Lecture 2 Flashcards
United States Evidentiary Standard for Approval of a New Drug of Biologic Product
• A drug or biological product approved in U.S. must:
– Demonstrate substantial evidence of effectiveness/clinical benefit
• Evidence of effectiveness
– Evidence consisting of adequate/well-controlled investigations on the basis of which it could fairly/responsibly be concluded that the drug will have the effect it purports to have under the conditions of use prescribed, recommended, or suggested in the labeling
• In the drug development setting, a defined exposure-response relationship is often a key supporting piece of evidence
Major Elements of an Adequate and Well-Controlled Study
• Clear statement of purpose
• Permits a valid comparison with a control
- Concurrent: placebo, no-treatment, active, dose-comparison
- Historical
• Method of selection of subjects
• Method of assigning patients to treatment/control groups
• Adequate measures to minimize bias
• Methods of assessment of response are well-defined and reliable
• Analysis of the results is adequate to assess the effects of the drug
Biomarkers
- Characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
- Can be measured accurately and reproducibly
- Examples: Serum creatinine, C-reactive protein, HIV viral load, blood glucose, blood pressure, cholesterol, tumor volume by imaging
Classification of Drug Response
Desired vs. adverse effect
- The measured response may be a
(1) clinical response
(2) surrogate endpoint
Clinical response (or clinical endpoint)
• A characteristic or variable that reflects how a patient feels, functions, or survives
• Endpoints that in themselves represent or characterize the clinical outcome of interest
– Objective: survival time, disease exacerbation, clinical event (e.g. MI, stroke)
– Subjective: assessed by patients (or caregivers) symptoms, nausea, pain, sense of mobility, “health related quality of life”
Surrogate Endpoint
• Clinical endpoints may not be manifested for several years, necessitating a more immediate measure
• A surrogate endpoint is a biomarker that is intended to be used as a substitute for a clinical endpoint
• Ideally, the surrogate should exist within the therapeutic pathway between the drug and meaningful benefit (i.e. the drug results in the therapeutic benefit by virtue of its effect on the surrogate)
• Changes induced by a drug on a surrogate endpoint are expected to reflect changes in the clinical endpoint
– Examples: BP, cholesterol levels, tumor size, blood sugar, bone mineral density, etc.
Graded and Quantal responses
Graded Response
• As the concentration of the drug increases, the magnitude of the pharmacologic effect produced also increases.
• The response is continuous and gradual
• Most responses are graded
Quantal Response
• All or nothing
• Binary - the response either does or does not occur
• Examples: death, suppression of a cardiac event
Placebo response
- Outcome that is not attributed to a specific treatment or intervention
- Common in psychiatric disorders, pain, nausea, etc.
- Prevalence may vary by population (e.g. adult vs pediatric)
- In a placebo-controlled trial, generally subtract the placebo response (in the placebo arm) from the response in the drug arm to estimate the drug’s ‘true’ efficacy
EC50 (also called E50 or C50)
The concentration that produces half of the maximal response. A measure of of a drug’s potency.
- Lower EC50 = greater potency (and vice-versa)
Emax: greatest possible effect that can be achieved with the drug; the maximal response. A measure of a drug’s efficacy.
Desirable pharmacodynamic characteristics
• Specificity – therapeutic effect with minimal adverse effects. The greater the separation between these effects, the greater the specificity of the drug
• Maximum effect – achieving the greatest possible effect (Emax)
– Partial agonists/antagonists, which fail to achieve the full effect even at high concentrations, may be less useful
• Steepness factor (y)
– If very high, may be difficult to manage because only a small change in concentration around the EC50 causes response to change from zero to full effect
– If very small, large changes in drug concentration are needed to cause response to change
• Potency (as measured by EC50)
– Higher potency generally desirable to reduce risk of off-target adverse events
Limitation of Emax Model
- It imposes an exact difference between concentration levels (very rigid)
Ex:
- Double the conc., effect increases by 33%
- Halve the conc., effect decreases by 33%
The Hill Equation
- addresses the limitation by adding a steepness factor, y, that allows for a more flexible description of concentration-response relationship
- the higher the value of y, the steeper is the E vs. log C curve in the region of C50
- when y is greater than 1, the curve is steeper and when it is less than 1, it is shallower than the Emax model
- when y = 1, it is equal to Emax model
