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New Drug Development and Approval Process

NEW DRUG DEVELOPMENT PROCESS NEW CHEMICAL ENTITY SOURCES: Organic Synthesis Molecular Modification Isolation from plants Genetic Engineering

PRECLINICAL STUDIES Including Chemistry Physical Properties

Pharmacology ADME



PRECLINICAL STUDIES (Continued) long term animal toxicity product formulation Manufacturing and controls Package and label design

Methods of Drug Discovery Although some drugs may be the result of fortuitous discovery, most of drugs are the result of carefully designed research programs of screening, molecular modification, and mechanism-based drug design

1. Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity

to detect an unknown activity of the test compound or substance to identify the most promising compounds to be studied by more sophisticated nonrandom or targeted screens to determine a specific activity

2. Molecular modification - is chemical alteration of a known and previously characterized organic compound (frequently a lead compound) for the purpose of enhancing its useful as a drug

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 the body 5. Reducing its toxicity 6. Changing its physical and chemical properties

3. Mechanism-based drug design

- is a molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process

The intention is the interaction of the drug with specific cell receptors, enzymes systems, or metabolic process of pathogens or tumor cells, resulting in blocking, disruption, or reversal of the disease process

Example of Mechanism-based drug design

1. Enalaprilat -Vasotec - inhibits the angiotensin-coverting enzymes that catalyzes the conversion of AI to the vasoconstrictor substance AII. Inhibition of the enzymes results decreased plasma AII, leading to decrease vasopressor effects and lower blood pressure

2. Ranitidine - Zantac - an inhibitor of histamine at the histamine H2receptors, including receptors on the gastric cells. Used to treat gastric ulcers 3. Sertraline - Zoloft - which inhibits the central nervous systems neuronal uptake of serotonin, making the drug useful in the treatment of depression.

Lead compound

-is a prototype chemical compound which has a fundamental desired biologic or pharmacologic activity.

Example of Lead Compound

1. Cephalosporin antibiotics - additional H2 antagonists from the pioneer drug Cimetidine

2. Large series of antianxiety drugs derived from Benzodiazepine structure and the innovator drug chlordiazepine -Librium.

3. Most drugs exhibit activities secondary to their primary pharmacologic action. Example: Finasteride -Proscar was originally developed and approved to treat benign prostatic hyperplasia. Later, the same drug Propecia was approved at lower recommended dosage to treat male pattern baldness

-is a term used to described a compound that requires metabolic biotransformation following administration to yield the desired pharmacologically active compound.

Example of Prodrug
Enapril maleate Vasotec -which, after oral administration, bioactivated by hydrolysis to enaprilat, an ACE inhibitor used in the treatment of hypertension
Prodrug may be design preferentially for solubility, absorption, biostability and prolonged release

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 facilitate absorption via the intended route of administration

Biostability - An active drug is prematurely destroyed by biochemical or enzymatic process, the design of a prodrug may protect the drug during its transport in the body Prolonged Release - Depending on a prodrugs rate of metabolic conversion to active drug, it may provide prolonged release and extended therapeutic activity

FDAs Definition of a New Drug

NEW DRUG - is any that is not recognized as being safe and effective in the conditions recommended for its use among experts who are qualified by scientific training and experience.

A combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered new if the change introduces a question of safety or efficacy.

- A new dosage schedule or regimen, a new rout of administration, new dosage form all cause a drug or drug products status to new and triggers reconsideration for safety and efficacy - A drug need not be a new chemical entity to be considered new. A change in a previously approved drug products formulation or method of manufacture constitutes newness under the law, since such changes can alter the therapeutic efficacy and/or safety of a product.

NOMENCLATURE OR NAMING OF DRUG The task of designating appropriate non-proprietary names for newly found chemical agents rests primarily with the USAN Council. The official name for a drug is referred to as the drug nonproprietary or public name

in contrast to the proprietary or brand names or trademark names given by the specific manufacturers or distributors of the drug.

