Lecture 9: Drug development Flashcards
1
Q
No-effect dose
A
Maximum dose at which specified toxic effect is not seen
2
Q
Clinical Trial Phases
A
Once IND is granted and IRB approves a study protocol, clinical trials may proceed
3
Q
Prephase I Studies
A
- Conducted under ‘exploratory IND’
- Very limited clinical investigations can be performed based on reduced amount of chemistry & animal toxicology data
- Limited to low doses & short duration of treatment
- Established to facilitate efficient drug development
4
Q
Phase I Studies
A
- 20-100 healthy normal subjects
- Intention is to establish safety, toxicity, kinetics & major adverse effects
- If high levels of toxicity are expected (eg, cancer drugs) patients with target condition may be used in place of healthy volunteers
- Subjects receive small doses anticipated to have little effect at first with increasing doses thereafter
- May involve non-blinded trials (subject & investigator are aware of what is being administered)
- Outcomes: Maximum tolerated dose, ADME
- Must yield enough information to enable determination of appropriate dose & dosing freq. for phase II & III trials
5
Q
Phase II Studies
A
- Involve up to several hundred subjects with medical condition of interest (n=100 to 200)
- Objectives include the acquisition of preliminary data regarding the efficacy of the drug for treatment of a particular condition
- Continue to monitor safety – capable of detecting less common adverse effects
- Evaluate dose-response & dosing regimens
- Single-blind or double-blind studies
- Compares several dosing regimens
- Results of phase II are critically important in establishing protocol for phase III trials
- Can pinpoint additional data to be collected in phase III trials eg, monitoring of liver function tests
- End Phase II Meeting
- Purpose is to establish safety of proceeding to Phase III studies
- FDA can mandate additional studies or issue a clinical hold before allowing Phase III studies to go ahead if data is not sufficient
6
Q
Phase III Studies
A
- Involve several hundred to several thousand patients (n=1000 to 6000)
- Conducted at multiple sites
- Randomized, controlled, double-blind trials with multiple study arms
- Usually performed in settings similar to those anticipated for drug’s ultimate use
- Based on specific endpoints (primary endpoints) eg, survival, improvement in patient functional status
- Surrogate endpoints (secondary endpoints) eg, markers for decreased disease burden (increase in cardiac output, tumor reduction)
- Although surrogate endpoints are easier to measure, a drug’s approval usually depends on demonstrating effectiveness in improving primary outcomes
New Drug Application (NDA)
- required before market approval can be given
- Requires full reports of all preclinical and clinical data
- Can take monthsyears for approval / denial
7
Q
Phase IV Studies
A
- Can begin once market approval is obtained
- Monitoring is continued under actual conditions of use in large numbers of patients
- Important in observing adverse effects that are rare or due to chronic dosing
- No fixed duration
- Post-marketing surveillance
8
Q
Orphan drugs
A
- Drugs for rare diseases
- Difficult to research, develop & market
- Proof of drug safety & efficacy in small populations must be established (difficult esp. in children)
- Little funding -> few recognized rational targets for drug action
- Low priority (low money-making possibility)
9
Q
Orphan drugs
A
defined as either:
- Affecting < 200,000 in US (eg. Cystic Fibrosis, Malaria) or,
- Affecting > 200,000 in US but, there is no reasonable expectation that the cost of drug for such disease will be recovered from sales in the US
Since 1983, >300 orphan drugs approved (>82 rare diseases)
10
Q
Off-label use
A
Refers to the use of an approved drug for any purpose, or in any manner, other than what is described in the drug’s labeling
Examples:
- Antidepressants for insomnia and pain;
- Corticosteroids for cancer pain;
- Antiarrhythmics for neuropathic pain;
- Ipratropium for asthma
11
Q
Black box warning
A
Medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects
Examples:
- All antidepressant medications warn they may result in increased risk of suicidal tendencies in children and adolescents.
- Warfarin, due to the risk of bleeding to death
- Fluoroquinolones, due to the risk of tendon ruptures etc
12
Q
Drug advertising
A
- Product Claim Advert: Names a drug, condition it treats, and discusses benefits and risks
- Reminder Advert: Gives drug’s name but not its use
- Help Seeking Advert: Describes a disease or condition but does not recommend or suggest specific drugs
13
Q
Controlled substances: schedule 1
A
- eg, Heroin
- High potential for abuse
- Has no currently accepted medical use in treatment in US
- Lack of accepted safety under medical supervision
14
Q
Controlled substances: schedule 2
A
- eg, Amphetamine
- High potential for abuse
- Has currently accepted medical use in treatment in US or a currently accepted medical use with severe restrictions
- Abuse of drug may lead to severe psychological or physical dependence
15
Q
Controlled substances: Schedule 3
A
- eg, Ketamine
- Potential for abuse less than the drugs in schedules 1 or 2
- Has currently accepted medical use in treatment in US
- Abuse may lead to moderate or low physical dependence or high psychological dependence
17
Q
Controlled substances: Schedule 5
A
- eg, Pregabalin
- Potential for abuse less than the drugs in schedules 4
- Has currently accepted medical use in treatment in US
- Abuse may lead to limited physical or psychological dependence relative to drugs in schedule 4
