U.S. Regulation of Drugs and Post-Marketing Surveillance Pt. 1 - Public Health & Policy

Briefly describe how the Sulfanilamide Tragedy influenced the history of drug development.

From Sep to Oct 1937, there were 100 deaths reported due to Diethylene Glycol (modern-day Antifreeze) poisoning

- Precipitated in the kidneys; kids especially have underdeveloped kidneys

Led to the passage of the 1938 Food, Drug, Cosmetic Act

- Increased authority of the FDA to regulate drugs

Briefly describe how the Thalidomide Tragedy influenced the history of drug development.

1960 - Increased incidence of Phocomelia (seal-like appendages instead of arms or legs) in Germany

Led to the passage of the 1962 Kefauver-Harris Amendment in the U.S.

- Required extensive preclinical pharmacological and toxicological testing of drugs before marketing

Who is responsible for regulation of drug products and devices in the U.S.?

What do they review new drug products for?

Responsibility of the federal government (specifically, the U.S. Food and Drug Administration; FDA)

FDA reviews new drug products for SAFETY and EFFICACY

What is required before a new drug product can be legally marketed or sold in the U.S.?

Must be granted approval by the FDA

What are the five functions of the U.S. FDA in the drug approval process?

1. Clear premarketing of all new drug products on the basis of Purity, Safety, and Efficacy

2. Regulate labeling (e.g., Advertising) of prescription drug products

3. Regulate manufacturing and instituting recalls of unacceptable products

4. Regulate Bioequivalence standards

5. Monitor and evaluate post-marketing surveillance to detect unanticipated ADRs and other problems associated with use of drug products

Briefly describe what happens during these stages of the U.S. Drug Approval Process:

- Phase I

- Phase II

- Phase III

PHASE I:

- Health persons (20 - 80 people)

- Focus on drug metabolism, safe dose range, and possible toxicities

PHASE II:

- Small number of patients (few dozen - 300 people)

- PK of drug, common ADEs, initial Safety and Efficacy data in diseased patients

PHASE III:

- Larger number of patients (500 - 3000) in RCTs

- Assess Safety, Efficacy, and appropriate dosage range

What step of the U.S. Drug Approval Process uses the INDA?

Preclinical animal testing (before Phase I)

What does the submission of the New Drug Application (NDA) mark?

Submission of NDA occurs after Phases I-III

If FDA approves NDA, drug may be marketed in the U.S.

Briefly describe what happens during Phase IV of the U.S. Drug Approval Process.

PHASE IV = Post-Marketing Surveillance of Drug

- Manufacturer must continue to submit info to FDA on regular basis

- Healthcare providers are asked to report ADRs or other concerns about a product to the FDA

- Continuous collection of info on additional SAFETY PARAMETERS and EFFECTIVENESS of the drug in real-world setting

What is the difference between Efficacy and Effectiveness in the U.S. Drug Approval Process?

EFFICACY = how well it works in trials

EFFECTIVENESS = how well it works in the real world

What are the five main limitations of Randomized Controlled Trials?

1. Number of patients (typically 500 - 3000)

2. Type of patients (homogenous; relatively few complications)

3. Duration of the trial

4. Cannot determine rare or serious ADEs until after marketing of a drug

5. Use of the drug (e.g., Compliance, Prescribing) used in real world settings

Briefly give an example of how inability to determine Rare or Serious ADEs until after marketing of a drug can be a limitation of RCTs?

Duract - analgesic introduced in July 1997

ADE of Liver Disease in 1 out of 10,000 people

What are seven examples of important questions NOT addressed by RCTs?

1. Safety and Effectiveness of drugs in larger populations

2. Effect of drug in subpopulations different than those in RCT (ex. Elderly, Children, more comorbidities)

3. Uncommon side effects

4. Delayed effects

5. Patterns of drug use

6. Effect of drug overdoses

7. Economic implications of drug use

What three factors explain why we have a need for Phase IV Surveillance?

1. Number of clinical trials is insufficient to adequately demonstrate drug's true Safety and Effectiveness profile

2. Ultimate experimental model is public utilization of a drug

3. Need a scientific discipline that can assess effects and uses of drugs in Populations

What is Clinical Pharmacology?

Study of the effects of drugs and their MOAs

What is Epidemiology?

How is this related to drug development?

