Pharmacology Week 1: Drug Development

Sulfonamides and Insulin
Penicillin was first synthesized in the 1930’s. What other drugs were also first produced at this time?
1950
In what year did we see an explosion in the amount of synthetic drugs produced?
Warfarin (Anticoagulant)

Cisplatin (Chemotherapy drug)

What two drugs are most well-known as drugs produced and patented by universities?
1) Forward Pharmacology

2) Reverse Pharmacology

What are the two approaches to Drug Discovery?
Forward
Which one came before the other between Forward and Reverse Pharmacology?
1) Discovery of compound

2) Development of assays to determine biological activity

3) Determine mechanism of action

What steps are involved in Forward Pharmacology?
1) Isolate a therapeutic target (e.g., beta-adrenergic receptor)

2) Identify a compound that affects the target

3) Modify the drug structurally to maximize beneficial effects and minimize deleterious effects

4) Demonstrate the desired effect in vivo

What steps are involved in Reverse Pharmacology?
Forward Pharmacology
Which one, Forward or Reverse Pharmacology, is cell or physiologically-directed?
Forward Pharmacology
Which one, Forward or Reverse Pharmacology, is unbiased regarding the mechanism of action?
Forward Pharmacology
Which one, Forward or Reverse Pharmacology, do you need to determined the mechanism of action in vivo and in vitro?
Reverse Pharmacology
Which one, Forward or Reverse Pharmacology, is molecularly target-directed?
Reverse Pharmacology
Which one, Forward or Reverse Pharmacology, involves already demonstrating in vitro activity and a need to demonstrate in vivo activity?
Receptors (45%)

Enzymes (28%)

The drug targets of most current therapies are what?
Hormones

Ion channels

Nuclear Receptors (RNA/DNA)

Aside from receptors/enzymes, what are other biochemical classes of drug targets?
1) Early research and preclinical testing

2) Submission of IND application

3) Submission of NDA

What are the stages of new drug development?
Investigational New Drug (IND)

Three – Phase I, II, and III

A clinical trial

What is IND?

How many phases are involved?

Each phase involves what?

New Drug Application (NDA)

FDA

What is an NDA and who approves it?
In vitro studies
The first stage of new drug development involves what?
Once the FDA approves the NDA

Phase IV = Post-Marketing Surveillance

When do Phase IV clinical trials start?

What do you call Phase IV?

Lead compound
The drug development stage that involves in vitro studies leads to the production of what?
biological products (natural)

chemical synthesis

The lead compound typically produced during in vitro studies can come from what two sources?
About 1 year
How long is the drug development stage that involves in vitro studies?
Test efficacy, selectivity, and mechanism in animal models
After being done with in vitro studies, you have a lead compound. What will now happen to the lead compound as you move into the next stage of new drug development?
Submit an IND to the FDA
If after testing in animals, your data comes back promising. What will now be the next step in drug development?
Phase I, II and III clinical trials
If the FDA approves of your IND, what can now commence?
Is the drug safe?
What is the primary research question in Phase I clinical trials (new drug development)?
Does the drug work?
What is the primary research question in Phase II clinical trials (new drug development)?
Does the drug work in a randomized control trial that is also a double-blind study?
What is the primary research question in Phase III clinical trials (new drug development)?
Researching the mechanism of drug metabolism and assess drug safety.
During the clinical trial (phase I, II, and III) stage of drug development, you are also actively doing what?
You file an NDA (New Drug Application) with the NDA
What happens after Phase III clinical trials (new drug development) are complete?
8-9 years
The new drug application is usually submitted how long after the initial studies?
The drug is then marketed to physicians and other clinicians. Phase IV can also begin.
If the new drug application is successful, what happens?
17 years
On average, how long after a patent is filed will it expire (generics become available)?
6.5 years
What is the average amount of time alotted to early research and preclinical testing (new drug development)?
In the laboratory, using animal models.
Early research and preclinical testing is often done where and using what models (new drug development)?
To assess safety and biological activity
What is typically the primary goal when it comes to early research and preclinical testing (new drug development)?
1 year
What is the average length of time for Phase I clinical trials to be complete?
About 20-80 HEALTHY volunteers, with the exception of testing of HIV or cancer drugs
Usually, how many and what kind of volunteers are recruited for Phase I clinical trials?
To assess dosage and safety.
What is typically the goal for Phase I clinical trial tests?
2 years
What is the average length of time for Phase II clinical trials to be complete?
Assess effectiveness and determine side effects (if any)
What is typically the goal for Phase II clinical trial tests?
100-200 patient volunteers
Usually, how many and what kind of volunteers are recruited for Phase II clinical trials?
3-4 years
What is the average length of time for Phase III clinical trials to be complete?
To verify effectiveness and monitor adverse reactions from long-term use.
What is typically the goal for Phase III clinical trial tests?
1000-3000 patient volunteers
Usually, how many and what kind of volunteers are recruited for Phase III clinical trials?
1.5 years
Review of NDA and approval by FDA can take as long as what?
After the drug has been approved for marketing, it is important for researchers to monitor any side effects of the drugs.

