Drug Discovery and Clinical Trials

Question 1

What are the three principal stages of drug discovery and development?

Answer 1

Drug Discovery
Pre-Clinical Development
Clinical Development

Question 2

What are the roles of the three stages of discovery and development in the drug development process?

Answer 2

Drug Discovery:

• Disease characterization
• Target selection and identification of “drug hits”
• Lead optimization
• Pharmacological profiling

Pre-Clinical Development

• In vitro and in vivo Animal models
• Pharmacokinetics and Toxicology
• Formulation and Synthesis scale up

Clinical Development

• Drug tested in human volunteers and patients
• Safety and Efficacy
• Pharmacokinetics and Toxicity

Question 3

What are the essential elements of compound-centered drug discovery?

Answer 3

Compound with interesting
activity and/or chemistry

Screen biological systems
for interesting biological
functional effects

then you have a drug lead

Question 4

What are the essential elements of targeted-centered drug discovery?

Answer 4

Identify protein target with known disease association/activity

Screen large chemical libraries to Identify drug hits that interact with target and modify activity

then you have a drug lead

Question 5

Define the role of lead drug optimization in the context of the drug development process.

Answer 5

Once you have a lead (it may not exhibit ideal drug properties) so you develop chemically modified drug variants; screen for improved pharmalogical profile

(You may increase potency, selectivity, duration of action, chemical stability, more favorable drug characteristics, improved PK profile)

Leads to Lead Compound (New Chemical Entity)

Question 6

What is the principal goal of pre-clinical drug development?

Answer 6

Goal: To provide evidence that a drug is safe for future testing in humans

New drug leads are tested for efficacy in
pre-clinical animal and cellular models of disease

• In vivo Animal models of disease
• In vitro cellular models of disease

Question 7

What are the major steps involved in the pre-clinical drug development? Describe the function of these steps.

Answer 7

Safety Pharmacology
-Evaluate drug using in vivo animal testing for the presence of any obvious
acute systemic toxic effects
(two different species and two routes of administration)

Determine:
No-effect dose: the maximum dose at which toxic effects are not seen
Median lethal dose (LD50): the dose that kills 50% of animals
- useful in helping determine dosing in initial Phase I clinical trials

B. Toxicology

• genotoxicity (Ames Test)
• carcinogenicity (especially if drug is likely to be taken chronically)
• reproductive toxicity & developmental toxicity (teratology & fertility)
• “anti-target testing” establish that drug DOES NOT interact with target proteins known to be frequently involved in Drug Adverse Effects
  e. g. - inhibition of hERG K+ channel involved in regulating heartbeat causes the long QT syndrome
• inhibition of 5HT2B receptor causes valvular heart disease

Pharmacokinetic testing
- fully characterize pharmacokinetic parameters: ADME

Drug Interaction studies

• determine metabolism by CYP450 family members
• identify any possible inhibitors of CYP450
• determine specificity for Drug Transporter proteins

Chemical and Pharmaceutical Development

• determine chemical stability
• develop scale up to large scale synthesis
• develop formulations suitable for clinical studies

Question 8

Describe the process by which a new drug candidate becomes an approved new drug.

Answer 8

A new drug candidate has gone through in vivo and in vitro testing…

An Investigational New Drug (IND) application is reviewed by FDA and IRB (ethics)

Question 9

What is the function of the FDA (Food and Drug Administration) in the drug approval process?

Answer 9

FDA does an Investigational New Drug (IND) review.

Question 10

Describe the composition of the IRB in the drug approval process.

Answer 10

Membership: more than 5 experts (physicians, scientists, nurses, statisticians)
+ lay members from appropriate backgrounds
e.g. clergy, attorneys, social workers, community advocates etc

Primary purpose is to ensure the rights and welfare of those individuals
participating in clinical trials

Question 11

Describe the functions of the IRB in the drug approval process.

