1. Regional

2.1 -2 TOC, Intro

2.3 Overall Quality Summary

2.4 Nonclinical overview

2.5 Clinical overview

3 Quality

4 Nonclinical Reports

5 Clinical Reports

Substance = API

Product = Finished Pharmaceutical material material ready for

Amendment = before approval

Supplement = after approval

Type I) Facilities

Type II) Drug Substance or Drug Product

Type III) Container/Closure

Type IV) Dyes/collorants/flavorings

Type V) Other

Oral Solids

Topicals

Parenterals

Inhalation

List of tests and the acceptance criteria you need to meet in order to claim that your material meets the compendial requirements

USP is for drug products & API

NF is for inactive ingredients (excipients)

Creams

Lotions

Ointments and

Gels

Immediate Release (IR)

Modified Release (MR)

Primary categories of drug development activities

(3)

• Technical
• Investigtaive
• Managerial

Decision points in Drug development (4)

• Early Selection
• Development in Humans
• Full Development
• Submission

Primary Causes of New Drug Failures

1) Pharmacokinetics

2)Lack of efficacy

Departments of the FDA (5)

1. CDER
2. CBER
3. CDRH
4. CVM
5. CFSAN

Define:

1. Statute

2. Regulation

3. Guidance/PTC

1. Law enacted by congress
2. FDA's interpretation of statutes
3. Advice with no legal enforcement

Pure Food and Drugs Act:

1. Year?
2. Precipitated by?
3. Prohibited?
4. Required?

1. 1906 
2. The Jungle
3. "misbranded" and "adulterated" food and drugs
4. Drugs labeled and ingredients identified.

FD&C Act

1. Year?
2. Precipitated by?
3. Required?
4. Established?

1. 1938
2. Sulfanilimide
3. Proof of safety, adequate directions for use
4. NDA

Kefauver-Harris Amendments:

1. Year?
2. Precipitated by?
3. Required?

1. 1962
2. Thialidomide
3. S&E, Protocols, IC, Animal Testing

Orphan Drug Act

1. Year?
2. Purpose?

1. 1983
2. Provide incentive for less lucrative drugs

 Waxman-Hatch Act

1. Year?
2. Established?

1. 1984
2. ANDA

Types of Noncommercial INDs (3)

1. Treatment 
2. Investigator
3. Emergency Use

1. Commercial
2. Noncommercial

1. Form FDA 1571
2. TOC
3. Intro
4. General Inestigational Plan
5. Investigator's brochure

IND Items 6-10

6. Clinical Protocol

7. CMC

8. Nonclinical

9. Previous Human Experience

10. Additional Info

1. Information
   • Pharma/Toxi-cology
   • Chemistry
   • Clinical
2. Protocol
   • New protocol
   • Changes to protocol
   • New/revised Investigators

IND Safety Reports:

1. 7-day
2. 15-day
3. Form

1. For Death or near death AE
2. Serious / Unexpected AE
3. FDA 3500A (MedWatch)

1. Pre-IND
2. End of PhI
3. End of PhII
4. Pre-NDA

1. 505(b)(1) - NCE
2. 505(b)(2) - "paper" NDA - lit.& previous FDA filings
3. 505(j) -ANDA

FDA Form in Mod. 1 of CTD?

