VY 3 Flashcards
Main Learning Outcome for L3 Drug Discovery and Pre-Clinical Research
To gain a brief understanding of the drug discovery process and the challenges ahead
A brief introduction to “pre-clinical research”
What are the 3 types of research approaches?
- Deductive: conclusions reached by reasoning from general laws to a particular case (testing an existing theory)
- Inductive: method of reasoning which obtains general laws from particular facts or examples (use the data to develop a theory)
- Empirical approach: discovery by chance, or systematic screening
How to prove a hypothesis?
Hypotheses can never be proven, only disproven
What are the 4 types of hypotheses?
- Null hypothesis: H0 (no relationship btw x and y)
- Correlative hypothesis: H1 (there is a relationship btw x and y)
- Alternative hypothesis: 2 possible alternatives (x1, x2)(confirm one alternative), NOT typical hypothesis type
- Directional hypothesis: there is a direction of the relationship btw x and y
What are the common problems associated with poor studies?
- failure to include adequate controls
- poor experimental design
- failure to recognise multiple causes underlying a phenomenon
- Conclusion not completely warranted by the data
How to prevent ‘failure to include adequate controls’?
“Controls” are the most impt ingredients in scientific experiments
Use positive and negative controls
What are the importance of positive and negative controls?
- Reference (gold standard): independent method to detect all true positives
- False-negative (concern): result -ve but actually +ve
- False positive: result +ve but actually -ve
Sensitivity: probability that a signal (Readout) that should actually BE there (=true positive) is PRESENT
Specificity: Probability that a signal that should actually NOT be there (= true negative) is ABSENT
When to use positive and negative controls?
Sensitivity: to detect false-negative results (use positive control)
Specificity: to detect a false positive result (use negative control)
Why is there poor experimental design in research?
- exclusion of other factors
- might need to de-challenge and re-challenge
- pattern (historical)
- correlation w exposure
there could be causation or correlation
- not enough sample size
- no time period to see whether toxicity develops
What should be done to recognise multiple causes of a phenomenon?
these multiple causes are equally valid for explaining the phenomenon.
Thus, need to design more experiments to reject all other possible causes.
What is the challenge in knowing and controlling variables?
Limitation in formulating hypothesis in resolving natural and biological phenomenon (in contrast to phenomenon associated with man-made objects)
- difficult to control all known variables
we should say: our data SUGGEST (we should not use the word prove)
Conclusions cannot be drawn due to _______
very limited results
A landmark piece of scientific work can solely be based on ________ data
- descriptive data (observation-driven)
- -> can drive to formulate novel hypothesis
does not always need to be hypothesis-driven
- a study can answer a specific question (discovery-driven) or test a hypothesis (hypothesis-driven)
How is a new chemical entity launched?
- Screening
- Preclinical
- Phase I
- Phase II
- Phase III
- Launch of NCE (new chemical entity) (not previously tested in humans; diagnostic agents excluded)
What are the steps of drug development process?
- discovery (target id, lead generation, lead optimisation, lab tests)
- preclinical (access safety, biological activity, and formulation; animal studies)
- IND
- Clinical (I, II, III)
I: determine safety and dosage (healthy volunteers)
II: evaluate safety and efficacy (pts)
III: confirm safety and efficacy (more pts) - NDA
- Approval (review application and approval)
What is the point of IND filing?
Summary of preclinical development (info required for clinical studies)
- needed for clinical trials
What 2 dimensions of R&D Productivity needs to be optimal?
- efficiency: more affordable drugs via less costly R&D
- effectiveness: more value for the pt via innovative drugs w high-qly info
What are some potential contributing factors to the rising cost, but declining output of NCEs?
- R&D budget VS % of sales
- pressures from shareholders
- merger mania
- blockbuster mania
- drug approval policies are inconsistent and errative
- change in approach to management as marketing executive have no scientific background is the one calling the shots
- technology?
Technologies only beneficial in the _____
long run
future advance in genomic and proteomic medicines
Drug development effort is hampered by poor knowledge in _________
- understanding of disease at molecular level (poor diagnosis and classification)
- genetic variations in patient responses (therapeutic toxicity)
Despite the challenges in commercial success, what can we do at the moment?
boost morale of scientists so they can be proud of their work in serving public good, but not just the company
Drugs are discarded during development during development for reasons that are not __________ or ________ in nature
- technical
- scientific
Income generated from the drug is not worth it
What is the approach that R&D is using that is reducing communication, cross-fertilisation, cooperation and teamwork?
- most pharmas separate their R&D divisions organisationally, operationally, operationally, and often geographically
- the ‘hands-off mentality’ results from the unrealistic presumption that development can be predictably managed
What kind of focus should the furture pharma look towards?
incremental improvements have historically been among the most important approaches to advances in therapeutic agents
Is there a larger role for non-profit institutions for creating novel drugs?
Yes, they can be mobilised to enhance its effort in drug discovery as well as development
What issue is pre-clinical research addressing?
issues concerning “SAFETY” must adhere to GLP in order for the data acceptable for submission to regulatory agencies
What is required for NCE Pre-clinical data package?
- develop a pharmacological profile of the drug
- determine the acute toxicity of the drug in at least 2 species of animals
- conduct short-term toxicity studies ranging from 2wks-3mths
What kind of lab testing/ profiling is done during Pre-clinical research?
in vitro and in vivo lab animal testing
drug candidates will also undergo extensive ADME profiling in animals
How is preclinical research done for medical devices?
GLP testing for safety of device and its components
undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model
