Drug Discovery and Clinical Trials Flashcards
What are the three principal stages of drug discovery and development?
Drug Discovery
Pre-Clinical Development
Clinical Development
What are the roles of the three stages of discovery and development in the drug development process?
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
What are the essential elements of compound-centered drug discovery?
Compound with interesting
activity and/or chemistry
Screen biological systems
for interesting biological
functional effects
then you have a drug lead
What are the essential elements of targeted-centered drug discovery?
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
Define the role of lead drug optimization in the context of the drug development process.
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)
What is the principal goal of pre-clinical drug development?
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
What are the major steps involved in the pre-clinical drug development? Describe the function of these steps.
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
Describe the process by which a new drug candidate becomes an approved new drug.
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)
What is the function of the FDA (Food and Drug Administration) in the drug approval process?
FDA does an Investigational New Drug (IND) review.
Describe the composition of the IRB in the drug approval process.
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
Describe the functions of the IRB in the drug approval process.
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
Describe the role of the IRB in the drug approval process.
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
What is the primary purpose of an Investigational New Drug Application (IND)?
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
List the major required components of the Investigational New Drug Application (IND).
- Animal Pharmacology and Toxicology data
- preclinical data providing evidence that drug is likely to be safe - 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
Describe the three distinct types of Investigational New Drug Application (IND) and their specific uses.
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
Describe the basic elements and primary purpose of the four stages of clinical trial.
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
Define the purpose and contents of a New Drug Application (NDA).
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
List the FDA-approved data that must be included on the approved drug packaging label.
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
Define the three classes of drug recall.
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
Describe the process by which generic drugs are approved.
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
What critical pharmacological information needs to be provided to support the application for getting a generic drug approved.
- 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
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
Toxicology of pre-clinical testing
What is the difference between emergency use IND and treatment IND?
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
What is the difference between a superiority trial and non-inferiority trial? When might the latter be used?
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
What is a cross over study?
- 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
Phase I studies
Typical number of participants?
The setting?
Typical Trial design?
End points?
Primary objective?
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
Phase II
Typical number of participants?
The setting?
Typical Trial design?
End points?
Primary objective?
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
Phase III
Typical number of participants?
The setting?
Typical Trial design?
End points?
Primary objective?
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
Phase IV
What is the purpose of this stage?
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
A quantity packaging error is what type of drug recall/withdrawal?
Class III
Use of drug is unlikely to cause adverse health consequences
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
Phase II
these are additional pharmacokinetic studies performed
