumers to choose goods and services with ease.

3. Quality
Consumers define a certain trade mark for its known quality.

4. Marketing
Trade mark play a significant role in promoting. It’s common for consumers to make purchases
based on continuous effect of advertising.

5. Economic
Recognized trade mark is a valuable asset. Trade marks may be licensed or franchised.
35
IMPORTANCE OF TRADE MARK REGISTRATION

Exclusive Rights – Registered trade marks owners have exclusive right to

use their marks in trading. They also have the rights to take legal action
for infringement under the Trade Mark Law against others who use their
marks without consent. They can either take civil action or lodge
complaints to Enforcement Division for appropriate actions under the
Trade Description Act 1972.
Legal Evidence – Registration certificate issued by Registrar Office is a
prima facie evidence of trade mark ownership. A certificate of
registration serves as an important document to establish the ownership
of goods exported to other countries.
36
DURATION OF REGISTRATION

▪ Trade mark registration is valid for ten years from the

date of application and may be renewed every ten
years.

37
Trademark application process

38
 INDUSTRIAL DESIGN (INDUSTRIAL
DESIGNS ACT 1996)
What is industrial design?
An industrial design means features of shape, configuration, pattern
or ornament applied to an article by any industrial process which
in the finished article appeal to the eye and are judged by the
eyes.

An industrial design may consist of:

• Three-dimensional features, such as the shape of an article

• Two-dimensional features, such as patterns, lines,39or color

 Industrial design
REGISTERABLE INDUSTRIAL DESIGN

•New in Malaysia or elsewhere

•The industrial design should be interpreted in order to
be fulfilled
•Not in conflict with public order or morality

40
NON-REGISTRABLE INDUSTRIAL DESIGN

▪ A method or principle of construction.

▪ The designs of articles depend upon the appearance of
another article which forms an integral part of the
article.
▪ It differs only in immaterial details or features.
▪ The features of the article are dictated solely by
function.
41
 IMPORTANCE OF INDUSTRIAL DESIGN
REGISTRATION
▪ Owner of a registered design has the exclusive right to
make, import, sell or hire out any article to which the
design has been applied.
PERIOD OF REGISTRATION
1. A registered industrial design is given an initial protection period of 5 years
from the date of filing.

2. Extendable for a further four consecutive terms. The maximum protection

period is 25 years. 42
WHO MAY APPLY?

1. Author
2. Company
3. Individual

43
Industrial design application process

44
 Importance of IP Management in
Pharmaceutical Industries
• Pharmaceutical sector, highly globalized, necessitates robust IP systems.
• Cost of introducing new drugs is substantial ($300 million to $1000 million),
prompting stringent IP protection.
• IP creation, acquisition, protection, and management should be integral to
corporate activities, akin to resource raising.
• Knowledge revolution underscores the need for prioritizing IP in decision-making
processes.

45
 Some Special Aspects of Drug Patent
Specification
Professional Skill in Patent Specification Writing:

▪ Requires scientific, technological, and legal knowledge.

▪ Claims form the essence of the patent seeking legal proprietary.

Patentability Considerations:
▪ Discovery of new property in known material not patentable.
▪ Invention possible if new property has practical use, leading to patentability.
▪ Combination of known substances patentable if exhibiting new result, even
without chemical reaction.
▪ Methods of treatment for humans and animals generally not patentable, except
in the USA.
46
 THANK YOU

www.um.edu.my universityofmalaya unimalaya uniofmalaya

Commercial Considerations
in Drug Development

OIA 3027 Drug Discovery and Development

Dr Janet Tan Sui Ling
Department of Pharmaceutical Technology
Faculty of Pharmacy

www.um.edu.my
Learning Outcomes

▪ CLO 4: Explain the safety evaluations, ethics of human and

animal experimentation, intellectual property and
commercial considerations in drug development.
» Explain the key commercial considerations in drug
development

2
Drug Development Process

Where does commercial considerations come in?

3
Importance of Commercial Consideration

▪ Costs associated with drug development:

» Research and development (R&D) expenses
» Clinical trial costs (patient recruitment, data management,
etc.)
» Regulatory submission fees
» Manufacturing and distribution costs
» Marketing and sales expenses

But only a small percentage of drug candidates make it from the lab to the
market!

4
Commercial Viability

▪ The ability of a drug to generate sufficient revenue to

recoup its development costs and provide a reasonable
return on investment.
▪ Ongoing process during the drug development process.
▪ Decision whether to continue to invest in a particular
drug candidate.
▪ Determine the position of drugs to ensure success in the
market.

5
Key Commercial Features

Market size /
potential

Marketing and
Competitive
sales
landscape
strategies

Key Commercial
Features

Regulatory Pricing and

requirements reimbursement

Intellectual
property
protection

6
 Market Size / Potential
▪ Market size: Who and how many needs the drugs?
▪ Potential revenue and return on investment.
▪ Break the market into segments based on demographics, disease
severity, and other relevant factors.
▪ If the market is too small, the drug may not recoup its development
costs.

