8/3/2019 Nwe Drug Development and FDA
1/125
New Drug Developmentand
Approval Process
8/3/2019 Nwe Drug Development and FDA
2/125
NEW DRUG DEVELOPMENT PROCESSNEW CHEMICAL ENTITY
SOURCES:
Organic Synthesis
Molecular Modification
Isolation from plants
Genetic Engineering
8/3/2019 Nwe Drug Development and FDA
3/125
PRECLINICAL STUDIESIncluding
Chemistry
Physical Properties
Biological
Pharmacology
ADME
Toxicology
Preformulation
8/3/2019 Nwe Drug Development and FDA
4/125
CLINICAL TRIALS Phase I Phase II Phase III
PRECLINICAL STUDIES (Continued) long term animal toxicity
product formulation Manufacturing and controls Package and label design
8/3/2019 Nwe Drug Development and FDA
5/125
Methods of Drug Discovery
Although some drugs may be the
result of fortuitous discovery, mostof drugs are the result of carefullydesigned research programs of
screening, molecular modification,and mechanism-based drug design
8/3/2019 Nwe Drug Development and FDA
6/125
1. Random or untargeted screening
involves the testing of large numbers ofsynthetic organic compounds orsubstances of natural origin for biologicactivity
Purposes:to detect an unknown activity of the test
compound or substance
to identify the most promising compounds tobe studied by more sophisticatednonrandom or targeted screens todetermine a specific activity
8/3/2019 Nwe Drug Development and FDA
7/125
2. Molecular modification
- is chemical alteration of a known
and previously characterizedorganic compound (frequently a
lead compound) for the purpose of
enhancing its useful as a drug
8/3/2019 Nwe Drug Development and FDA
8/125
PURPOSES:1. Enhance its specificity for a particular body
target site
2. Increasing its potency
3. Improving its rate and extent of absorption
4. Modifying the advantage its time-course in thebody
5. Reducing its toxicity
6. Changing its physical and chemical properties
8/3/2019 Nwe Drug Development and FDA
9/125
3. Mechanism-based drug design
- is a molecular modification to design adrug that interferes specifically withthe known or suspected biochemicalpathway or mechanism of a diseaseprocess
8/3/2019 Nwe Drug Development and FDA
10/125
PURPOSE:The intention is the interaction of the drugwith specific cell receptors, enzymessystems, or metabolic process of pathogensor tumor cells, resulting in blocking,disruption, or reversal of the diseaseprocess
8/3/2019 Nwe Drug Development and FDA
11/125
Example of Mechanism-based drug
design
1.Enalaprilat -Vasotec - inhibits theangiotensin-coverting enzymes thatcatalyzes the conversion of AI to thevasoconstrictor substance AII. Inhibition ofthe enzymes results decreased plasma AII,
leading to decrease vasopressor effectsand lower blood pressure
8/3/2019 Nwe Drug Development and FDA
12/125
2. Ranitidine - Zantac - an inhibitor ofhistamine at the histamine H2-receptors, including receptors on thegastric cells. Used to treat gastric
ulcers
3. Sertraline - Zoloft - which inhibits
the central nervous systemsneuronal uptake of serotonin,making the drug useful in the
treatment of depression.
8/3/2019 Nwe Drug Development and FDA
13/125
Lead compound
-is a prototype chemical
compound which has afundamental desiredbiologic or pharmacologic
activity.
8/3/2019 Nwe Drug Development and FDA
14/125
Example of Lead Compound
1. Cephalosporin antibiotics - additionalH2 antagonists from the pioneer drug
Cimetidine
2. Large series of antianxiety drugs
derived from Benzodiazepine structureand the innovator drug chlordiazepine-Librium.
8/3/2019 Nwe Drug Development and FDA
15/125
3. Most drugs exhibit activities
secondary to their primarypharmacologic action.
Example: Finasteride-Proscarwas originally developed andapproved to treat benign prostatic
hyperplasia. Later, the same drug -Propeciawas approved at lowerrecommended dosage to treat malepattern baldness
8/3/2019 Nwe Drug Development and FDA
16/125
Prodrugs
-is a term used to described a
compound that requiresmetabolic biotransformationfollowing administration to yield
the desired pharmacologicallyactive compound.
