Lecture 3- Drug Development

Question 1

CDER

Answer 1

Center for Drug Eval and Research

Question 2

CBER

Answer 2

Center for biologics eval and resarch

Question 3

CDRH

Answer 3

center for devices and radiological health

Question 4

CFSAN

Answer 4

Center for food safety and applied nutrition

Question 5

CVM

Answer 5

center for veterinary medicine

Question 6

mission of FDA

Answer 6

The FDA’s mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use. Our work is a blending of law and science aimed at protecting consumers

Question 7

two definitions for a new drug

Answer 7

A new drug is defined as one that is not generally recognized as safe and effective (GRASE) for the indication proposed

A drug is a substance that exerts an action on the structure of function of the body by chemical action or metabolism and is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

Question 8

cGMPs

Answer 8

current good manufacturing practices

Question 9

GLPs

Answer 9

good laboratory practices

Question 10

New Drug Development step 1

Answer 10

drug discovery and development
(2-10yrs)
(5,000-10,000 compounds)

Question 11

New Drug Development step 2

Answer 11

Pre-clinical research and development
(3-6yrs)
(250 compounds)

Question 12

New Drug Development step 2.5

Answer 12

IND submission

Question 13

New Drug Development step 3

Answer 13

clinical trial
(6-7yrs)
(5 compounds)

Question 14

New Drug Development step 3.5

Answer 14

NDA submitted

Question 15

New Drug Development step 4

Answer 15

FDA reviews NDA
(1-2yrs)
(One FDA approved drug)

Question 16

New Drug Development step 4.5

Answer 16

FDA approval

Question 17

New Drug Development step 5

Answer 17

manufacturing

Question 18

3 ways to identify NME

Answer 18

Compound-Centered Drug Discovery
typically endogenous to the body or found in nature

Target-Centered Drug Discovery
designed to hit a specific target

Serendipity

Question 19

Purpose of drug discovery (step 1)

Answer 19

provide evidence to prove that the drug is effective for its indicated uses, that the risks associated with that drug are known on the basis of reasonable testing, and that the nature of the known risks is appropriate with the anticipated benefit for the indication.

Question 20

Lead Optimization (step 1)

Answer 20

Finding the right match/lead compound is achieved through:
1. De novo - Rational drug design
2. High-throughput screening
3. Combinational chemistry
4. Serendipity

Hundreds of manipulations are made to:
Maximize receptor affinity
Improve pharmacokinetic properties

Question 21

Preclinical purpose and requirements (step 2)

Answer 21

assess potential therapeutic effects of the NME on living organisms and to gather sufficient data to determine its reasonable safety in human through laboratory experimentation and animal investigation.
Follow GLPs
Compliance of GLP status reports that are submitted to FDA for approval for clinical investigations.
Takes 1 to 3 years
No prior approval to begin

Question 22

Clinical purpose (step 2.5/3)

Answer 22

part of IND
Purpose: Establish the efficacy and safety of the drug
Protect the health and safety of human test subjects
Ensure the integrity and usefulness of the clinical study data

Question 23

5 Clinical questions to answer (step 3)

Answer 23

1. Does drug have the effect it is supposed to
2. How much and how often should it be given?
3. What side effects are associated with the drug and can they be managed?
4. How is the drug broken down and how long does it stay in the body?
5. Which foods, drinks, or other drugs can be used at the same time or should be avoided?

Question 24

IND process (step 2.5)

Answer 24

submit to FDA.
Cover sheet, table of content, introductory statement and investigation plan, brochure, protocols, NME’s chemistry, manufacturing and controls, pcol/tox info, any previous human experience with the NME, others.
After submission, wait for 30 days before commencing trials.
FDA does not “approve” an IND, if FDA does not object within 30-day period, the trials may begin.

Question 25

Role of IRB in Clinical trials

Answer 25

protect human test subject rights as well as maintains rigorous medical and scientific standards.

must also review and approve informed consent documents prior to commencing the trials.

Participants must be informed adequately about the risks, benefits and treatment alternatives before participation in the trials.

All these documents should be open to FDA inspection at any time.

Question 26

Gold Standard

Answer 26

DBCT

Have more than one intervention
Participants are assigned to one of the intervention groups randomly.
Ensure that composition is identical
Should not be known by patient, MD, drug company personnel, etc

Question 27

3 statistical comparisons for clinical trials

Answer 27

Superiority design- comparison with a placebo

Noninferiority design – confirms that one intervention IS NOT inferior to a comparator

Equivalence design – determines whether one intervention is statistically no different in effectiveness than another.

Question 28

2 types of efficacy data for clinical trials

Answer 28

Continuous – interval, ration, mean difference
Dichotomous – all or none items

Expresses as:
Relative Risk Reduction (RRR)
Absolute Risk Reduction (ARR)

Question 29

4 safety data aspects of clinical trials

Answer 29

Adverse Event
Serious Adverse Event
The number needed to harm (NNH)
The number needed to treat (NNT)

Question 30

Phase I of IND

Answer 30

Establishes the PK profile, safety and dosage
Uses healthy volunteers (w/o the dx)
Open label
Fast-tract conditions allows for persons with the dx to be a part of the study
Study size – small, less than 100 subjects
Duration – short (couple of doses, one year or less)
Results used to develop Phase II

Question 31

Phase II of IND

Answer 31

First controlled clinical trial to establish the PK profile, safety and efficacy
Phase IIa is the pilot study to determine initial efficacy
Phase IIb is the controlled study
Single or double blinded
Fast-tract conditions allows for persons with the dx to be a part of the study
Study size – medium, several hundred subjects
Duration – weeks to months

Question 32

Phase III of IND

Answer 32

Establishes the PK profile, safety and efficacy, final formulation, indications, labelling, marketing claims, product stability and packaging and storage conditions
Double-blind
Study size – large
Duration – months to years
THIS IS THE FINAL STAGE BEFORE DRUG APPROVAL.
Notice of Compliance is filed with FDA to determine whether a drug is approved for widespread use.
New Drug Application (NDA)