1. Prior approval
2. Prior approval not required (CBE, CBE-30)
3. Changes in NDA annual report

__ of __ marketed drugs make adequate ROI

Drug Development Timeline

1. Discovery + Preclinical
2. Clincal Ph 1-2
3. Clinical Ph3 to NDA

1.  3-5 yrs
2. 4 yrs
3. 2-4 yrs

1. Safety
2. Single/Repeat dose tox
3. Local Tolerance
4. TK

1. Bioavailability (BA)
2. Metabolism/elimination
3. Determine dosing regimens

1. Efficacy
2. dose-response
3. Determine dose regimens

1.  Parallel groups
2. Crossover
3. Factorial

1. Food effect
2. DDI
3. ADME
4. BA/BE
5. Hepatic Impairment
6. Renal Impairment
7. Age/Gender/Race Effects

1. Semi-solids
2. Transdermals
3. Opthalmics

1. Small volume Parenteral <= 100 mL
2. Large Volume Parenteral > 100 mL

1. Nasal Sprays
2. Metered Dose
3. Dry powder inhalers

USP Definitions for

1. Book

2. Organization

1. Book describing drugs, chemicals and medicinal preparations especially ones issued by an officially recognized authority and serving as a reference standard.
2. Organization that sets the standards that appear in the "book" as well as other activities

1. Name & Descriptive info 
2. Definition
3. Packaging and Storage information
4. USP reference standards
5. Identification tests
6. Additional tests

1. USP monograph in front
2. "other" materials in middle
   • General test methods
   • reagants, inidcators and solutions
   • reference tables
   • nutritional supplements
3. NF monographs in back

Definition of CRO

An organization contracted by a drug sponsor to manage various steps in the clinical process, from study design to trial execution, data management, analysis and medical writing.

1. Major
2. Midsize
3. Niche
4. Hybrid

Benefits of using a CRO (6)

1. Increased external capacity
2. reduced cycle time
3. accelerated learning curve
4. econmics of scale
5. rapid go/ no-go decisions
6. innovation

___% of US trials fail to meet contracted subject enrollment goals

___% of trials were delayed by 1 month

___% of trials were delayed by >1 month

70

___% of trials were on schedule

Approximately ___,000 clinical trials are ongoing in the US.

For every subject enrolled __ to __ must be screened for eligibility

75%

1. Natural = safe
2. Approved for one indication = safe for another
3. Historical use = no risks
4. Not toxic to animals = safe
5. Toxic to animals = not safe
6. Pushing dose to MDT in animals is not relevant to human safety
7. A "toxic" product would never be allowed for use in humans

Strategies in toxicology (4)

1. science
2. clinical profile
3. regulators
4. CMC

1. pharmacology
2. ADME
3. CYP 450
4. genotox
5. safety pharmacology
6. acute toxicity
7. subchronic toxicity

Chonic (6, 9 or 12 months)

Duration of:

1.  Acute

2.  Subacute

3. Subchronic

4. Chronic

1.  Single dose

2.  7, 14 or 28 day

3.  1, 3, or 6 months

4.  6, 9, or 12 months

1.  Identify NOAEL

2.  establish toxicity profile in repeat dose

3.  Identify target organ tox

4.  Establish dose regimen for subchronic study.

Purpose of subchronic tox studies.

1.  Identify NOAEL

2.  Characterize target organ tox

3.  Establish MTD for future carc and chronic studies

Purpose of chronic tox studies.

1. Identify accumulative toxicity and carcinogenic potential
2. Dose at MTD, 1/2 MTD, and 1/4 MTD
3. AUC 25x humans

Rodent species

Mice, rats, guinea pigs, and hamsters

1. AMES (bacterial mutagenesis)
2. Human lymphocyte abberation
3. Mouse lymphocyte abberation
   

1. rat micronucleus test
2. mouse micronucleus test

Strategic principles for a toxicology program

1. Kill a drug early
2. Don't underestimate the non-clinical safety/toxicology program
3. Know where you need to be covered
4. Feedback from regulators
5. Integrate with CMC and clinical

Definition of genotoxic

Minimum test battery for genotoxicity

1. AMES test
2. mouse micronucleus test
3. Mouse lymphoma or chromosome abberations

• initiation (mutation)
• promotion (reversible)
• progression (irreversible)

$2 to $5 million

1. Hypothesis generation
2. Target Discovery
3. Target validation
4. Assay development (4 wks - 6 mos)
5. Screen development (3-4 wks)
6. screening (2-6 wks)
7. follow-up (2-6 wks)
8. Lead Optimization

1. Robotics
2. Configurations
3. Readers
4. LIMS
5. Results Databases