Answer 11

Minimize potential risk to human subjects

Determine whether potential risk is reasonable relative to anticipated benefit

Ensure equitable selection of subjects

• ensure that no undue pressure to participate is applied
• avoid disproportionate share of burden on any single group
• ensure that burdens and benefits from research fairly distributed e.g. patients with targeted disease

Document informed consent process
Participants are made aware of potential risks and benefits and make an informed decision to voluntarily participate

Provide safeguards for vulnerable populations
e.g. children/mentally disabled/prisoners or others that may be unduly influenced into participating

Require reporting of serious adverse effects and/or deaths

Can stop clinical trial if there are significant safety concerns

Question 12

Describe the role of the IRB in the drug approval process.

Answer 12

All clinical trials must be reviewed, approved and monitored by an IRB

Primary purpose is to ensure the rights and welfare of those individuals participating in clinical trials

Question 13

What is the primary purpose of an Investigational New Drug Application (IND)?

Answer 13

Vehicle for providing evidence to the FDA that a new drug drug is a viable candidate for further development and appropriate for initial limited use in humans (i.e. “reasonably safe”)
- also provides exemption from the Federal Law that only approved drugs may be shipped across state lines

Question 14

List the major required components of the Investigational New Drug Application (IND).

Answer 14

1. Animal Pharmacology and Toxicology data
   - preclinical data providing evidence that drug is likely to be safe
2. Manufacturing information
   - evidence of composition and stability of drug
   - evidence that the drug can can be consistently manufactured

Clinical Protocols and Investigator information

• detailed proposed clinical protocols
• Investigator qualifications
• Commitment to seek informed consent and IRB approval

Question 15

Describe the three distinct types of Investigational New Drug Application (IND) and their specific uses.

Answer 15

Investigator IND
-request to study an unapproved drug
-request to study an already approved product for either:
- a new indication
- a change in the route of administration
- a change in the approved patient population (e.g. children/elderly)
submitted by an individual/company who will be responsible for initiating and conducting a clinical trial of the drug

Emergency use IND
-Allows authorization of an experimental drug in an emergency situation for use in a single patient that has a serious or immediately life-threatening condition where no other therapy is available and there is insufficient time to obtain IRB approval

Treatment IND
allows promising experimental drugs that have not yet been approved
to be used in patients with serious or immediately life-threatening conditions where no other therapy is available and death is likely

Question 16

Describe the basic elements and primary purpose of the four stages of clinical trial.

Answer 16

Phase I - 20 to 100 healthy volunteers; Is it safe? Tolerability and PK

Phase II - 100-200 patients
Does it work in patients? Dosing

Phase III- 1,000-6,000 patients
Does it work in large patient populations?

Regulatory approval

Phase IV-
Post marketing surveillance
adverse effects
interactions
compliance

Question 17

Define the purpose and contents of a New Drug Application (NDA).

Answer 17

When Phase III trial is complete the sponsor applies to the FDA for approval

• known as a New Drug Application (NDA)

NDA contains all pre-clinical and clinical data collected during a drug’s
research and development

Question 18

List the FDA-approved data that must be included on the approved drug packaging label.

Answer 18

Approved indications

Clinical Pharmacology

• Dosage
• Adverse Reactions
• Contraindications
• Special warnings and precautions (BLACK BOX)
  e. g. not for pregnancy/specific condition

Promotional material from the pharmaceutical company cannot deviate from information provided on the insert
i.e. cannot market drug for an unapproved indication

Question 19

Define the three classes of drug recall.

Answer 19

Class I: Reasonable probability that use of drug will cause serious adverse
health consequences or death e.g. microbial contamination

Class II: Use of drug will cause temporary adverse health consequences, although probability of serious health consequences is remote

Class III: Use of drug is unlikely to cause adverse health consequences e.g. quantity packaging error

Question 20

Describe the process by which generic drugs are approved.

Answer 20

Once a patent has expired any company may submit an Abbreviated New
Drug Application (ANDA) to allow marketing of a GENERIC VERSION
of the drug
- no need to provide evidence of efficacy and safety

Question 21

What critical pharmacological information needs to be provided to support the application for getting a generic drug approved.