8/3/2019 Nwe Drug Development and FDA
17/125
Example of Prodrug
Enapril maleate Vasotec-which, after oral administration, bioactivated
by hydrolysis to enaprilat, an ACE inhibitorused in the treatment of hypertension
Prodrug may be design preferentially for
solubility, absorption, biostability andprolonged release
8/3/2019 Nwe Drug Development and FDA
18/125
Solubility- Enabling the use of specifically
desired dosage forms and routes of
administration
Absorption- A drug may be made more water or
lipid soluble, as desired, to facilitateabsorption via the intended route ofadministration
8/3/2019 Nwe Drug Development and FDA
19/125
Biostability
- An active drug is prematurelydestroyed by biochemical or enzymaticprocess, the design of a prodrug may
protect the drug during its transport inthe body
Prolonged Release
- Depending on a prodrugs rate ofmetabolic conversion to active drug, itmay provide prolonged release and
extended therapeutic activity
8/3/2019 Nwe Drug Development and FDA
20/125
NEW DRUG - is any that is not recognizedas being safe and effective in the conditionsrecommended for its use among expertswho are qualified by scientific training andexperience.
A combination of two or more old drugs or a
change in the usual proportions of drugs in anestablished combination product is considerednew if the change introduces a question ofsafety or efficacy.
FDAs Definition of a New Drug
8/3/2019 Nwe Drug Development and FDA
21/125
- A new dosage schedule or regimen, a new
rout of administration, new dosage form allcause a drug or drug products status to new
and triggers reconsideration for safety andefficacy
- A drug need not be a new chemical entity tobe considered new. A change in a previouslyapproved drug products formulation or method
of manufacture constitutes newness under
the law, since such changes can alter thetherapeutic efficacy and/or safety of a product.
8/3/2019 Nwe Drug Development and FDA
22/125
NOMENCLATURE OR NAMING OF
DRUGThe task of designating appropriatenon-proprietary names for newly found
chemical agents rests primarily with theUSANCouncil.
The official name for a drug is referredto as the drug nonproprietary orpublic name
8/3/2019 Nwe Drug Development and FDA
23/125
in contrast to the proprietary or brand
names or trademark names given bythe specific manufacturers ordistributors of the drug.
The term generic name, has beenused extensively in referring to thenonproprietary names
of the drugs.Brand nameis registered as atrademark with the United StatesPatent Office
8/3/2019 Nwe Drug Development and FDA
24/125
CATEGORY OR USE
In general, drugs exert their effects by
one of three means:
1. By exerting a physical action suchas the protective effects of
ointments and lotions upontopical application
8/3/2019 Nwe Drug Development and FDA
25/125
2. By reacting chemically outsidethe body cells.
Example: antacids counteractexcess acidity in the stomach or
antibiotics to act against invading
pathogenic microorganism.
8/3/2019 Nwe Drug Development and FDA
26/125
3. By modifying the metabolicactivity of the bodys cell.
Majority of the drugs belong
to the 3rd manner wherebrain, liver, kidney, etc. areaffected
8/3/2019 Nwe Drug Development and FDA
27/125
Proposals for NonproprietaryNames
1. Be short and distinctive insound and spelling and notbe such that it is easily
confused with existingnames
8/3/2019 Nwe Drug Development and FDA
28/125
2.Indicate the general pharmacologic
or therapeutic class into which thesubstance falls or the generalchemical nature of the substance if
the latter is associated with thespecific pharmacologic activity
3. Embody the syllable or syllablescharacteristic of a related group ofcompounds
8/3/2019 Nwe Drug Development and FDA
29/125
Pharmacology
pharmaco= drugs;
logos = study of; is thescience concerned withdrugs, their sources,
appearance, chemistry,actions, and uses.
