day 2

what is mechanism drug design

molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism (Target) of a disease process.

what is a lead compound

a prototype compound that has a fundamental desired biologic or pharmacologic activity.

what are new chemical entities (NCE)

an active ingredient that has never been marketed in the USA in some form.

in what cases does a new drug NOT have to be an NCE

New formulations, new manufacturing change, new uses, new dosage schedule, new routes of administration

Combinations of two or more old drugs at certain ratios

if a european drug is introduced into america, is it an nce

yes because it has never been marketed in the US

which example may meet the fda definition fo a new drug without being a nce

a new dosage form of a previously marketed active ingredient

which study is part of preformulation rather than the biological portion fo preclinical testing

measurement of the drug’s partition coefficient

what does preclinical testing include

¤Pharmacology – study drugs’ chemistry, actions and uses

¤Drug metabolism

¤Toxicology

• Acute or short-term toxicity studies, e.g. a single day

• Subacute or long-term toxicity studies, e.g. 90-180 days at different dose levels in different species

• Carcinogenicity studies

• Reproduction studies

• Genotoxicity of mutagenicity studies

what do preformulation studies include

these intrinsic chemical and physical characteristics including:

¤Drug’s solubility

¤Partition coefficient

¤Dissolution rate

¤Physical form

¤Stability

how can you do human testing

file with the fda an ind before the drug may be given to human subjects

¤To protect the rights and safety of the subjects

¤To ensure the investigational plan is sound and is designed to achieve the stated objectives

when applying for a new use, strength, dosage form, or route of administration for a previous approved drug, the sponsor must:

file a new IND, and then a New Drug Application (NDA).

what is a clinical hold

After 30 days of the date that the FDA acknowledges the receipt of the IND application, the sponsor could start human studies, unless receiving a clinical hold issued by the FDA to delay the study.

when are you able to file a new drug application (NDA)

If the three phases of clinical testing during the IND period demonstrate sufficient drug safety and therapeutic effectiveness

what is the purpose of an NDA

to gain permission to market the drug product in the United States

what must you file to be approved for an nda

complete presentation of all of preclinical and clinical results

what does an nda request in addition to documentations

on-site preapproval inspection

who is the nda review committee composed of

the FDA and outside advisory

what happens after nda review

FDA issues an action letter to let a sponsor of an NDA know for “approval” or for “complete response”.

what are key elements of an nda

¤Application form

¤Chemical, the dosage form, its strength, route administration

¤Detailed summary of all aspects of the application, including intended labeling, CMCs, pharmacology, toxicology, human pharmacokinetics, statistical analysis, clinical trial data, benefit and risk consideration

¤Detailed technical sections on CMCs for drug substance, including physical and chemical characteristics, methods of identification, assay and controls

¤Detailed technical sections on drug product, including its composition, specifications, methods of manufacture and equipment used, in-process controls, batch and master production record, containers and closure systems, stability, and expiration dating.

what is an snda

supplemental new drug application that a sponsor of an approved nda may make changes

what can you change through a snda

Change in the method of synthesis

Change in manufacturing facility

Change in the formulation, analytical standards, method of manufacture, or in-process controls

Change in container and closure system

Extension of the expiration date

Any labeling change

After marketing, Phase 4 clinical studies continue to understand:

Drug’s mechanism or scope of action

Possible new therapeutic uses of the drug

The need for additional dosage strengths, dosage forms, or routes of administration

Additional side effects and drug interaction

a sponsor wants to study a new route of administration for a drug that is already fda approved. which regulatory pathway is required according to the lecture

a new ind followed by a new nda

what agency oversees the end product of drug discovery to drug product

FDA

what agency oversees the approval process

center for drug evaluation (CDER)

why is speed in development importent

patent protection expires

why is drug development high risk

because it is high cost

what is the order for the new drug development process

new chemical entity → preclinical studies → investigational new drug application (IND) → clinical trials → new drug application (NDA) → postmarketing

if applying for a new use, strength, dosage form, or route of administration for a previously approved drug, the sponsor must

file a new IND, and then a new drug application (NDA)

what is drug solubility

measure how much drug can dissolve in aqueous and other solvents

what is partition coefficient

measure of drug distribution in a lipophilic hydrophilic phase system

what is dissolution rate

speed at which a drug substance dissolved in a medium

what is physical form

includes crystal or amorphous forms, and/or particle size of drug substance

what is stability

includes chemical and physical stability of a drug dubstance alone, and when combined with formulation components

what are all preformulation components focused on

the API

who are the test subjects in preclinical trials

lab and animal studies

who, how many are the subjects in phase 1 clinical trials and what is the purpose and success rate

safety study

20-80 people

70% success rate

who, how many are the subjects in phase 2 clinical trials and what is the purpose and success rate

safety study

identify side effects

measure effectiveness

100-300 people

33% success rate

who, how many are the subjects in phase 3 clinical trials and what is the purpose and success rate

measure effectiveness

monitor side effects

1000-3000 people

25-30% success rate

what is the purpose of stage 4 clinical trials

monitor long term side effects