3. Drug Safety & Post-Marketing Surveillance

Stages of Drug Development (4)
Stage 1: Discovery
Stage 2: Pre-clinical testing
Stage 3: Clinical testing
Stage 4: Approval & Post-clinical testing
Stages of Drug Development: Stage 1
-Scientists identify viable compounds and proteins
-Scientists recommend one “best” candidate for further testing

-5,000 – 10,000 compounds can be synthesized/tested
-250 may make it to pre-clinical testing

Stages of Drug Development: Stage 2
-Determine if the drug is safe to test in humans, i.e. first tested in animals

<0.1% of potential drugs make it through pre-clinical testing and enter clinical testing stage

Stages of Drug Development: Stage 3
Investigational New Drug (IND) application must be submitted to the FDA to begin testing in humans

Clinical Trials: Phase I, II, III

IND
Investigational New Drug
Stage 3: Phase I clinical trials
Goal: Learn how the drug works in humans

Subjects: <100 Healthy individuals Toxicity testing: maximum tolerated doses, metabolism, excretion, dose-limiting toxicities

Stage 3: Phase II clinical trials
Goal: Assess the EFFICACY (proof of concept)

Subjects: a few hundred individuals with the target disease

-Continue safety (toxicity) in patients to assess short-term/common side effects/risks
-Single arm studies (No comparison group)

Stage 3: Phase III clinical trials
Goal: establish strong evidence for efficacy AND safety

Subjects: a few thousand people with the target disease in randomized, controlled trials

-Use doses and settings more like real-world practice
-Adequate and well-controlled randomized trials are needed to move to the next stage of approval

Stages of Drug Development: Stage 4
-New Drug Application (NDA) is submitted to the FDA upon successful completion of clinical testing
-FDA reviews the application and makes a decision: Approval or approvable (approval with additional studies) or Not Approvable

Phase IV

NDA
New Drug Application
Stage 4: Phase IV
Post-marketing Evaluation
-post-marketing surveillance in larger samples and for longer periods of time
-Evaluate safety and effectiveness that may not have been detected in earlier trials
-Efficacy vs. Effectiveness **

ie. MedWatch, FAERS

MedWatch
-FDA’s adverse event reporting program
-Health professionals are encouraged to report unusual/rare or previously unseen adverse events
-Manufacturers are required to report adverse events
FAERS (FDA Adverse Event Reporting System)
-Database that contains all adverse drug event reports that the FDA has received from manufacturers as required by regulation as well as healthcare professionals and consumers via MedWatch
FAERS
FDA ADVERSE EVENT REPORTING SYSTEM
Goals of Post-Marketing Surveillance (4)
1. Examine the long-term effects of drugs
2. Detect low-frequency events (i.e., rare outcomes)
3. Assess the effectiveness in general practice
4. Identify modifiers of effectiveness (ie. concomitant pharmacotherapy, co-morbid disease)
When should the FDA require a postmarketing study?
When risk factors may include:

1. Drugs approved through surrogate endpoints that provide conflicting evidence about associated health outcomes

2. First-in-class approval that used surrogate endpoints used in a different drug class

3. Drugs with a troublesome safety profile that could impact a large number of people, trigger serious side effects, or may have a biological rationale

Surrogate endpoints
a measure that is PREDICTIVE of a clinical outcome
(ie. Lowered blood pressure)
Clinical endpoints
a DIRECT measure of the actual health outcome (ie. heart attack, stroke, mortality)
Efficacy
A measure of the success of a therapeutic intervention carried out under IDEAL conditions.

-“ideal conditions” are achieved in clinical trials

Effectiveness
A measure of the success of a therapeutic intervention carried out in a typical clinical environment on typical patients
Major Concepts in Drug Safety Evaluation
1. Adverse Events
2. Safety Signals
3. Adverse Drug Reactions
Adverse Events
-An unintended ‘untoward’ medical occurrence that may or may not be due to the medication
-Causal association is not determined
-Should be reported to the FDA via spontaneous system, even if it is not caused by the medication
-FDA evaluates such reports to determine if it warrants further investigation
Safety Signals
-FDA definition: ‘an excess of adverse events compared to what would be expected’

-A report on a potential causal association between drug exposure and a previously unknown/undocumented adverse event
-Signals indicate the need for further investigation of what may/may not result in a causal association

Safety Signals from Post-Marketing Surveillance:
-Passive surveillance
-Active surveillance

Safety Signals: Passive Surveillance
-MedWatch SPONTANEOUS reporting is the cornerstone of signal generation in the US
-FAERS is the database the supports the FDA post-marketing safety surveillance program

Advantage: relatively inexpensive

Limitation: Do not have the total number of people exposed to the drug, so it is impossible to estimate the risk

Safety Signals: Active Surveillance
-PROACTIVE evaluation of drug exposure and the event of interest
-Use administrative databases to assess drug exposure and safety signals

Advantage: Large population of exposed individuals

Limitation: Do not always have key information

Adverse Drug Reaction (ADR) definition
adverse event where there is a reasonable possibility that the drug caused the event
-noxious & unintended reaction
ADR Types (2)
Type A: predictable, dose-related

Type B: not predictable, dose independent

Food and Drug Administration Amendments Act of 2007

(FDAAA; Public law 110-85)

FDA has the authority to require a Risk Evaluation & Mitigation Strategy (REMS) “when the Agency determines that a REMS is necessary to ensure that the benefits of a drug outweigh its risks.”
REMS
Risk Evaluation and Mitigation Strategies
REMS: what is it?
-Strategy to manage known or potential risks with drugs
-FDA can mandate REMS at the time the drug is approved for marketing or when a safety concern emerges
REMS: need is based on…
1. Size of the population exposed
2. Seriousness of the underlying condition being treated
3. Anticipated benefit of the drug
4. Anticipated duration of treatment
5. Seriousness of the adverse event
6. New molecular entity
REMS: Different Types
1. Medication guide or package insert
2. Communication plan for health care professionals (i.e., educational seminars or presentations)
3. Elements To Assure Safe Use (ETASU)
ETSASU
Elements To Assure Safe Use

A type of REMS that involves documentation and assurance of:
1. Training, experience, and specialty of prescriber
2. Certification of the pharmacy dispenser
3. Other possible requirements: restricted to certain healthcare settings, patient monitoring, and/or a patient registry.

Intellectual Property Rights (IPR)
IPR protects the innovator product by allowing limited market exclusivity.

The 2 main effects are
1. Provide incentives for innovative drug development
2. Allow companies to control the market (get a higher price)

FDA’s Expedited Drug Development Pathway
Program for speeding up the approval process for new drugs that look promising and demonstrate a favorable benefit-to-harm risk
-Shortened review process for drugs that may have a therapeutic advantage

The public health risk with this new initiative: approving new drugs when key safety questions are not fully answered