8/3/2019 Nwe Drug Development and FDA
30/125
The term can be expanded toinclude
1. Properties2. Biological and physiologic
effects
3. Mechanism of actions4. ADME
8/3/2019 Nwe Drug Development and FDA
31/125
Pharmacodynamics = the study
of the biochemical and physiologiceffects of drugs and their mechanism
of action
Pharmacokinetics = ADME
Clinical Pharmacology = appliespharmacologic principles to the studyof the effects and actions of drugs in
humans
8/3/2019 Nwe Drug Development and FDA
32/125
Pharmacologic profile = In vitro
cultures of cells and enzymes systemsand in vivo animal models are used todefine a chemicals pharmacologic
profile
= Most animal testing is done on
small animals, usually rodents (mouse,rats) for a number of reasons includingcost, availability, the small amount ofdrug required for a study,
8/3/2019 Nwe Drug Development and FDA
33/125
the ease of administration by
various routes (oral, inhalation,intravenous) and experience withdrug testing in these species
Animal models: dog or rat -for hypertension; dog and guinea
pig - for respiratory effects; dog-for diuretic activity; rabbit - forblood coagulation; mouse andrats - for CNS studies
8/3/2019 Nwe Drug Development and FDA
34/125
Drug Metabolism
1. The extent and rate of drugabsorption from various routes of
administration, including the oneintended for human use
2. The rate of distribution of thedrug through the body and the site orsites and duration of the drugs
residence
8/3/2019 Nwe Drug Development and FDA
35/125
3.The rate, primary and secondarysites, and mechanism of the
drugs metabolism in the body
and the chemistry andpharmacology of any metabolites
4. The proportion of administered
dose eliminated from the bodyand its rate and route ofelimination
8/3/2019 Nwe Drug Development and FDA
36/125
Toxicology
Deals with the adverse orundesired effects of drugs
Not all side effects of newdrugs to be tested in animals will be
detected but the greater the
likelihood the effect will also beseen in humans
Example: headache
8/3/2019 Nwe Drug Development and FDA
37/125
Purpose of Safety Evaluation and
Toxicity Studies
1.The substances potential for toxicitywith short-term (acute effects) or
long- term use (chronic effects)
2.The substances potential for
specific organ toxicity3.The mode, site, and degree of
toxicity
8/3/2019 Nwe Drug Development and FDA
38/125
4.Dose-response relationships forlow, high, and intermediate
doses over a specified time
5.Gender, reproductive, orteratogenic toxicities
6. The substances carcinogenic
and genotoxic potential
8/3/2019 Nwe Drug Development and FDA
39/125
Acute or Short-Term Toxicity
Studies
These studies are designed
to determine the toxic effects of atest compound when administered
in a single dose and/or in multiple
dose doses over a short period,usually a single day.
8/3/2019 Nwe Drug Development and FDA
40/125
Animals are observed: eating anddrinking habits; weight changes; toxic
effects; psychomotor changes; fecesand urine are collected.
Animal death: recorded; study on
histology; pathology and statistically
evaluated on the basis of doseresponse
8/3/2019 Nwe Drug Development and FDA
41/125
Subacute or Subchronic Studies
Animal toxicity studies of aminimum of 2 weeks of daily drug
administration at three or moredosage levels to two animal species
are required to support the initial ad
ministration of a single dose inhuman clinical testing.
8/3/2019 Nwe Drug Development and FDA
42/125
Chronic toxicity studies
The initial human dose is
usually one-tenth of the highest
nontoxic dose (in milligrams perkilogram of subjects weight) shownduring the animal studies. For drugs
intended to be given to humans for a
week or more, animal studies of 90to 180 days must demonstrate
safety.
8/3/2019 Nwe Drug Development and FDA
43/125
If the drug is to be used for a chronichuman illness, animal studies 1 year orlonger must be undertaken to supporthuman use.
Compare the strain, sex, age, doselevels and ranges, routes ofadministration, duration of treatment,
observed effects, mortality, body weightchanges, food and water consumption,
8/3/2019 Nwe Drug Development and FDA
44/125
physical examination(electrocardiography, ophthalmic,examination), hematology, clinical
chemistry, organ weights, grosspathology, neoplastic pathology,histopathology, urinalysis, ADME
data
8/3/2019 Nwe Drug Development and FDA
45/125
Carcinogenicity Studies
Usually component of chronic testingand is undertaken when compound hasshown sufficient promise as a drug to enter
human clinical trials.Carcinogenicity studies are long term
(18-24 months), with surviving animals killedand studied at defined weeks during the testperiod
8/3/2019 Nwe Drug Development and FDA
46/125
Data on the causes of animaldeath, tumor incidence, type and
site, and necropsy findings are
collected and evaluated
Preneoplastic lesions and/or
tissue-specific proliferationeffects are important findings
8/3/2019 Nwe Drug Development and FDA
47/125
Reproduction Studies
Reproduction studies areundertaken to reveal any effect of an
active ingredient on mammalian
reproduction
Included in these studies are
fertility and mating behavior; earlyembryonic, prenatal, and postnatal
development, multigenerational
effects, teratology
8/3/2019 Nwe Drug Development and FDA
48/125
In these studies, the maternalparent, fetus, neonates, and
weaning offspring are evaluated for
anatomic abnormalities, growth, anddevelopment. The animal used in
other toxicity studies in reproductive
studies, usually the rats.