The term generic name, has been used extensively in referring to the nonproprietary names of the drugs. Brand name is registered as a trademark with the United States Patent Office

CATEGORY OR USE In general, drugs exert their effects by one of three means: 1. By exerting a physical action such as the protective effects of ointments and lotions upon topical application

2. By reacting chemically outside the body cells. Example: antacids counteract excess acidity in the stomach or antibiotics to act against invading pathogenic microorganism.

3. By modifying the metabolic activity of the bodys cell. Majority of the drugs belong to the 3rd manner where brain, liver, kidney, etc. are affected

Proposals for Nonproprietary Names 1. Be short and distinctive in sound and spelling and not be such that it is easily confused with existing names

2.Indicate the general pharmacologic or therapeutic class into which the substance falls or the general chemical nature of the substance if the latter is associated with the specific pharmacologic activity 3. Embody the syllable or syllables characteristic of a related group of compounds

pharmaco= drugs; logos = study of; is the science concerned with drugs, their sources, appearance, chemistry, actions, and uses.

The term can be expanded to include 1. Properties 2. Biological and physiologic effects 3. Mechanism of actions 4. ADME

Pharmacodynamics = the study of the biochemical and physiologic effects of drugs and their mechanism of action

Pharmacokinetics = ADME
Clinical Pharmacology = applies pharmacologic principles to the study of the effects and actions of drugs in humans

Pharmacologic profile = In vitro cultures of cells and enzymes systems and in vivo animal models are used to define a chemicals pharmacologic profile = Most animal testing is done on small animals, usually rodents (mouse, rats) for a number of reasons including cost, availability, the small amount of drug required for a study,

the ease of administration by various routes (oral, inhalation, intravenous) and experience with drug testing in these species

Animal models: dog or rat for hypertension; dog and guinea pig - for respiratory effects; dogfor diuretic activity; rabbit - for blood coagulation; mouse and rats - for CNS studies

Drug Metabolism
1. The extent and rate of drug absorption from various routes of administration, including the one intended for human use
2. The rate of distribution of the drug through the body and the site or sites and duration of the drugs residence

3.The rate, primary and secondary sites, and mechanism of the drugs metabolism in the body and the chemistry and pharmacology of any metabolites 4. The proportion of administered dose eliminated from the body and its rate and route of elimination

Deals with the adverse or undesired effects of drugs Not all side effects of new drugs to be tested in animals will be detected but the greater the likelihood the effect will also be seen in humans Example: headache

Purpose of Safety Evaluation and Toxicity Studies 1.The substances potential for toxicity with short-term (acute effects) or long- term use (chronic effects) 2.The substances potential for specific organ toxicity 3.The mode, site, and degree of toxicity

4.Dose-response relationships for low, high, and intermediate doses over a specified time

5.Gender, reproductive, or teratogenic toxicities 6. The substances carcinogenic and genotoxic potential

Acute or Short-Term Toxicity Studies These studies are designed to determine the toxic effects of a test compound when administered in a single dose and/or in multiple dose doses over a short period, usually a single day.

Animals are observed: eating and drinking habits; weight changes; toxic effects; psychomotor changes; feces and urine are collected. Animal death: recorded; study on histology; pathology and statistically evaluated on the basis of dose response

Subacute or Subchronic Studies

Animal toxicity studies of a minimum of 2 weeks of daily drug administration at three or more dosage levels to two animal species are required to support the initial ad ministration of a single dose in human clinical testing.

Chronic toxicity studies

The initial human dose is usually one-tenth of the highest nontoxic dose (in milligrams per kilogram of subjects weight) shown during the animal studies. For drugs intended to be given to humans for a week or more, animal studies of 90 to 180 days must demonstrate safety.

