Drug Approval Process and Disease Frequency

CDER

Division of the FDA that regulate the safety and efficacy of drugs

Who gave CDER authority

Food, drug, and cosmetic act of 1938 (established FDA)

Kefauver-Harris amendment of 1962 (requires both safety and efficacy)

Does the FDA test new drugs

No, sponsor conduct studies which are then submitted to the FDA for review and approval

What is considered to be a new drug entity

Small molecules, biologics, reformulations, new formulation, and combo products

Who makes up the FDA review team

Clinical reviewer (physician), pharmacology/toxicology reviewer, product quality reviewer, virology reviewer as needed, statistic reviewer, regulatory project manager

Parts of the drug approval process

Pre-clinical research

Clinical studies (phases 1-3)

NDA review

IND

Investigational New drug

Pre-IND (before human trials)

Drug is created (synthesis and purification)

INDs chemical properties are defined

Animal studies are done to test pharmacology and toxicology

Develop clinical protocols and have a Pre-IND meeting with the FDA

Purpose of Pre-IND procedures

Avoid unnecessary nonclinical studies, avoid premature IND submission, resolve safety issue, discuss development plan, and provide regulatory guidance.

Pre-IND briefing

Bring plan to FDA showing the INDs chemical description, manufacturing plans, studies, and proposed clinical protocols for clinical trials.

Commercial IND application

For drug companies. Goal is to approve the drug so they can sell it.

Research IND

For advanced scientific knowledge to gain knowledge about a drug not necessarily sell it

Investigator IND

A physician/researcher runs the study. Common in research.

Emergency Use IND

Used in urgent life-threatening situations where there is no time for full approval or no acceptable treatment. Usually only done in one patient. Drug can be administered before application submission to the FDA.

Treatment IND

Used when no good alternatives exist and the drug shows good promise. For life-threatening conditions. Allows early access before full approval, while the IND is in clinical trials or done with trials and the sponsor is actively pursuing FDA approval.

Phase one clinical trials

Looking for safety. Duration is usually several months. Need healthy volunteers. Closely monitored. Gathering information about how a drug interacts with the human body. Usually 20-80 people. Not testing to see if the drug actually works for the given disease.

Phase two clinical trials

This is when the drug’s effectiveness for a condition is tested. Closely monitored. Subjects may have limited or no comorbidities. Looking for short term risks and side effects. Several months long. 100-300 patients.

Phase three clinical trials

Confirm effectiveness. Can be several years long. 500+ patients. Compare risks vs benefits. Ideally want multiple phase 3 trials that confirm each other.

Phase IV

Post marketing studies

NDA

New drug application. Request to market the drug.

What is in an NDA

Clinical safety and efficacy data

PK

Pharmacology/toxicology

The drug chemistry

Package labeling and administrative information

NDA review

Analysis of target condition and available treatments, clinical assessment of risks and benefits. Strategies for managing risks (REMS)

Accelerated approval

A way for the FDA to approve a drug faster. Can use surrogate endpoints. Requires phase IV confirmatory trials.

Surrogate endpoints

A substitute measurement instead of the real clinical outcome. For example, lowering BP instead of waiting for MIs. Usually faster and easier to measure.

Fast track

Facilitate development and expedites review. For serious or life-threatening conditions and demonstrates potential to address an unmet need.

Priority reveiw

Drug provides safe and effective therapy when no satisfactory alternative exists. Significant improvement over marketed drugs.

Breakthrough therapy

treats a serious or life-threatening condition and represent a substantial improvement in marketed therapies.

Advisory committee

Evaluate each section of the review. Provide expert opinions and make recommendations.

How are generic drugs approved

They submit an ANDA (abbreviated new drug application)

Do not repeat full clinical trials

Required to be bioequivalent and bioavailable

Must provide manufacturing process and controls

Justification of inactive ingredients and stability data

EUA

Emergency Use authorization. Permitted under food and drug cosmetic act. Respond to threats. Allows the FDA to authorize unapproved medical products to prevent serious or life threatening disease.

EUA process

1. Declare an emergency

2. HHS Secretary declares that EUA is justified

3. FDA Commissioner issues EUA

4. EUA is terminated

Function of public health

To study what is effecting the population

What is epidemiology

Study of the distribution and determinants of disease frequency in human populations and the application of this study to control health problems. Considered the science of public health. Assumes disease does not occur at random and if causes can be identified disease can be prevented

How to describe disease

time, place, and person

Population

Groups of people with common characteristics

Fixed population

Membership is permanent and defined by an event

Dynamic population

membership is transient and defined by being in or out of membership L

Life Expectancy

The average number of years that a person can expect to live at a given age, usually birth based on current death rates

What should measure of disease frequency take into account

Number of individuals affected with the disease, size of source population, length of time the population was followed

Purpose of mathematical parameters

Used to relate the number of cases of disease, the size of population, and the time. Need to specify if measure represents events or people

Ratio

Division of one number by another, numbers don’t have to be related

Proporition

Numerator is a subset of denominator

Rate

Time is an intrinsic part of denominator

Prevalence

In a population at one point in time. # of cases/ # of persons

Incidence

Quantified number of new cases of disease that develop in a population at risk during a specific time period

Three concepts of incidence

New disease events, or for disease that can occur more than once, usually first occurrence.

Population at risk, can't have disease already, should have relevant organs

Time must pass for a person to move from health to disease

Cumulative incidence

number of new cases/number of persons at risk in population

Over a specific period of time. Proportion with no unites. Computed when all subjects followed for the same length of time in a closed population.

Incidence rate

number of new cases/person-time of observation among those at risk.

Over a specified period of time. True rate is with units in time.

Person-time accrual

Time unit for person-time: person-year, person-month

Ex: 100 people followed for 1 year each = 100 person-years

What is prevalence rate increased by

Number of new cases, reductions in death, and new treatments that prolong life but don’t cure disease

What are prevalence rates decreased by

reduced number of new cases, increased number of cures

Mortality rates

Total number of deaths from all causes. Usually expressed for a 1-year period.

Disease rate

Number of existing or new cases of a particular disease or condition. Expressed as incidence or prevalence.

Attack rate

Number of new cases of disease that develop per the number in a healthy population at risk at the start of a period. Cumulative incidence measure. Ex: infectious disease or foodborne outbreaks

Survival rate

number of living cases per number of cases of disease.