8/3/2019 Nwe Drug Development and FDA
49/125
In embryotoxicity studiesonly, a second mammalian species
traditionally has been required. The
rabbit is the preferred choice forpractically and the extensivebackground knowledge
accumulated on this species.
8/3/2019 Nwe Drug Development and FDA
50/125
Genotoxicity or Mutagenicity
Studies
Performed to determine whether
the test compound can affect genemutation or cause chromosome orDNA damage. Strains Salmonella
typhimurium are routinely used inassays to detect mutations.
8/3/2019 Nwe Drug Development and FDA
51/125
Early Formulation Studies
- As a promising compound ischaracterized for biological activity, it is
also evaluated with regard to chemicaland physical properties that havebearing on its ultimate and successful
formulation into stable and effectivepharmaceutical product
8/3/2019 Nwe Drug Development and FDA
52/125
- This is the area of responsibilityof pharmaceutical scientists and
formulation pharmacists trainedin pharmaceutics
8/3/2019 Nwe Drug Development and FDA
53/125
Preformulation Studies
- Each drug substance has intrinsicchemical and physical characteristic that
must be considered before thedevelopment of a pharmaceuticalformulation
-Among these are the drugs solubility,partition coefficient, dissolution rate,physical form, and stability
8/3/2019 Nwe Drug Development and FDA
54/125
Drug Solubility
- A drug substance administered by anyroute must posses some aqueoussolubility for systemic absorption and
therapeutic response- Poorly soluble compounds (exampleless than 10mg per ml aqueous
solubility) may exhibit incomplete,erratic, and or slow absorption and thusproduce a minimal response at desired
dosage
8/3/2019 Nwe Drug Development and FDA
55/125
Partition Coefficient
-A drug partition coefficient is a measureof its distribution in a lipophilic-hydrophilic phase system and indicates
its ability to penetrate biologicmultiphase system
Dissolution Rate
- Is the speed at which a drug substancedissolves in a medium
8/3/2019 Nwe Drug Development and FDA
56/125
Physical Form
-The crystal or amorphous forms and or theparticle size of a powdered drug can affectthe dissolution rate, thus the rate and extentof absorption, for a number of drugs
Stability
- The chemical and physical stability of a
drug substance alone, and when combinedwith formulation components, is a critical topreparing a successful pharmaceuticalproduct
8/3/2019 Nwe Drug Development and FDA
57/125
Initial Product Formulation and
Clinical Trial Materials
- Prepared for Phase 1 and Phase 2
for clinical trials
- Phase 1 studies, for orallyadministered drugs, capsules areemployed containing the activeingredient alone, withoutpharmaceutical excipients
8/3/2019 Nwe Drug Development and FDA
58/125
-Phase 2, the final dosage form is selected and
developed for Phase 3 trials, this is the formulationthat is submitted to the FDA for marketing approval
Clinical Supplies or Clinical Trial
Materials
- Comprise all dosage formulations used in theclinical evaluation of a new drug
- This includes the proposed new drug, placebos(inert substances for controlled studies) and drugproducts against which the new drug is to becompared (compactor drugs or drug products)
8/3/2019 Nwe Drug Development and FDA
59/125
Blinded Studies
-Are controlled studies in which at leastone of the parties (example, patient,
physician) does not know whichproduct is being administered
= Some studies are open label, inwhich case all parties may know whatproducts are administered
8/3/2019 Nwe Drug Development and FDA
60/125
In all clinical study programs, the packagelabel of the investigational drug must bearthe statement Caution: new drug limitedby federal ( or United States) law toinvestigational use
- Blister packagingis commonly used inclinical studies, with intermediate labelscontaining the clinical study or protocol number,patient identification number, sponsor number,directions for use, code number to distinguishbetween investigational drug, placebo, and orcompactor product, and other relevantinformation
8/3/2019 Nwe Drug Development and FDA
61/125
NEW DRUG APPLICATION (NDA)
Submission
FDA Review
Pre-approval Plant inspection
FDA action
8/3/2019 Nwe Drug Development and FDA
62/125
INDApplication for permission to administer a
new drug to humans
Outlines the proposal to use the newdrug for human testing in clinical trials
Studies in humans can only begin after
IND is reviewed and approved by the
FDA and an institutional review board
(IRB)
8/3/2019 Nwe Drug Development and FDA
63/125
INVESTIGATIONAL NEW DRUG
1.Full description of new drug
2.Where and how it is manufactured
2.All quality control information andstandards
4.Stability
8/3/2019 Nwe Drug Development and FDA
64/125
5. Analytical method
6. Pharmacology
7. Toxicology
8. Efficacy in animals
9. Persons who will do the clinicalstudies
8/3/2019 Nwe Drug Development and FDA
65/125
Clinical drug evaluation & Authorization
Investigational new drug (IND) submission
-the rationale for the drug and
patient group to be treated-all pre clinical safety and efficacy data
-detailed plan for clinical development
-CIB( clinical investigators brochure)
Submitted to FDA for review and permission toproceed.