If the drug is to be used for a chronic human illness, animal studies 1 year or longer must be undertaken to support human use. Compare the strain, sex, age, dose levels and ranges, routes of administration, duration of treatment, observed effects, mortality, body weight changes, food and water consumption,

physical examination (electrocardiography, ophthalmic, examination), hematology, clinical chemistry, organ weights, gross pathology, neoplastic pathology, histopathology, urinalysis, ADME data

Carcinogenicity Studies
Usually component of chronic testing and is undertaken when compound has shown sufficient promise as a drug to enter human clinical trials. Carcinogenicity studies are long term (18-24 months), with surviving animals killed and studied at defined weeks during the test period

Data on the causes of animal death, tumor incidence, type and site, and necropsy findings are collected and evaluated Preneoplastic lesions and/or tissue-specific proliferation effects are important findings

Reproduction Studies
Reproduction studies are undertaken to reveal any effect of an active ingredient on mammalian reproduction

Included in these studies are fertility and mating behavior; early embryonic, prenatal, and postnatal development, multigenerational effects, teratology

In these studies, the maternal parent, fetus, neonates, and weaning offspring are evaluated for anatomic abnormalities, growth, and development. The animal used in other toxicity studies in reproductive studies, usually the rats.

In embryotoxicity studies only, a second mammalian species traditionally has been required. The rabbit is the preferred choice for practically and the extensive background knowledge accumulated on this species.

Genotoxicity or Mutagenicity Studies

Performed to determine whether the test compound can affect gene mutation or cause chromosome or DNA damage. Strains Salmonella typhimurium are routinely used in assays to detect mutations.

Early Formulation Studies

- As a promising compound is characterized for biological activity, it is also evaluated with regard to chemical and physical properties that have bearing on its ultimate and successful formulation into stable and effective pharmaceutical product

- This is the area of responsibility of pharmaceutical scientists and formulation pharmacists trained in pharmaceutics

Preformulation Studies
- Each drug substance has intrinsic chemical and physical characteristic that must be considered before the development of a pharmaceutical formulation
- Among these are the drugs solubility, partition coefficient, dissolution rate, physical form, and stability

Drug Solubility

- A drug substance administered by any route must posses some aqueous solubility for systemic absorption and therapeutic response
- Poorly soluble compounds (example less than 10mg per ml aqueous solubility) may exhibit incomplete, erratic, and or slow absorption and thus produce a minimal response at desired dosage

Partition Coefficient -A drug partition coefficient is a measure of its distribution in a lipophilichydrophilic phase system and indicates its ability to penetrate biologic multiphase system Dissolution Rate

- Is the speed at which a drug substance dissolves in a medium

Physical Form
-The crystal or amorphous forms and or the particle size of a powdered drug can affect the dissolution rate, thus the rate and extent of absorption, for a number of drugs

Stability - The chemical and physical stability of a

drug substance alone, and when combined with formulation components, is a critical to preparing a successful pharmaceutical product

Initial Product Formulation and Clinical Trial Materials - Prepared for Phase 1 and Phase 2 for clinical trials - Phase 1 studies, for orally administered drugs, capsules are employed containing the active ingredient alone, without pharmaceutical excipients

-Phase 2, the final dosage form is selected and developed for Phase 3 trials, this is the formulation that is submitted to the FDA for marketing approval

Clinical Supplies or Clinical Trial Materials

- Comprise all dosage formulations used in the clinical evaluation of a new drug
- This includes the proposed new drug, placebos (inert substances for controlled studies) and drug products against which the new drug is to be compared (compactor drugs or drug products)

Blinded Studies
-Are controlled studies in which at least one of the parties (example, patient, physician) does not know which product is being administered

= Some studies are open label, in which case all parties may know what products are administered

In all clinical study programs, the package label of the investigational drug must bear the statement Caution: new drug limited by federal ( or United States) law to investigational use

- Blister packaging is commonly used in

clinical studies, with intermediate labels containing the clinical study or protocol number, patient identification number, sponsor number, directions for use, code number to distinguish between investigational drug, placebo, and or compactor product, and other relevant information


FDA Review Pre-approval Plant inspection FDA action


Application for permission to administer a

new drug to humans

Outlines the proposal to use the new

drug 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)


1.Full description of new drug

2.Where and how it is manufactured 2.All quality control information and standards 4.Stability

5. Analytical method

6. Pharmacology
7. Toxicology 8. Efficacy in animals

9. Persons who will do the clinical studies

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 to proceed.

