Introduction to

Drug development &

Regulation
Associate Professor Kellie Charles &
Dr Slade Matthews
FMH, Pharmacology (SoMS)

The University of Sydney Page 1

Lecture 1 – Overview of drug development and regulation
Lecture 2 - Pre-clinical pharmacology
Lecture 3 – Toxicology
Lecture 4 – Clinical trials
Lecture 5 – Research seminar – The good, the bad and the ugly
(of drug development)

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 Disclosures
Kellie Charles
– Previously employed on a post-doctoral fellowship paid for by J&J Pharmaceuticals
(2004-2008)
– Conducted clinical trials on infliximab, etanercept and bortezomib in people with
cancer sponsored by J&J Pharmaceuticals (2004-2008)
– Medical Advisor for Tetra Pharmaceuticals (supplier of medicinal cannabis products
and clinical prescribing support information, Current)

Slade Matthews
– External Assessor for TGA since 2010
– Aflibercept, Vemurafenib, Pertuzumab, Romidepsin, Alogliptin, Canagliflozin,
Alemtuzumab, Catridecocog, Riociguat, Sofosbuvir, Buprenorphene, Sucroferric
Oxyhydroxide, Secukinumab, Faldaprevir, Netupitant, Ledipasvir, Cobimetinib,
Grazoprevir, Pixantrone, Velpatasvir, Letermovir, Lanadelumab
The University of Sydney Page 3
 Learning Outcomes
• Describe the critical activities required for each stage of the
drug development pathway.

• Outline the ethical considerations for researchers participating

in drug development.

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PCOL2012

Getting new drugs to market

Three distinct stages:
Discovery
– Finding lead molecules
Development
– Pre-clinical pharmacology and toxicology
– Clinical trials
Regulation
– Registration – TGA Approval
– Reimbursement – PBS Approval

The University of Sydney Page 5

 Drug development pipeline

In the lab
Chemistry or biology labs
Patent new molecular entity
In silico – computer modelling
In vitro - cells
In tissues (animal)
In vivo – whole animals

In the clinic
In patients
Ex vivo – clinical samples
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 1 in 1 million compounds
makes it to being an
approved drug

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 Pharma drug development activity
% activity at each stage
Research areas Drug target classes of DD in pharma

Drug design approach

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 Drug class and stage of drug development
https://www.nejm.org/doi/full/10.1056/NEJMp1806930?query=featured_home

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 New drug approvals – FDA (2018)

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 2018 approval by class

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 Projected drug sales 2015 (changes in 2017)

CV Not in top 10

Cancer $8b, 2nd

RA
Asthma Not in top 10

Cancer
Cancer
Cancer, RA
Diabetes $5b,10th
RA 1st
HCC $7b, 5th

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 Drug development pipeline

Must obtain ethical

approval prior to
starting projects

Pre-clinical
Animals are essential

Clinical
Humans are essential
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 Ethical considerations of drug development

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Animal ethics

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 Preclinical pharmacology - Animal ethics
• What do we use animals for and is this OK?
• What are the controls and are these OK?
• What benefits have we derived from the use of
animals in research?
• What animals are used in teaching?
• Why are animals still being used?

Use of animals in medical research

• To understand anatomy and physiology
• As models to study disease
• To test potential treatments
• To test drugs for efficacy and safety

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 Use of animals (Australia 2011)
Individual consumption of animals for FOOD in 2011
38 kg poultry
33 kg beef/veal
24 kg pork
14 kg lamb
?? Fish
Total number of animals in food production – 300,000,000

Animal use for research in 2011 - 500,000

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 Animal Research Act (1985)
Regulations (2010)
State legislation

Animal Research Review Panel

• ensure compliance with the law
• license and inspect facilities (laboratories, animal
houses)

National Health and Medical

Research Council Code of Practice

The University of Sydneywww.animalethics.org.au Page 18

 Animal Ethics Committee (AEC)
• Veterinarian
• Person with current animal research
involvement
• Animal welfare representative
• Lay person

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 Code of Practice (1.3)
Projects using animals may be performed
only after a decision has been made
that they are justified
weighing
the predicted scientific or educational
value of the project
against
the potential effects on the
welfare of the animals
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 All projects need to consider 3Rs

• Replacement of animals with other methods

• Reduction in the number of animals used

• Refinement of techniques to reduce adverse impact on animals

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 Number of animals/student in University Teaching

~ 4.5 animals per student in 1970

~ 0.01 animals per student in 2005
99.77% reduction

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Human ethics

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 New treatments - 1800-1950
Many competing treatments
Drug choice was based on
clinician’s experience
‘Standard’ treatments never
adequately tested
New drugs introduced
without regulation only
truthful of ingredients

