Drug Development Canada (2) Flashcards
Canadian Biopharmaceutical Industry
- Only 3% of sales in the world
- R+D = 78% of total sales
- Generic = 22% of total sales
R/D companies
- Research and development
- They develop new drugs to treat various diseases
How to Generic companies work?
- Manufacture cheaper drugs after a big company’s patent expires (17-20 years)
- Hire lawyers to make patent “weak”/get their patent
- Drug needs to be proven effective and safe in order for generic companies to take over
- They will release the drug close to the expiry date so that they don’t lose $$$
Theories as to why the pharma industry is so big ($$)
- 1st world nations are much wealthier
- Older/sicker populations
- We utilize more healthcare than needed
Drug development General Process: Timeline, major phases (4), approval
- Timeline: 8-18 years
- Major phases:
1. Pre-Clinical R&D (3-8 years)
2. Clinical trials (4-8 years)
3. New Drug Application (2 years)
4. Post-marked surveillance - Approval for drug occurs after phase 3
Preclinical R+D; cost
- First + most important phase
1. Understand Disease/condition
2. Where will you intervene in the disease pathology?
3. Identify a lead compound + drug candidate
4. Development of appropriate bio assay
5. Chemical synthesis
6. Testing for Toxicity - $5-10 million
How to Identify a lead compound? (1)
- Could be an accidental discovery
- Natural library of compounds (complex structural diversity)
- HTS (high put screening)
How to develop a bio assay? (1)
- Test a compound every 5 days
- Need to identify “food” concept
- Need to isolate the enzyme and see when and if molecules will bind to its substrate (in vitro)
What is a bio assay?
- The use “in vivo” or “in vitro” to determine the biological activity of a substance
- Guides the rational design for the drug
In vitro
- Test tubes – tissue or cell
- Immortalize cells (liver or kidney)
In vivo
- Testing on animal or plant models
- Ex. Dog RBC’s are very similar to humans’
Suicide inhibitor
Kills the enzyme as it will stay locked in the substrate
Why do we need to perform chemical synthesis? (1)
- Optimize destruction of the lead compound
- Need to change properties of the compound to see what essentially happens
- Need to identify which parts of the compound is essential for the drug
- Improves efficacy, efficiency and solubility of lead compound
Designer drugs
- Having different structures of a specific compound that doesn’t affect the overall process
- OR- - a compound that is designed to mimic the pharmacological effects of the original drug
- ex. cocaine (50-60’s)
Efficacy vs Efficiency (1)
- Efficacy: Ability of a compound to inhibit an enzyme completely (100%) - MAXIMIZE EFFECT
- Efficiency/effectiveness: Measure of how well the drug works + concentration at which inhibition is reached (amt of drug that - POWER TO PRODUCE THE DESIRED EFFECT WITH A LOWER DOSE
IC50 values
- Shows the % of inhibition (y-axis) a certain amount of a compound can do on an enzyme (x-axis)
- normally in the nano-molar range
- measure of how effective a drug is
How to test for toxicity + activity (1)
- Studies are mostly done on animals (but also in vitro)
- Massive dosages are used in vivo to test toxicity/activity (metabolic workups)
- Very expensive (animals need to have certain size + perfect genes)
- Documented thoroughly to prevent errors
Clinical Trials; Step 1
Timeline, Volunteers, Purpose, cost
- 1-2 months
- 20 healthy volunteers
- Purpose: safety of drug (based on the toxicity studies done on pre-clinical)
- Need to document everything for Health Canada for review
- $15-20 million
Clinical Trials; Step 2
Timeline, Volunteers, Purpose, cost
- 3 months-1 year
- Small highly controlled group of patients (who have the condition you are trying to treat) - 50 patients
- Assess the EFFICACY and SAFETY of the drug
- $15-20
Clinical Trials; Step 3
Timeline, Volunteers, Purpose, cost
- 3-8 years
- Large + DIVERSE test subjects (100-1000)
- Generates most of the data
- Assesses EFFICACY + SAFETY
- Costly + waiting game - $400-500 million
- Most critical!!
New Drug Application Review + Regulatory Approval (NDA) (3)
- Need to convince the FDA or Health Canada that the drug is safe and works!
- Need allll data; $5-10 million
What data is needed for NDA?
a) Material manufacture specifications (GMP- good manufacture procedure)
b) Extensive knowledge of metabolism/pharmacokinetics + ADME
c) Safety - no toxic effects
ADME
Absorption (how and when), Distribution(where does it go in the body), Metabolism(how long it lasts in body) and Excretion(urine or what?)
If 1000 compounds have been identified in pre-clinical R&D… How many will enter each step of clinical trials? What is the success rate of this?
Step 1: 1000 compounds Step 2: 600 compounds Step 3: 400 compounds After step 3: 50 compounds 5% SUCCESS RATE :O
Total cost of drug development
650+ million
Post Marketing Surveillance (4) + biggest concerns
- Monitoring the safety of the drug as it is out of the market
- Genetic diversity in the world makes it impossible to test for ALL adverse effects
- Drugs that treat more severe conditions = bigger SE’s
- Chemo drugs are not selective -lots of side effects
Blackbox warnings
- commercial that claims all the warnings of a drug
How to manage cost and increase success rates?
- “Weed out” poor candidates before clinical trials
- Apply ADME
- Lipinski’s rules
Lipinski’s rules
- No more than 5 H bond donors (NH,OH)
- No more than 10 hydrogen bond acceptors (N, O + LP)
- ## Molecular mass of less than 500
What kinds of molecules allow/don’t allow excretion?
- Aromatic compounds are not soluble in water – will not go through the body
- Nitrogen is found in metabolites in urea = good
What if there is an epidemic? Do we spend up to 18 years trying to get a treatment?
- Pharmacists will create a “cocktail” of various drugs that treats all the elements of a disease process
- Hope it works while they look for another option
- reasons why some vaccines may not work (ie polio)
How does pharma decide on a disease to treat?
- Reacting to an opportunity.
- New development in the understanding of a disease process (Cox 1-2 with merck + pfizer) - Filling a need (when something is urgent and is untreatable)
- HIV (took a very long time to figure it out, so you have to develop a drug)