Declaration of Helsinki-1964 The clinical trial must minimize the risk for participants Provision for care of the patients Terminate the trial when the risk becomes incompatible with the goals of the trial Adverse events to be reported immediately to an ethical committee

Ethics Committees

The ethics committee reviews a protocol before the study is allowed to start. Their job is to ensure that the risks of being in the study are not greater than the potential benefit.

IRB( Institutional Review Board) IEC (Independent Ethical Committee)

To ensure the rights and welfare of the participants FDA regulations mandates to review the clinical trial protocols for ethical and legal issues Also has the authority to approve, modify or disapprove it

Informed Consent

Participation in clinical trials is always voluntary.

No, thank you, Id rather not participate. Yes, I would like to participate.


Informed Consent

Purpose Medicine to be studied Procedures and schedule

Risks Potential benefits Alternatives to participation Confidentiality

Clinical Trials & Research


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.


trials have a long history even if not acknowledged as Clinical trials 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]


of scientific background



hypothesis/hypotheses to be


design -type -study population PROTOCOL -statistical analysis -enrollment of subjects -intervention -follow up of subjects Organization

Phases of Clinical Trials

Phase I: Safety (1530 people)



Phase II: Safety and Effectiveness (Fewer than 100 people)


Phase III: Effectiveness compared to standard of care; Safety (More than 100 to a few thousand)







Clinical Trials & Research


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

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

Phase 2

Evaluate efficacy and therapeutic benefit

Involve 80-100 Patients

Identify common short term side effects

Establish dosing regimen and dose


Validate the design of phase 3

Duration : 1-2year

Phase 2A

Pilot study Dose defining and dose form Safety and efficacy PK/PD data Risk benefit ratio

Phase 2B

Controlled pivotal study Placebo Double blind Safety and efficacy

Phase 3

Large multi-center Randomized study

Involve 1000-3000 patient volunteers

Placebo controlled blind studies to clearly demonstrate efficacy, safety and therapeutic benefit Package insertion and labeling

Adverse drug reactions

Duration: 2-3 years

No fixed time and population purpose is usually to support the marketing campaign Rare ADRs Drug interaction New clinical indication (Phase 5)


The Impact of Clinical TrialsSuccessful

Some clinical trials have been critical to patient health & provision of health care For instance:
Protocol 076: HIV perinatal transmission 1st trial of AZT o Various cancer treatments o Development of other HIV related medications like PIs

The Impact of Clinical TrialsUnsuccessful

Medications did not work as in pre clinical study Loss of Follow-Up Harmful substance Unethical & poorly conducted study (Ex: Gene Replacement Study)


Once all clinical data has been submitted, reviewed and approval is granted to license in market Post marketing surveillance Approval takes 6 months to 2 years


clinical pharmacology/Toxicology additional indications

Adverse Reaction Reporting Product Defect Reposting Product Line Extension

Content of the IND

The content of an IND is prescribed in the Code of Federal Regulations and is submitted under a cover sheet (Form FDA1571):
Name, address, and telephone number of the sponsor of the drug

Name and title of the person responsible for monitoring the conduct and progress of the investigation

Names and titles of the persons responsible for the review and evaluation of information relevant to the safety of the drug Name and address of any contract research organization involved in the study Identification of the phase or phases of the clinical investigation to be conducted

Introductory statement and general investigational plan

Description of the investigational plan

Brief summary of previous human experience with the drug (domestic or foreign) Chemistry, manufacturing, control information Pharmacology and toxicology information

If the new drug is a combination of previously investigated components, a complete preclinical summary of these components when administered singly and any data or expectations relating to the effect when combined Clinical protocol for each planned study Commitment that an Institutional Review Board has approved the clinical study and will continue to review and monitor the investigation

Investigator brochure
Commitment not to begin clinical investigations until the IND is in effect, the signature of the sponsor or authorized representative, and the date of the signed application

Clinical Protocol As a part of IND application, clinical protocol must be submitted to ensure the appropriate design and conduct of the investigation Clinical Protocol include: Statement of the purpose and objectives of the study Outline of the investigational plan and study design

Estimate of the number of patients to be involved Basis for subject selection, with inclusion and exclusion criteria Description of the dosing plan, including dose levels, route of administration, and duration of patient exposure Description of the patient observations, measurements, and tests to be used

Clinical procedures, laboratory tests, and monitoring to be used in minimizing patient risk

Names, addresses, and credentials of the principal investigators and co investigators

Locations and descriptions of the clinical research facilities to be used

FDA Review of an IND Application

To protect the safety and rights of the human subjects and to help ensure that the study allows the evaluation of the drugs safety and effectiveness.

