BS374:Modern Approaches to
Human Disease
!
Maroulina Georgiadi
,LECTURE 1: INTRODUCTION TO EVIDENCE BASED MEDICINE
There are three main processes that are needed for
a drug to become available in the rest of the world:
1st Basic Science: looking at cell based models
and animal models to prove that the drug we are
looking at actually does what it is supposed to be
doing.
2nd Clinical Research: Clinical trials where you have the evidence that something works in animal
models and cell line. You then put it in humans in order to try and repeat the outcomes in multiple
trials.
3d Clinical Medicine: Also known as clinical practice. It is controlled by regulatory bodies. There
are two types of regulatory bodies. One is the regulatory body that reviews basic science to
approve clinical trials (such as FDA MRC) and the second one is the one used to review clinical
trial data and then it recommends whether something can enter clinical practice.
Terminology of Evidence based medical approaches
BASIC SCIENCE: Basically if a drug works in cell lines in the lab. Once you can demonstrate that the
drug does what it is supposed to do in a cell line, then you move into animal models and see if it
works on the animal model (mouse, rabbit, monkey).
ANIMAL MODELS: Basically if a drug works on an animal model. Therapeutic and lethal dose. The
therapeutic dose is questioning if the drug actually works and how much of it should I give to the
animal so that there is the expected outcome. Lethal dose is questioning the toxicology, so what
dose starts to kill the animal. In toxicology studies you need to check if the therapeutic and the lethal
dose of a drug are close to each other. If they are too close then the drug will NEVER get to the clinical
trial stage. If they are far apart then there is a good chance that the drug will go to clinical trial. You are
also looking for side effects. It isn’t about just killing but need to check things such as if the drug is
triggering:
- modification of the genome
- changes in protein
- renal effects
- cardiac effects
Once you have the basic science in the animal data you can then move onto the clinical trials step.
Evidence from both basic science and animal models are essential for a regulatory body to approve a
clinical trial.
CLINICAL TRIAL: What you are looking for in a clinical trial is whether the drug works in humans.
Does it cause side effects in humans? Does it cause beneficial outcomes in human patients? Also
clinical trials need to be repeated to remove bias and show that the drug actually does work and is
beneficial for human patients. Once you are done with that you need to get throw regulatory bodies
reviews. So after gathering all clinical trial data, regulatory bodies will review with meta analysis of
multiple trials to be bale to confirm whether something works or not.
Once it works the regulatory bodies will compare the drug that you are testing against other current
therapies to show that there is an improvement in clinical management.
Spinal Muscular Atrophy will be used as an example to understand those terms and processes.
,What is evidence based medicine?
An example of two different drugs
Through a Kaplan Meier graph:
Drug A: 25% mortality within 20 months.
Drug B: 25% morality within 80 months
- On the y axis there is survival probability that starts at 100% at
start of trial, so at day 0. As the
Trial goes along, people will die and the lines will start to drop,
showing that people do start dying. T
- The data from the two drugs show that A has less benefit or at least fewer beneficial effects
than B, as more people are dying at a quicker rate. That doesn’t mean necessarily that the drug
is worse than B. In order to come into conclusion on the best out of the two drugs, you need to
also check the Kaplan Meier graph along with the side effects, the long term impacts of taking
each drug. So evidence based medicine is not one anecdotal piece of evidence, but it is a collation
of multiple pieces evidence so you can evaluate and truly access which of these true drugs is better.
What is evidence?
Authority: The most important piece of evidence. An authority piece of evidence is when
something has been peer reviewed and it is a clinical trial based analysis. So for example an
article says: “drug A is better than drug B”
Anecdote: It is still important, but it has less of a weight than authority evidence. A good
example is when we re looking at case studies. So when a clinician treats one patient with drug
A and they lived and one with drug B and they died. It does no statistics, but there is much
more bias than authority tests
Law: based on analysis, based on process, regulations the legal requirements to give one drug
rather the other irrespected of whether drug B is worse than drug A. Because it might have side
effects, long term effects etc.
Different types of evidence have different types of biases.
, Review on Spinranza
- The first FDA approved treatment for spinal muscular atrophy (SMA).
- SMA is an easy target for molecular therapies due to SMN2.
SPINAL MUSCULAR ATROPHY
*alpha motor neurone are in
the spinal cord and are
motor neurone that link the
spinal cord to the skeletal
muscles. If you loose these
muscles you up with
skeletal muscle atrophy
**Both parents need to have
one mutative form of the
normal gene. The kid needs
to inherit one copy of each
parents.
There are three main types of SMA:
(In reality there are 5 but the 3 are the most important and most common ones)
1. Type I SMA - severe form:
Onset: 4-6 months, presents as “floppy babies”
Characteristics: high intercostal involvement
Prognosis: poor (death usually between 2-4 years old)
2. Type II SMA - intermediate form
Onset: more than 12 months
Characteristics: intermediate intercostal involvement
Prognosis: poor (death usually between 8-16 years old)
3. Type III SMA - mild form
Onset: more than 2 years
Characteristics: low intercostal involvement
Prognosis: good (relatively normal life span but will need help with walking and movement)
Human Disease
!