Answer 21

• no need to provide evidence of efficacy & safety

But must establish bioequivalence:

• drug formulation contains equal amounts of the active ingredient
• comparative pharmacokinetics and pharmacodynamics
• similar rate and extent of absorption into the blood
• GMP compliance with manufacturing process and facilities

Question 22

What stage of drug development does the following fit into?

“anti-target testing” establish that drug DOES NOT interact with target proteins known to be frequently involved in Drug Adverse Effects

e. g.
- inhibition of hERG K+ channel involved in regulating heartbeat causes the long QT syndrome
- inhibition of 5HT2B receptor causes valvular heart disease

Answer 22

Toxicology of pre-clinical testing

Question 23

What is the difference between emergency use IND and treatment IND?

Answer 23

Emergency- Allows authorization of an experimental drug in an emergency situation for use in a SINGLE patient that has a serious or immediately life-threatening condition where no other therapy is available and there is insufficient time to obtain IRB approval

Treatment IND
allows promising experimental drugs that have not yet been approved to be used in patients with serious or immediately life-threatening conditions where no other therapy is available and death is likely

Question 24

What is the difference between a superiority trial and non-inferiority trial? When might the latter be used?

Answer 24

Superiority Trial
- a trial designed to demonstrate that one treatment is clinically superior to either placebo or another drug

Non-inferiority Trial
- a trial designed to demonstrate that one drug is not appreciably less effective than the standard therapy -used when a placebo group would not be ethical, or the drug is not expected to be Superior, but may have less side effects , is cheaper or easier to admin

Question 25

What is a cross over study?

Answer 25

• Alternating period of administration of placebo and test drug
• Typically used for short term outcomes in chronic diseases
• Reduces problems with confounders, as each patient serves as their own control
• Statistically efficient requires fewer participants

Question 26

Phase I studies

Typical number of participants?

The setting?

Typical Trial design?

End points?

Primary objective?

Answer 26

20-100 participants (healthy volunteers typically)

in patient setting to allow close monitoring of any adverse reactions

trial design- open label w escalating dosing (initially 1/10th projected dose)

purpose- establish safety and tolerability

Initial PK studies:
how well absorbed, drug half life and metabolism

Question 27

Phase II

Typical number of participants?

The setting?

Typical Trial design?

End points?

Primary objective?

Answer 27

100-200 participants (with target condition)

Trial design: single blinded or double blinded randomized controlled trial

• evaluated against placebo or standard of care
• can be parallel or crossover in design

Obj- preliminary data on drug efficacy (proof of concept)
continued safety monitoring ( detects less common adverse effects)

End point:
EITHER definitive end point (actual goal of therapy like decreased MI)
or surrogate end point (associated with disease like lower LDL)

Additional Pharmacokinetic studies performed

• dose response and determination of optimal dosing regimen
• investigate PK differences in different ethnic groups
• effects of renal and hepatic impairment on dosing regimen

Question 28

Phase III

Typical number of participants?

The setting?

Typical Trial design?

End points?

Primary objective?

Answer 28

500-6,000+ participants (large scale clinical trial)

Trial Design:

• double blinded randomized controlled trial
• typically evaluated against standard of care (or placebo)
• performed at multiple clinical sites in settings similar to those where the drug will ultimately be used

Primary objectives
- establish efficacy and safety of drug

End Point
- EITHER definitive OR surrogate end point trials using surrogate end points are cheaper and take less time, although trials using definitive end points provide more confidence

Question 29

Phase IV

What is the purpose of this stage?

Answer 29

Phase IV studies: Post-marketing surveillance
(Pharmacovigilance)

Monitors safety of new drug under actual conditions of use in large patient populations

Relies on practicing physicians to report adverse effects/toxicities

Large sample size allows for identification of rare adverse effects

Question 30

A quantity packaging error is what type of drug recall/withdrawal?

Answer 30

Class III

Use of drug is unlikely to cause adverse health consequences

Question 31

In what phase are the following evaluated?

• dose response and determination of optimal dosing regimen
• investigate PK differences in different ethnic groups
• effects of renal and hepatic impairment on dosing regimen

Answer 31

Phase II

these are additional pharmacokinetic studies performed