Translation: Stroke

Question 1

Animal experiments

Answer 1

in neuroprotection trials shows a high effectiveness in therapy (20-40% effect size)

Question 2

What’s the issue of the clinical translation from bench to bedside?

Answer 2

Thousands of animal studies does not work in real humans; for stroke only TPA worked

Question 3

Steps for drug to be on public

Answer 3

1. Discovery: synthesis of certain compounds
2. Pre-clinical: disease targeted drug usage and safety
3. Phase I: Try general safety of drug on healthy individual (<100) !Not done by pharma, usually have a company dedicated to this step!
4. Phase II: First time drug is tested on patients (<200) with a focus on safety check rather than efficacy
5. Phase III: Checking whether the drug actually works (several thousands) with a focus on efficacy
6. (After 2 successful Phase III) Approval
7. Guideline: State that certain drug MUST be used on certain occasions; stable income for pharma

Question 4

Why is preclinical to approval becoming easier each year?

Answer 4

Because all the basic mechanism drug is being found, so nowadays the discovered drug with smaller effect size needs to be approved as well.

Question 5

2 Types of translation

Answer 5

Type 1: Innovation (discovery to approval)

Type 2: Implementation (approval to guideline and implementation)

Question 6

How can a drug be approved but not have an effect?

Answer 6

1. Drug may not be reaching the patients due to e.g. lack of guideline knowledge on doctors
2. Drug not being taken properly/enough

Question 7

In successful case, how long does it take from discovery to approval?

Answer 7

10-15 years

Question 8

What is the only clinically proven pharmacological therapy of acute schemic stroke?

Answer 8

IV Thrombolysis (TPA); which can only applied to few patients
There are currently no neuroregeneration therapy for human

Question 9

Why is translation such a “black box”?

Answer 9

• Complexity
• Low hanging fruits have been picked (easy researches have been done); time to focus on small effect sizez
• Flawed clinical design (due to time window/sensitivity of stroke; median medication is given at 16h after stroke)
• mouse is not human

Question 10

Limitation of animal models

Answer 10

• We can model what happens after the stroke (e.g. occulusion) but not how it happens
• Due to smaller size, time frame of progress is most likely different (may not be true comparing the tPA)

Question 11

What is bias

Answer 11

subjective reality informed by one’s preference

Question 12

What is the issue of “bias” in stroke research

Answer 12

-attrition bias
-sex bias
-bias from low sample size
-winner’s curse
- low external validity
-HARKING
-publication bias
-Low prevalence of methods to prevent bias:
randomisation 40%
blinding 40%
sample size calculation 0
conflict of interest statement 5%

Question 13

What is attrition bias?

Answer 13

Unexplained “missing” animal on the paper
This is huge bias because excluding one outlier from the already small sample size, the result is most likely be significant

Question 14

What is a disease that has a high comorbidity with stroke?

Answer 14

Depression

Question 15

Animal model for depression

Answer 15

e.g. Anhedonia test: checking the wanting of sucrose

Question 16

What is statistical power

Answer 16

probability of a hypothesis test of finding an effect if there is an effect to be found (20% for neuroscience due to the small sample size); the bias against the null hypothesis

Question 17

What is the new true?

Answer 17

The true result and the false positives (5%)
The key is to focus on “true” significance but this is impossible information t gain.
In reality, 40-50% of significant result could be false positives

Question 18

Low sample size bias

Answer 18

mean group size in neuroscience for pre-clinical steps: 8 animals
mean statistical power: 45%
false positives: 50%
overestimation of true effects: 50%

Question 19

Winner’s curse

Answer 19

Lower power studies will lead to

1) high rate of false positives
2) out of the true significant finding, its effects will be overestimated

Question 20

HARKING

Answer 20

Hypothesising After the Result are kNown

Question 21

Low external validity

Answer 21

validity of applying the conclusions of a scientific study outside the context of that study

e. g. for stroke research, it is like “healthy, male twins raised in a super secured room feeding healthy granola” can the result of such study be applied to real life patients?
e. g. SPF fallacy… mouse model for stroke (SPF) has immune system characteristics of a new born baby as they are raised in super secure environments all their life

Question 22

What is publication bias

Answer 22

aka “file drawer problem”

Only positive results are being published

Question 23

How can our research finding be more “true”

Answer 23

1. Reduce bias
   - blinding
   - randomisation
   - in/exclusion criteria
   - report results according to guideline e.g. ARRIVE
2. Increase power
   - check power and achieve at least 80%
   - do appropriate sample size calc
   - replicate
3. Use stats sensibly
   - do not be deceived by p-value
   - think biological significance and effect size
   - replicate
4. Practise open sciences
   - preregister (tell the protocol beforehand)
   - publish NULL results
   - make original data available

Question 24

Monetary bottlenecks

Answer 24

Phase I-III & implementation is where the big money can be earned

Question 25

Which process of drug design uses public funding?

Answer 25

pre-clinical and implementation

Question 26

What is “phase 4”?

Answer 26

Mysterious phase proposed by big pharma to claim where the money goes, where doctors are asked to keep the record of patients
Doctors make money by this step; which leads to promoting drugs

Question 27

How can researchers find money for early drug discovery phase?

Answer 27

Pharma companies will not risk their money at early stage. Venture capital firm who has money but also are risky will be a good partner for funding

Question 28

Around which phase will big pharma start to invest money?

Answer 28

When the drug has been somewhat proven to show efficacy by venture capital firm investment, around phase III big pharma takes over

Question 29

What is the paradox in the field of intellectual property?

Answer 29

Not claiming IP are unethical
However, when the paper is published, by default it enters the public domain without claiming the IP. This makes it impossible for the researchers to recover the costs used for their clinical testing

Question 30

How is the IP situation in US?

Answer 30

They have Bayh Dole Act which permits a university, small business or non-profit institution to maintain the patent.

Question 31

How is the IP situation in Germany?

Answer 31

“Faculty privilege” exists but are rarely used as researches do not gain money directly but the university does. Also license fee and other annual fees prevent them to actually take advantage of this patent system.

Question 32

Why stay away from claiming IP?

Answer 32

• Time consuming and make people money oriented
• Generates bias towards results that favour monetisation and bias against those that harm commercial interest
• It generates conflict of interest
• Disclosure of IP may have negative effects on review process
• Risk of publication delay
• Claiming IP excludes society (uni etc) who pays for research

Question 33

What are the students movement on IP?

Answer 33

Universities Allied for Essential Medicines claims for equitable licensing of university (=Public) IP

Question 34

What’s one potential solution for IP?

Answer 34

• Public funding of clinical trials on grand scale
• By collecting money from stake holders (=insurers) which they can be compensated by cheaper medicine
• Public should hold the IP to avoid the exploding costs of health system
• Issue: Pharma, politicians will not like it