Lecture 3- Drug Development Flashcards
CDER
Center for Drug Eval and Research
CBER
Center for biologics eval and resarch
CDRH
center for devices and radiological health
CFSAN
Center for food safety and applied nutrition
CVM
center for veterinary medicine
mission of FDA
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
two definitions for a new drug
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
cGMPs
current good manufacturing practices
GLPs
good laboratory practices
New Drug Development step 1
drug discovery and development
(2-10yrs)
(5,000-10,000 compounds)
New Drug Development step 2
Pre-clinical research and development
(3-6yrs)
(250 compounds)
New Drug Development step 2.5
IND submission
New Drug Development step 3
clinical trial
(6-7yrs)
(5 compounds)
New Drug Development step 3.5
NDA submitted
New Drug Development step 4
FDA reviews NDA
(1-2yrs)
(One FDA approved drug)
New Drug Development step 4.5
FDA approval
New Drug Development step 5
manufacturing
3 ways to identify NME
Compound-Centered Drug Discovery
typically endogenous to the body or found in nature
Target-Centered Drug Discovery
designed to hit a specific target
Serendipity
Purpose of drug discovery (step 1)
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.
Lead Optimization (step 1)
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
Preclinical purpose and requirements (step 2)
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
Clinical purpose (step 2.5/3)
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
5 Clinical questions to answer (step 3)
- Does drug have the effect it is supposed to
- How much and how often should it be given?
- What side effects are associated with the drug and can they be managed?
- How is the drug broken down and how long does it stay in the body?
- Which foods, drinks, or other drugs can be used at the same time or should be avoided?
IND process (step 2.5)
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.
Role of IRB in Clinical trials
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.
Gold Standard
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
3 statistical comparisons for clinical trials
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.
2 types of efficacy data for clinical trials
Continuous – interval, ration, mean difference
Dichotomous – all or none items
Expresses as:
Relative Risk Reduction (RRR)
Absolute Risk Reduction (ARR)
4 safety data aspects of clinical trials
Adverse Event
Serious Adverse Event
The number needed to harm (NNH)
The number needed to treat (NNT)
Phase I of IND
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
Phase II of IND
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
Phase III of IND
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)