Maroulina Georgiadi
,LECTURE 1: INTRODUCTION TO EVIDENCE BASED MEDICINE
There are three main processes that are needed for
a drug to become available in the rest of the world:
1st Basic Science: looking at cell based models
and animal models to prove that the drug we are
looking at actually does what it is supposed to be
doing.
2nd Clinical Research: Clinical trials where you have the evidence that something works in animal
models and cell line. You then put it in humans in order to try and repeat the outcomes in multiple
trials.
3d Clinical Medicine: Also known as clinical practice. It is controlled by regulatory bodies. There
are two types of regulatory bodies. One is the regulatory body that reviews basic science to
approve clinical trials (such as FDA MRC) and the second one is the one used to review clinical
trial data and then it recommends whether something can enter clinical practice.
Terminology of Evidence based medical approaches
BASIC SCIENCE: Basically if a drug works in cell lines in the lab. Once you can demonstrate that the
drug does what it is supposed to do in a cell line, then you move into animal models and see if it
works on the animal model (mouse, rabbit, monkey).
ANIMAL MODELS: Basically if a drug works on an animal model. Therapeutic and lethal dose. The
therapeutic dose is questioning if the drug actually works and how much of it should I give to the
animal so that there is the expected outcome. Lethal dose is questioning the toxicology, so what
dose starts to kill the animal. In toxicology studies you need to check if the therapeutic and the lethal
dose of a drug are close to each other. If they are too close then the drug will NEVER get to the clinical
trial stage. If they are far apart then there is a good chance that the drug will go to clinical trial. You are
also looking for side effects. It isn’t about just killing but need to check things such as if the drug is
triggering:
- modification of the genome
- changes in protein
- renal effects
- cardiac effects
Once you have the basic science in the animal data you can then move onto the clinical trials step.
Evidence from both basic science and animal models are essential for a regulatory body to approve a
clinical trial.
CLINICAL TRIAL: What you are looking for in a clinical trial is whether the drug works in humans.
Does it cause side effects in humans? Does it cause beneficial outcomes in human patients? Also
clinical trials need to be repeated to remove bias and show that the drug actually does work and is
beneficial for human patients. Once you are done with that you need to get throw regulatory bodies
reviews. So after gathering all clinical trial data, regulatory bodies will review with meta analysis of
multiple trials to be bale to confirm whether something works or not.
Once it works the regulatory bodies will compare the drug that you are testing against other current
therapies to show that there is an improvement in clinical management.
Spinal Muscular Atrophy will be used as an example to understand those terms and processes.
,What is evidence based medicine?
An example of two different drugs
Through a Kaplan Meier graph:
Drug A: 25% mortality within 20 months.
Drug B: 25% morality within 80 months
- On the y axis there is survival probability that starts at 100% at
start of trial, so at day 0. As the
Trial goes along, people will die and the lines will start to drop,
showing that people do start dying. T
- The data from the two drugs show that A has less benefit or at least fewer beneficial effects
than B, as more people are dying at a quicker rate. That doesn’t mean necessarily that the drug
is worse than B. In order to come into conclusion on the best out of the two drugs, you need to
also check the Kaplan Meier graph along with the side effects, the long term impacts of taking
each drug. So evidence based medicine is not one anecdotal piece of evidence, but it is a collation
of multiple pieces evidence so you can evaluate and truly access which of these true drugs is better.
What is evidence?
Authority: The most important piece of evidence. An authority piece of evidence is when
something has been peer reviewed and it is a clinical trial based analysis. So for example an
article says: “drug A is better than drug B”
Anecdote: It is still important, but it has less of a weight than authority evidence. A good
example is when we re looking at case studies. So when a clinician treats one patient with drug
A and they lived and one with drug B and they died. It does no statistics, but there is much
more bias than authority tests
Law: based on analysis, based on process, regulations the legal requirements to give one drug
rather the other irrespected of whether drug B is worse than drug A. Because it might have side
effects, long term effects etc.
Different types of evidence have different types of biases.
, Review on Spinranza
- The first FDA approved treatment for spinal muscular atrophy (SMA).
- SMA is an easy target for molecular therapies due to SMN2.
SPINAL MUSCULAR ATROPHY
*alpha motor neurone are in
the spinal cord and are
motor neurone that link the
spinal cord to the skeletal
muscles. If you loose these
muscles you up with
skeletal muscle atrophy
**Both parents need to have
one mutative form of the
normal gene. The kid needs
to inherit one copy of each
parents.
There are three main types of SMA:
(In reality there are 5 but the 3 are the most important and most common ones)
1. Type I SMA - severe form:
Onset: 4-6 months, presents as “floppy babies”
Characteristics: high intercostal involvement
Prognosis: poor (death usually between 2-4 years old)
2. Type II SMA - intermediate form
Onset: more than 12 months
Characteristics: intermediate intercostal involvement
Prognosis: poor (death usually between 8-16 years old)
3. Type III SMA - mild form
Onset: more than 2 years
Characteristics: low intercostal involvement
Prognosis: good (relatively normal life span but will need help with walking and movement)