Study of distribution and determinants of diseases in Populations

Drugs are one kind of determinant that influence the distribution of diseases

What is Pharmacoepidemiology?

Application of epidemiologic knowledge, methods, and reasoning to the study of the effects (Beneficial and Adverse) and uses of drugs in human populations

What does Pharmacoepidemiology (PE) provide us the key to understanding?

Key to understanding the many questions that arise in the process of drug development, prescribing, and use

Briefly describe the Basic Epidemiological Study Layout in regards to the goal of PEpi Studies.

EPI:

- Exposure (Determinants) --(RELATIONSHIP; ASSOCIATION)--> Outcome (Disease)

PEPI:

- Exposure (Determinants) --> Exposed to Drug (Users) and Not Exposed to Drug (NonUsers)

- Outcome (Disease) --> Adverse Effect or Beneficial Effect

What two factors do we use to quantify PE Studies?

What are these factors used to quantify?

1. Measures of FREQUENCY

- Used to quantify the uses and effects of drugs

2. Measures of ASSOCIATION

- Used to quantify the relationship between use and effect of drugs

What are the two important types of Proportions in Pharmacoepidemiology (PE)?

1. Prevalence

2. Incidence

What is Prevalence?

How does it relate to Effect?

How does it relate to Use?

Proportion of individuals in a population who have:

- Experienced a particular effect at a point in time [EFFECT]

- Used a particular drug at a point in time [USE]

What is the equation for [Effect] when looking at Prevalence (P)?

[Use]?

[EFFECT] P = Number of Existing Cases / Total Population

[USE] P = Number of Existing People Exposed / Total Population

What is Incidence?

How does it relate to Effect?

How does it relate to Use?

Proportion of people from a population of individuals at risk during a specified time period who:

- Have NEWLY developed an effect [EFFECT]

- Are NEW drug users [USE]

What is the equation for [Effect] when looking at Incidence (I)?

[Use]?

[EFFECT] I = Number of New Cases of an Effect During a Given Time Period / Total Population at Risk

[USE] I = Number of New Drug Users During a Given Time Period / Total Population at Risk

What is the Numerator representative of in the Incidence equation?

Denominator?

NUMERATOR = New Cases or New Exposed Individuals

DENOMINATOR = Total Population at Risk

- Population who did NOT have the disease [EFFECT] at the start of the specific time period

- Population from which NEW cases can arise or individuals who can MOVE to the Numerator

What does Prevalence measure?

What use does it serve?

Measures existence of disease [EFFECT]

Used to project healthcare needs (e.g., health facilities and manpower needs) by assessing burden of disease

What does Incidence measure?

What use does it serve?

Measures emergence of disease [EFFECT]

Used to determine etiology or causes of disease

What do Descriptive Epidemiological Study Designs describe?

Generally, what do they aim for?

Describe general characteristics of the distribution of the Effect or Use of drugs with respect to person, place, and time

Aims for Hypothesis Generation

What do Analytical Epidemiological Study Designs study?

Generally, what do they aim for?

Study of Determinants or Reasons for the relative frequency of an Adverse Effect in a specific group or population; DOES THE MATH

Aim for Hypothesis Testing

What do Case Reports / Case Series designs report?

Give two examples.

What is their measure of association?

Reports of single / small groups of patients

- Ex. MedWatch, Post-Marketing Surveillance

MEASURE OF ASSOCIATION = NONE

What is the advantage of Case Reports / Case Series?

Disadvantage?

ADVANTAGE - useful for generating hypotheses about drug effects

DISADVANTAGE - usually insufficient to show causation

What do Ecological (Correlational) Studies examine?

Give an example of an Ecological (Correlational) Study.

What is their Measure of Association?

Examines trends in Exposure (drug use) and trends in Outcome (effect)

EXAMPLE - Sales data from oral contraceptives and comparison to death rates from Venous Thromboembolism using vital statistics data

MEASURE OF ASSOCIATION = Correlation Coefficient

What is the main advantage of Ecological (Correlational) Studies?

Disadvantage?

ADVANTAGE - hypothesis generation; additional evidence in Support or Against a Hypothesis

- Ex. Smoking in women and lung canceer

DISADVANTAGE - data at the population, NOT individual, level

- Ex. individuals who used OC were not necessarily the same individuals who experienced a Venous Thromboembolism event