8/3/2019 Nwe Drug Development and FDA
66/125
Ethics
Declaration of Helsinki-1964
The clinical trial must minimize the riskfor participants
Provision for care of the patients
Terminate the trial when the risk
becomes incompatible with the goals ofthe trial
Adverse events to be reportedimmediately to an ethical committee
8/3/2019 Nwe Drug Development and FDA
67/125
Ethics Committees
The ethics committee reviews a protocol beforethe study is allowed to start. Their job is toensure that the risks of being in the study are
not greater than the potential benefit.
8/3/2019 Nwe Drug Development and FDA
68/125
IRB( Institutional Review Board)IEC (Independent Ethical Committee)
To ensure the rights and welfare of theparticipants
FDA regulations mandates to review theclinical trial protocols for ethical and legal
issues
Also has the authority to approve, modify ordisapprove it
8/3/2019 Nwe Drug Development and FDA
69/125
69
Informed Consent
Participation in clinical trials is alwaysvoluntary.
No, thank you, Idrather not participate.
Yes, I wouldlike to
participate.
8/3/2019 Nwe Drug Development and FDA
70/125
Clinical Trials & Research 70
Informed Consent
Purpose
Medicine to be
studied Procedures and
schedule
Risks
Potential benefits
Alternatives toparticipation
Confidentiality
Wh t i Cli i l T i l?
8/3/2019 Nwe Drug Development and FDA
71/125
71
What is a Clinical Trial?
Identify a health question.
Develop a plan.
Enroll volunteers and follow the plan.
Study the information collected.
Share the results with others.
Improve treatment.
8/3/2019 Nwe Drug Development and FDA
72/125
Clinical trials have a long history even if not
acknowledged as Clinical trials
Formal record of clinical trials dates back to the
time of the Trialists:
Dr. Van Helmonts proposal for a therapeutic trial of
bloodletting for fevers [1628]
Dr. Linds, a ship surgeon, trial of oranges & limes for
scurvy [1747]
NY/VI AETC
8/3/2019 Nwe Drug Development and FDA
73/125
8/3/2019 Nwe Drug Development and FDA
74/125
Review of scientific background
Written hypothesis/hypotheses to betested
Study design-type-study population
-statistical analysis-enrollment of subjects-intervention-follow up of subjects
Organization
PROTOCOL
8/3/2019 Nwe Drug Development and FDA
75/125
Phase 0
8/3/2019 Nwe Drug Development and FDA
76/125
Phase 0
Recent designation as per FDA-2006 guidelines
First in humans
100th of the pharmacological dose
Early PK and PD data
Minimal pre clinical study
Adv : unreliable in vitro and animal study
Disadv : safety/efficacy
8/3/2019 Nwe Drug Development and FDA
77/125
Phase 1
Participants (fewer than 100 healthy people)
Dose
Determines safety of the drug
Involve dose ranging studies to determine toxicity
and major adverse effects
May provide early evidence of efficacy
End point- toxicity
8/3/2019 Nwe Drug Development and FDA
78/125
Phase 2
Evaluate efficacy and therapeutic benefit
Involve 80-100 Patients
Identify common short term side effects
Establish dosing regimen and dose
optimization
Validate the design of phase 3
Duration : 1-2year
8/3/2019 Nwe Drug Development and FDA
79/125
Phase 2A
Pilot study
Dose defining and dose form
Safety and efficacy
PK/PD data
Risk benefit ratio
8/3/2019 Nwe Drug Development and FDA
80/125
Phase 2B
Controlled pivotal study
Placebo Double blind
Safety and efficacy
Phase 3
8/3/2019 Nwe Drug Development and FDA
81/125
Phase 3
Large multi-center Randomized study
Involve 1000-3000 patient volunteers
Placebo controlled blind studies to clearly demonstrateefficacy, safety and therapeutic benefit
Package insertion and labeling
Adverse drug reactions
Duration: 2-3 years
8/3/2019 Nwe Drug Development and FDA
82/125
No fixed time and population
The purpose is usually to support the marketingcampaign
Rare ADRs
Drug interaction
New clinical indication (Phase 5)