Still from The Matrix

The University of Sydney Page 24
 Clinical Trials: Human Ethics
Nuremberg Code (1945) – 10 points for ethical research in humans
– Voluntary informed consent with no coercion
– Conducted for the good of society
– Based on animal experiments/biology of the disease
– Should not injure/cause harm/death to the participant
– Risk of experiment should not be greater than the benefit to society
– Conducted by scientifically qualified researchers
– Participant able to withdraw from trial at any time, without repercussions
– At any stage during the trial, the lead scientist should be able to terminate the
trial to limit further risk to patients

Declaration of Helsinki (1964)

– consent was changed to “if at all possible” but allowed for guardian approval as well

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 Australian Ethics Approval
All studies must have Human Research Ethics Committee (HREC) Approval
– National Ethics Approval form (NEAF form, 70+ pages online)
– CVs of all investigators – proof of scientific ability
– Proposal of the study
– Participant information sheets
– Participant consent/withdrawal forms
– Associated documents given to patients (e.g. questionnaires)

All studies must have site-specific assessments (SSA)

– Approves the study at a specific hospital, uni, private practice site

Approval given for 3-5 years, with yearly reviews

Depending on the nature of the trial reporting may be back to HREC and/or TGA
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Conflict of interest in drug development

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https://www.propublica.org/article/fda-repays-
industry-by-rushing-risky-drugs-to-market

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 – Balancing act – funding needed for project, but researchers
need to remain independent.
– Scientists need to stay honest open and transparent
– Disclosure of all interactions with potential sources of conflicts
of interest must be revealed at all points of publication or
presentation in public.

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 Regulatory approval

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 Drug Registration
– All pharmaceuticals must be registered in OECD countries
before they can be marketed

– Each country has its own regulatory authority

– Drug companies must apply for market authorisation in each

jurisdiction

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 Regulatory Authorities
– TGA (Therapeutic Goods Administration)
– Australian register of Therapeutic Goods (ARTG)

– EMA (European Medicines Agency)

– EU guidelines for registration adopted

– FDA (Food & Drug Administration)

– FDA guidelines consulted where no EU

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 ICH
– ICH (International Council for Harmonisation – of technical
requirements for registration of pharmaceuticals for human use)

– Focus on Safety, Quality and Efficacy

– Guidelines for scientific studies to establish these

– Established a standard format for registering drugs

– Common Technical Document (CTD)

The University of Sydney https://www.ich.org/products/guidelines.html Page 33

 Common Technical Document

– Internationally agreed set of specifications for a submission

dossier
– Same structure for member countries
– Consists of 5 Modules containing particular data
– Module 4 contains non-clinical data
– Studies on pharmacology, pharmacokinetics and toxicity in
animals

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 Common Technical Document

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 Why Non-clinical?
– What experiments could be conducted to determine the safety
of a new pharmaceutical?
– First in human dose based on NOAEL in non-clinical studies and
(more recently) MABEL (Minimal Anticipated Biological Effect
Level)
– E.g Test dose = NOAEL/Species factor x (modifying factor)
– Considerations: Appropriate species? BSA? Pharmacology?
– Animal testing aims to prevent disaster when molecule first
tested in human

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 Do disasters really happen?
– Yes – since 1937

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 Diethylene glycol

– Both ethylene glycol and diethylene glycol very toxic

– Interestingly…
– PEG common excipient in medications
– PEG are usually molecules containing many (>=9 for
PEG400) repeats of the ethyl ether.

– But here they used diethylene glycol!

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 What is the PBS and the PBAC?
– Australia has a system for ensuring important medicines are
available to the public for the overall good of the country
– The PBS (Pharmaceutical Benefits Scheme) provides a Schedule
lists all of the medicines available to be dispensed to patients
at a Federal Government-subsidised price.
– The PBAC (Pharmaceutical Benefits Advisory Committee)
decides which medicines go on the PBS
– If the PBAC considers a medicine cost effective for significant
medical conditions (i.e. if the improvements in health outcomes
justify the additional costs) it will approve the addition to PBS
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 Challenges in drug regulation

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 Gingko biloba & memory

Which one?
How effective &
safe is this drug?

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The University of Sydney Page 42
 Medicinal cannabis & pain

Many unregulated and clinically

unproven medicinal cannabis products
on the web

TGA approved medicinal cannabis

– Sativex

Approved for:

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 Fecal transplants & Antibiotic-resistant Clostridium difficle infections

March, 3, New York Times

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 How different
Is it from this?

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 FDA approved
3D printed drugs – benzodiapezam
Tonic seizures in epilepsy
Alternative formulations
Mixed reaction chemistry?
Who prints?

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 Challenges in drug regulation

What do we patent?

How do we test for efficacy and safety?

Do these products need same process of regulation?

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 Summary – key points
– Structured pathway for drug development
– Preclinical - clinical – regulatory review – approval?
– Animal and human ethics are critical aspects of drug development

– Regulatory approval is independent from vested interests

– Challenges to drug development of new therapeutics, which

may need changes to the drug development paradigm

The University of Sydney Page 48