| Steps to New Drug Discovery Pre-clinical Trials | 1 Drug Target
2 Develop Bioassay
3 Screening chemical compounds in assay
4 Establish EFFECTIVE & TOXIC amounts
5 File INVESTIGATIONAL NEW DRUG (IND)
DDSEF |
| PRECLINICAL TESTING
1 to ensure BIOLOGICAL ACTIVITY in vivo
2 to ensure ADEQUATE QUANTITIES OF HIGH PURITY DRUG can be made
3 to CHARACTERIZE VARIOUS CHEMICAL PROPERTIES, develop the initial drug delivery system, and DETERMINE THE STABILITY of the compound
4 to ensure LIMITED TOXICITIES of the LEAD AGENT | .
1 Discovery testing
2 Chemical synthesis scale-up
3 Formulation development and stability testing
4 Animal safety testing |
| PRECLINICAL TESTING
1 __ provide STANDARDS for the design and conduct of studies
Qualifications of personnel are specified
Requirements for SOP are established | .
1 Good Laboratory Practice (GLP) |
| High level of purity __Percent→toxicity testing | >0.1 % |
| PHYSICOCHEMICAL PROPERTIES of active compound
DRUG DELIVERY SYSTEM for human testing are DEVELOPED
Animal testing→ ADME in living system (may be
corrected)
Possible side effects and toxicities (same with human, min. of 2 weeks)→
1 RODENT, 1 NON-RODENT
ADMINISTRATION: Animals same route of dosage form with humans
ANIMAL SAFETY TESTING: highest no-effect dose, plasma concentrations | Preclinical Stage |
| 1 “LIVE” systems that is used to MEASURE DRUG EFFECT
It may be a CULTURE OF CELLS or ORGANS or WHOLE ANIMALS
2 Example of this is __
You can see the effects of drugs on bone density, blood vessel growth and many other systems of the zebra fish | 1 BIOASSAY
2 Zebra fish embryo |
| 1 this is the ACTUAL TEST of the DRUG
DETERMINE if the drug is SAFE & EFFECTIVE (before being tested in humans)
2 Most drugs have a TOXIC level or an amount at which the drug will become harmful instead of helpful | 1 Screening of the drug in the Bioassay
(Step 3)
2 Establish EFFECTIVE & TOXIC amounts
(Step 4) |
| In this Step, you must show how the drug is:
1 Manufactured
2 Appears (color, solubility, melting point, particle size, moisture content)
3 Formulated (Pills, liquid, etc + inactive ingredients)
4 Will be analyzed for purity, concentration, stability
5 Will be tested for safety (BASIS for human testing) | application is made to the Food & Drug Administration as an Investigational New Drug (IND)
STEP 5 |
| SMALL NUMBER of HEALTHY INDIVIDUALS
To assess the compound’s SAFETY
Life-threatening disease (AIDS, cancer)- SICK IND. MAY BE ENROLLED
STARTING DOSE IS LOW (1/10 of the highest no-effect dose)
Preliminary ADME (parent drugs and metabolites)
P’KINETICS AND PCOL EFFECTS are OBTAINED | Phase 1 clinical trials |
| Phase 1 clinical trials
STARTING DOSE: __ | 1/10 of the highest no-effect dose |
| Clinical trial protocols→ FDA ( prior to trial)
Focus is from SAFETY→ EFFICACY
100-300 pts., SUFFER FROM TARGET ILLNESS
SIDE-EFFECTS are being INVESTIGATED
FAILURE IS COMMON | Phase 2 clinical trials |
| Sponsors meet with FDA → review of the past trials,
design future trials, drug development plan
PROPOSED PROTOCOL→ inclusion/exclusion criteria, dosing regimens, methods and timing of data
collection, duration of tx and follow-up assessments,
etc.→ limit the bias of trial results
*AGREEMENT ( FDA and Sponsor) → data required for NDA
LONGEST, MOST COMPREHENSIVE TRIAL regarding efficacy and safety of new compounds
1000-3000 AFFLICTED WITH TARGET ILLNESS→ recruited, tested and monitored
ADR are also monitored; New drug is COMPARED TO COMPETITOR DRUGS or PLACEBO | Phase 3 clinical trials
- 95% chance of being approved by FDA
- Help establish the appropriate format of the
submission
- Determine if additional animal or human trial is
necessary |
| Phase 3 clinical trials
1 inclusion/exclusion criteria, dosing regimens, methods and timing of data collection, duration of tx and follow-up assessments, etc.→ LIMIT THE BIAS of TRIAL RESULTS
2 data required for NDA
3 Prior to start of Phase 3- __ should be optimized | .
1 PROPOSED PROTOCOL
2 AGREEMENT ( FDA and Sponsor)
3 final market formulation |
| POST-APPROVAL clinical trials
For SPECIFIC PATIENT POPULATION to further assess
efficacy and side effects
ASSESS LONG-TERM SAFETY of the drug | Phase 4 clinical testing |
| LAST HURDLE prior to APPROVAL AND MARKETING
NDA document - hundreds to thousand of pages
containing highly detailed information
FDA REVIEWS the proposed PRODUCT LABELING and
PACKAGE INSERT | New Drug Application (NDA) |
| hundreds to thousand of pages
containing highly detailed information | NDA document |
| Information required in NDA | 1 SAFETY and EFFICACY of the drug treatment
2 COMPONENTS of drug products
3 DESCRIPTION OF METHODS AND CONTROLS used in the manufacturing the AI, drug delivery system and packaging
4 Proposed LABELING
SCD P |
| 1 GIVEN TO NEW DRUG PRODUCTS with
IMPROVED THERAPEUTIC EFFECTS, safety, side effects in COMPARISON to the MARKETED DRUG, reviewed in timely manner
2) 60 days- decision to accept NDA from the date of
submission | 1 “P” Priority review
2 “S” Standard review |
| If NDA is accepted - __ | 1 detailed evaluation, 180 DAYS from
submission for FDA to complete the review
Comments and recommendations are made
Approve the product to be marketed, approve with
specific conditions (Conditional Approval),
disapprove the products |
| Prior to NDA approval - __
Usually conducted WITHIN 45 DAYS of NDA
Acceptance | FDA conducts an INSPECTION
of the sponsor’s facilities to ensure compliance with
cGMPs |
| 1 In NDA, if Deficiencies are noted - __
2 Once resolved -
3 Companies hold __ | 1 a LETTER is SENT TO SPONSOR
2 company must PROVIDE WRITTEN
CERTIFICATION and FDA will CLEAR the application
WITHIN 45 days if corrections are adequate
3 mock pre-approval audits |
| Reasons for drug disapproval | 1 LACK of demonstrated SAFETY and EFFICACY
2 ISSUES with the MANUFACTURING/processing PROCEDURES
3 FALSE/MISLEADING LABELING
LIF |
| IF NDA is approved
1 __ is sent to the sponsor
2 __ - combination of the draft and revisions by
reviewing section of FDA | .
1 Approval letter and draft of product labeling
2 Label |