▪ Early stages: Initial market assessments inform go/no-go decisions for

drug candidates.
▪ Clinical trials: As clinical data emerges, refine market models based on
the drug's actual performance and target patient populations.
▪ Pre-launch: Conduct detailed market research to understand patient
needs, prescriber preferences, and market access dynamics.

7
Market Trends and Future Projections

▪ Predicting how the market will change in the future.

▪ Forecasting market growth, technological
advancements, and changes in healthcare policies that
could impact the drug's commercial potential.

8
Competitive Landscape
▪ To know the potential competitors:
» Helps in positioning of the drug,
» Differentiating it from existing therapies
» Forecasting market share

Early stages: Identify potential competitors and their pipelines to

anticipate future competition.
Clinical trials: Compare the drug's efficacy and safety profile to
existing and emerging therapies to highlight its advantages.
Pre-launch: Develop strategies to address competitive threats, such
as head-to-head trials, targeted marketing, and pricing adjustments.

9
Pricing and Reimbursement
▪ Determine whether patients can afford the drug and whether
healthcare payers (insurance companies, governments) are willing to
cover it.

▪ Early stages: Preliminary pricing models are developed based on

market research, competitive analysis, and anticipated development
costs.
▪ Clinical trials: Health economics and outcomes research (HEOR)
data is gathered to demonstrate the drug's value to payers.
▪ Pre-launch: Negotiations with payers are conducted to secure
favorable reimbursement terms.

10
 Pricing and Reimbursement
▪ Pricing strategies: Determine market access and competition with
generics.
» Value-based pricing,
» Cost-plus pricing,
» Competitive pricing.

▪ Factors that influence pricing decisions:

» Cost of development
» Clinical benefits of the drug,
» Prices of competing therapies.

11
Pricing Strategies

Cost

Market
Access
12
Intellectual Property Protection

▪ Intellectual Property refers to legal rights that protect creations of

the mind, such as inventions, literary works, and symbols. In
pharmaceuticals, IP primarily revolves around patents, which grant
exclusive rights to manufacturers for a specific period (usually 20
years).

▪ Early stages: File patents on the drug's composition, formulation,

and method of use to secure broad protection.
▪ Throughout development: Monitor the patent landscape for
potential infringements and develop strategies to extend patent life.
▪ Pre-launch: Prepare for potential patent challenges from
competitors and develop strategies to defend IP rights.

13
Intellectual Property Protection

Ownership rights of written

material or images, in
Exclusive rights to Copyrights technical or commercial
manufacture, use, and publications
sell the drug for a
specific period. They
are crucial for
recouping investment
and generating profits.

Company logos or
Patents Trademarks branding

14
Patent Strategies

▪ Strategies for filing patents early, protecting key

innovations, and extending patent life through various
mechanisms (e.g., formulation patents, method-of-use
patents).

15
 Regulatory Requirements

▪ To obtain drug approval and ensure patient safety.

Throughout development: Adhere to Good Laboratory Practices

(GLP) in preclinical studies and Good Clinical Practices (GCP) in
clinical trials to ensure data integrity.
Regulatory submissions: Prepare comprehensive regulatory
submissions (e.g., NDA, MAA) with all required data and
documentation.
Post-market: Continuously monitor the drug's safety and efficacy and
comply with post-market surveillance requirements.

16
Recap on the drug approval
process…..

17
Marketing and Sales Strategies
▪ To create awareness, driving demand, and achieving market
success.

Early stages: Conduct market research to understand target patient

populations and prescriber preferences.

Clinical trials: Gather data to support marketing claims and develop

key messages.

Pre-launch: Develop a comprehensive marketing plan, including

advertising, public relations, and sales force deployment.

18
Marketing and Sales Strategies
▪ Various strategies for marketing and selling a drug:
» Direct-to-consumer advertising,
• Medicine Advertisement Act 1956 & Its Regulations
» Detailing to physicians,
• Sales visits, sponsorships
» Partnerships with patient advocacy groups.

▪ Distribution channels
» Wholesalers, pharmacies, and specialty distributors.

19
Lifecycle Management
▪ Effectively handling the decline phase due to competition from
generic alternatives – optimizing profits over time.
▪ Strategies for extending the commercial life of a drug, such as
developing new formulations, indications, or delivery methods.
▪ Line extensions: reformulations of the original products /
different physical or chemical forms affecting formulation
» Ranitidine reformulated as ranitidine bismuth citrate (Tritec®)
to target Helicobacter pylori.
» Astra Zeneca separated the chiral forms of omeprazole
(Losec®) to extend patent life – market as esomeprazole
(Nexium®).
▪ New formulations can be patented if they demonstrated
improvement over original product.
» Diclofenac was formulated as Voltaren® gel for topical
application.
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