If side effects are uncommon (1/100,000), Phase I-III will not have enough subjects for such a side effect to surface.

Why is Phase IV so important?
5000
As many as how many compounds can be evaluated during preclinical testing?
5
How many compounds usually enter clinical trials?
1
From the initially lot of 5000, the NDAs of how many compounds are usually approved by the FDA?
11%
What is the success rate for new drugs – from the time it underwent preclinical trials to it being approved for marketing by the FDA?
North America
In what continent do we see the most use of drugs (determined by sales of prescription drugs)?
1) The drug has acceptable benefit to risk ratio
2) The informed consent is appropriate
3) The procedures are appropriate
4) The research design is appropriate
The IRB will only approve the use of human subjects if what requirements are met?
After marketing (approved by FDA).

For this reason, there is a disclaimer on medication for pregnant women about inadequate human testing and benefits outweighing the risks.

When are new drugs typically tested in pregnant women?
Category A, B, C, D, X
What are the five categories for pregnancy medication established by the FDA?
There are no risks in animal studies, but there are no human studies to confirm.
A Category B indicates that a drug for use during pregnancy will have what risk(s) to the fetus/person taking it?
There is demonstrated risk to the fetus, but the person may continue taking it despite the risk.
A Category D indicates that a drug for use during pregnancy will have what risk(s) to the fetus/person taking it?
The risks of taking the drug outweighs any benefits.
A Category X indicates that a drug for use during pregnancy will have what risk(s) to the fetus/person taking it?
Controlled studies on pregnant women have shown no risks.
A Category A indicates that a drug for use during pregnancy will have what risk(s) to the fetus/person taking it?
Adverse fetal effects in animals, but can be used if the benefits outweighs the risks
A Category C indicates that a drug for use during pregnancy will have what risk(s) to the fetus/person taking it?
Yes, but children have not been used as subjects historically.
Can children be used as subjects in drug development studies?
Also known as FDAMA. It provides incentives in the form of patent extension for drug companies to test new drugs on children (so that we know what the effects are on children).
What is the FDA Modernization Act of 1997?
That studies involving children should be conducted unless there is a valid reason not to do so.
The Pediatric Rule of 1998 demands what?
Historically, they have been excluded, but are now included in studies – especially those that the elderly are the target population (Alzheimer’s, Heart Failure, etc.).
Are elderly adults used as test subjects in new drug studies?
Voluntary Post-market Adverse Reaction Reporting (Voluntary)

Some safety-related labeling required

The FDA place what kind of regulation(s) on dietary supplements?
Same as dietary supplements
The FDA place what kind of regulation(s) on conventional food items?
Premarketing approval required

Voluntary Post-market Adverse Reaction Reporting (Voluntary)

Some mandatory Post-marketing Adverse Reaction Reporting

Safety-related labeling required

The FDA place what kind of regulation(s) on food additives?
Product regulation require

Voluntary Post-market Adverse Reaction Reporting (Voluntary)

Safety-related labeling required

The FDA place what kind of regulation(s) on over the counter drugs?
Product regulation require

Premarketing approval required

Voluntary Post-market Adverse Reaction Reporting (Voluntary)

Mandatory Post-marketing Adverse Reaction Reporting

Safety-related labeling required

The FDA place what kind of regulation(s) on NDA drugs?
Product regulation required

Voluntary Post-market Adverse Reaction Reporting (Voluntary)

Mandatory Post-marketing Adverse Reaction Reporting

Safety-related labeling required

The FDA place what kind of regulation(s) on infant formulas?