8/3/2019 Nwe Drug Development and FDA
83/125
The Impact of Clinical Trials-
Successful Some clinical trials have been critical to patient
health & provision of health care
For instance:
o Protocol 076: HIV perinatal transmission
1st trial of AZT
o Various cancer treatmentso Development of other HIV related medications like
PIs
8/3/2019 Nwe Drug Development and FDA
84/125
The Impact of Clinical Trials-Unsuccessful
Medications did not work as in pre clinicalstudy
Loss of Follow-Up
Harmful substance
Unethical & poorly conducted study (Ex:Gene Replacement Study)
8/3/2019 Nwe Drug Development and FDA
85/125
APPROVAL
Once all clinical data has been submitted,reviewed and approval is granted to license inmarket
Post marketing surveillance
Approval takes 6 months to 2 years
8/3/2019 Nwe Drug Development and FDA
86/125
POST MARKETING TRIALS
Phase IV Clinical Trials
clinical pharmacology/Toxicology
additional indications
Adverse Reaction Reporting
Product Defect Reposting
Product Line Extension
8/3/2019 Nwe Drug Development and FDA
87/125
Content of the IND
The content of an IND is prescribed inthe Code of Federal Regulations and issubmitted under a cover sheet (Form FDA-
1571):
Name, address, and telephone number ofthe sponsor of the drug
Name and title of the person responsiblefor monitoring the conduct and progress ofthe investigation
8/3/2019 Nwe Drug Development and FDA
88/125
Names and titles of the persons
responsible for the review and evaluationof information relevant to the safety of thedrug
Name and address of any contractresearch organization involved in thestudy
Identification of the phase or phases ofthe clinical investigation to be conducted
8/3/2019 Nwe Drug Development and FDA
89/125
Introductory statement and general
investigational plan
Description of the investigational plan
Brief summary of previous humanexperience with the drug (domestic orforeign)
Chemistry, manufacturing, controlinformation
Pharmacology and toxicology information
8/3/2019 Nwe Drug Development and FDA
90/125
If the new drug is a combination ofpreviously investigated components, acomplete preclinical summary of thesecomponents when administered singly andany data or expectations relating to the
effect when combined
Clinical protocol for each planned study
Commitment that an Institutional ReviewBoard has approved the clinical study andwill continue to review and monitor theinvestigation
8/3/2019 Nwe Drug Development and FDA
91/125
Investigator brochure
Commitment not to begin clinicalinvestigations until the IND is in effect,the signature of the sponsor orauthorized representative, and thedate of the signed application
8/3/2019 Nwe Drug Development and FDA
92/125
Clinical Protocol
As a part of IND application, clinicalprotocol must be submitted to ensure theappropriate design and conduct of the
investigationClinical Protocol include:
Statement of the purpose and
objectives of the study Outline of the investigational plan andstudy design
8/3/2019 Nwe Drug Development and FDA
93/125
Estimate of the number of patients to be
involved
Basis for subject selection, with inclusionand exclusion criteria
Description of the dosing plan, includingdose levels, route of administration, andduration of patient exposure
Description of the patient observations,measurements, and tests to be used
8/3/2019 Nwe Drug Development and FDA
94/125
Clinical procedures, laboratory tests,
and monitoring to be used inminimizing patient risk
Names, addresses, and credentials ofthe principal investigators and coinvestigators
Locations and descriptions of theclinical research facilities to be used
8/3/2019 Nwe Drug Development and FDA
95/125
FDA Review of an IND
Application
To protect the safety and
rights of the human subjects andto help ensure that the study
allows the evaluation of the drugs
safety and effectiveness.
8/3/2019 Nwe Drug Development and FDA
96/125
FDA Drug Classification System
By Chemical Type
Type 1 New Molecular entity, not
marketed in USType 2 New ester, new salt, or otherderivative of an approved active moiety
Type 3 New formulation of a drugmarketed in US
8/3/2019 Nwe Drug Development and FDA
97/125
Type 4 New combination of two ormore compounds
Type 5 New manufacturer of a drugmarketed in US
Type 6 New therapeutic indication
for an approved drug
8/3/2019 Nwe Drug Development and FDA
98/125
By Therapeutic Classification
Type P Priority review, a
therapeutic gain
Type S Standard review, similar to
other approved drugs
8/3/2019 Nwe Drug Development and FDA
99/125
Additional Classification
Type AA For treatment of AIDS
or HIV-related disease
Type E For life-threatening orseverely debilitating disease
Type F Review deferred pendingdata validation
8/3/2019 Nwe Drug Development and FDA
100/125
Type G Data validated,removal of F rating
Type N Nonprescription drug
Type V Drug having orphandrug status
8/3/2019 Nwe Drug Development and FDA
101/125
Drug Dosage and Terminology
The safe and effective dose of a drugdepends on different FACTOR:
1.Characteristics of the drug substance
2.The dosage form and its route ofadministration
3.Variety patient factors - age, bodyweight, general health status, pathologicconditions
4. Concomitant drug therapy
8/3/2019 Nwe Drug Development and FDA
102/125
Usual adult dose - the amount ofdrug that will produce the desired effectin most adult patients.
Usual Dosage range - indicatesthe quantitative range or amounts of thedrug that may be prescribed safely
within the framework of usual medicalpractice.
8/3/2019 Nwe Drug Development and FDA
103/125
Underdosage / Overdosage -
doses falling outside of the usual range
Usual Pediatric dose - doseusually given to children
Schedule of dosage or Dosageregimen - determined during the clinicalinvestigation and is based largely on a
drugs inherent duration of action, itspharmacokinetics, and characteristics ofthe dosage form
8/3/2019 Nwe Drug Development and FDA
104/125
MEC Minimum Effective
Concentration -An average blood serumconcentration represents the minimumconcentration that can be expected toproduce the drugs desired effects in a
patient
MTC Minimum toxic
Concentration - The second level ofserum concentration of drugs expected toproduce dose-related toxic effects in the
average individual
8/3/2019 Nwe Drug Development and FDA
105/125
MED Median Effective Doseof adrug is the amount that will produce
the desired intensity of effect in 50%of the individuals tested.
8/3/2019 Nwe Drug Development and FDA
106/125
MTD Median Toxic Dose - is the
amount that will produce a defined toxiceffect in 50% of the individuals tested
The relationship between thedesired and undesired effects of a drugis commonly expressed as theTherapeutic index and is defined asthe ratio between a drugs median toxic
dose and its median effective dose,TD50/ED50.
8/3/2019 Nwe Drug Development and FDA
107/125
Some factors of patients considered indetermining a drugs dose in clinical
investigations and in medical practice includethe following:
Age
Body Weight
Body Surface Area
Sex Pathologic State
Tolerance
Therapeutic and Toxic Blood Level Concentrations of Some Drugs
Drug Substances concentration, mg/L DrugS b t Th ti T i L th l
8/3/2019 Nwe Drug Development and FDA
108/125
Substance Therapeutic Toxic Lethal
Acetaminophen 10-20 400 1500
Amitriptyline 0.5-.20 0.4 10-20
Barbiturate
Short Acting 1 7 10Intermediate 1-5 10-30 30Long Acting ~10 40-60 80-100
Dextropropoxyphene 0.05-0.2 5-10 57
Diazepam 0.5-2.5 5-20 :50
Digoxin 0.0006-0.0013 0.002-0.009 --
Imipramine 0.05-0.16 0.7 2
Lidocaine 1.2-5.0 6 --
Lithium 4.2-8.3 13.9 13.9-34.7
Meperidine 0.6-0.65 5 30
Morphine 0.1 -- 0.05-4
Phenytoin 5-22 50 100
Quinidine 3-6 10 30-50
Theophylline 20-100 -- --
8/3/2019 Nwe Drug Development and FDA
109/125
Therapeutic Indices For Various Drug Substances
Less Than 5 Between 5 and 10 Greater Than 10
Amitriptyline Barbiturates Acetaminophen
Chlordiazepoxide Diazepam Bromide
Diphenhydramine Digoxin Chloral hydrate
Ethchlorvynol Imipramine Glutethimide
Lidocaine Meperidine Meprobamate
Methadone Paraldehyde Nortriptyline
Procainamide Primidone Pentazocine
Quinidine Thioridazine Propoxyphene
Routes Of Drug Administration
8/3/2019 Nwe Drug Development and FDA
110/125
Routes Of Drug Administration
TERM SITE
oral mouth
peroral (per os, p.o.)gastrointestinal tract via mouth
sublingual under the tongue
parenteral other than GIT (by injection)
intravenous veinintraarterial artery
8/3/2019 Nwe Drug Development and FDA
111/125
intracardiac heartintraspinal/intrathecal spineintraosseous bone
intraarticular jointintrasynovial joint-fluid areaintracutaneous/intradermal skinsubcutaneous beneath the skin
intramuscular muscle
TERM SITE
8/3/2019 Nwe Drug Development and FDA
112/125
Routes Of Drug Administration
TERM SITE
epicutaneous (topical) skin surface
transdermal skin surface
conjunctival conjunctiva
8/3/2019 Nwe Drug Development and FDA
113/125
intraocular eyeintranasal noseaural ear
intrarespiratory lungrectal rectumvaginal vagina
urethral urethra
TERM SITE
8/3/2019 Nwe Drug Development and FDA
114/125
Drug Product Labeling (Package
Inserts)
1. Description of the product
2. Clinical Pharmacology
3. Indications and usage
4. Contraindications
5. Warnings
8/3/2019 Nwe Drug Development and FDA
115/125
6.Precautions
7.Adverse reactions
8.Drug abuse and Dependence
9.Over dosage
10.Dosage and Administration
11. How supplied
8/3/2019 Nwe Drug Development and FDA
116/125
8/3/2019 Nwe Drug Development and FDA
117/125
8/3/2019 Nwe Drug Development and FDA
118/125
Some products, however, have
been approved and later removedfrom the market for safety reasons,
including the following:
Grepafloxacin HCL (Raxar)
Brofenac sodium (Duract)
Cisapride (Propulsid) Alosetron HCL (Lotrovec) Fenfluramine HCL (Pondimin)
8/3/2019 Nwe Drug Development and FDA
119/125
Dexfenfluramine HCL (Redux) Terfenadine (Seldane) Cerivastatin (Baycol) Mibefradil (Posicor) Astemizole (Hismanal)
Troglitazone (Rezulin)
Preclinical Clinical NDA Review Post Marketing Research andResearch and Development Surveillance Development
Initial synthesis Adverse
8/3/2019 Nwe Drug Development and FDA
120/125
and reactioncharacterization Phase 1
Phase 2 Surveys/sampling
testing
Phase 3
Animal testing
Short term
Long term Inspection
Average 61/2 Average 7 years Average 1 1/2years years
FDA 30-day safety review NDA submitted NDA approval
Average of approx. 15 years from initial synthesis to approval of NDA
8/3/2019 Nwe Drug Development and FDA
121/125
Drug Discovery and Drug Design
- R and D activities on new Rx drugs for human
- OTC drugs, generic drugs, biotechnologyproducts, animal health care drugs,
diagnostic products, and medical devices
- development of new agents, such asvaccines to protect against poliomyelitis,measles, and influenza
8/3/2019 Nwe Drug Development and FDA
122/125
New pharmacologic categories of drugs including oral
hypoglycemic drugs effective against certain types ofdiabetes mellitus
- Antineoplastic or anticancer drugs,
- Immunosuppressive agents to assist thebodys acceptance of organ
transplant- Contraceptives to prevent pregnancy
- Tranquilizers and antidepressantdrugs to treat the emotionallydistressed
8/3/2019 Nwe Drug Development and FDA
123/125
New and Important Innovative Therapeutic
Agents Approved by FDA
1. Efavirenz - Sustiva - to treat AIDS2. Didanosine - Videx EC - to treat AIDS
3. Tenofovir - Viread - to treat AIDS4. Leuprolide acetate - Eligard prostate cancer5. Triptorelin pamoate - Trelstar - prostate cancer6. Lovastatin - Mevacor - hyperlipidemic
7. Treprostinil sodium - Remodulin - pulmonaryarterial hypertensive
8 M ifl i HCl A l i f i di
8/3/2019 Nwe Drug Development and FDA
124/125
8. Moxifloxacin HCl - Avelox - infectious disease9. Montelukast sodium - Singulair - chronic
asthma10. Tegaserod maleate - Zelnorm - irritable bowel
syndrome in women11. Sodium oxybate -Xyrem - cataplexy in patient
with narcolepsy12. Galantamine HCl - Reminyl - dementia withAlzheimers disease
13. Fondaparinux sodium - Arixtra - deep veinthrombosis
14. Voriconazole - Vfend - infectious disease
S l t l Abb i t d d
8/3/2019 Nwe Drug Development and FDA
125/125
Supplemental, Abbreviated, and
Other Applications
Supplemental New Drug Application
Abbreviated New Drug Application
Biologics License Application
Animal Drug Applications
Top Related