FDA Drug Classification System

By Chemical Type

Type 1 New Molecular entity, not marketed in US Type 2 New ester, new salt, or other derivative of an approved active moiety Type 3 New formulation of a drug marketed in US

Type 4 New combination of two or more compounds Type 5 New manufacturer of a drug marketed in US Type 6 New therapeutic indication for an approved drug

By Therapeutic Classification Type P Priority review, a therapeutic gain Type S Standard review, similar to other approved drugs

Additional Classification Type AA For treatment of AIDS or HIV-related disease Type E For life-threatening or severely debilitating disease Type F Review deferred pending data validation

Type G Data validated, removal of F rating

Type N Nonprescription drug

Type V Drug having orphan drug status

Drug Dosage and Terminology The safe and effective dose of a drug depends on different FACTOR: 1.Characteristics of the drug substance

2.The dosage form and its route of administration

3.Variety patient factors - age, body weight, general health status, pathologic conditions 4. Concomitant drug therapy

Usual adult dose - the amount of drug that will produce the desired effect in most adult patients.

Usual Dosage range - indicates the quantitative range or amounts of the drug that may be prescribed safely within the framework of usual medical practice.

Underdosage / Overdosage doses falling outside of the usual range

Usual Pediatric dose - dose usually given to children Schedule of dosage or Dosage regimen - determined during the clinical investigation and is based largely on a drugs inherent duration of action, its pharmacokinetics, and characteristics of the dosage form

MEC Minimum Effective Concentration - An average blood serum

concentration represents the minimum concentration that can be expected to produce the drugs desired effects in a patient

MTC Minimum toxic Concentration - The second level of

serum concentration of drugs expected to produce dose-related toxic effects in the average individual

MED Median Effective Dose of a

drug is the amount that will produce the desired intensity of effect in 50% of the individuals tested.

MTD Median Toxic Dose - is the amount that will produce a defined toxic effect in 50% of the individuals tested
The relationship between the desired and undesired effects of a drug is commonly expressed as the Therapeutic index and is defined as the ratio between a drugs median toxic dose and its median effective dose, TD50/ED50.

Some factors of patients considered in determining a drugs dose in clinical investigations and in medical practice include the following: Age

Body Weight
Body Surface Area Sex Pathologic State Tolerance

Therapeutic and Toxic Blood Level Concentrations of Some Drugs Substance

Acetaminophen Amitriptyline Barbiturate Short Acting Intermediate Long Acting Dextropropoxyphene 0.05-0.2 Diazepam Digoxin Imipramine Lidocaine Lithium Meperidine 0.5-2.5 0.0006-0.0013 0.05-0.16 1.2-5.0 4.2-8.3 0.6-0.65 1 1-5 ~10 5-10 5-20 0.002-0.009 0.7 6 13.9 5 7 10-30 40-60 57 :50 -2 -13.9-34.7 30 10 30 80-100

Drug Substances concentration, mg/L Drug Therapeutic Toxic Lethal

10-20 0.5-.20 400 0.4 1500 10-20

Phenytoin Quinidine Theophylline

5-22 3-6 20-100

-50 10 --

100 30-50 --

Therapeutic Indices For Various Drug Substances

Less Than 5

Between 5 and 10

Greater Than 10


Barbiturates Bromide


Chlordiazepoxide Diazepam Diphenhydramine Digoxin Ethchlorvynol Lidocaine Imipramine Meperidine

Chloral hydrate Glutethimide Meprobamate

Procainamide Quinidine

Primidone Thioridazine

Pentazocine Propoxyphene

Routes Of Drug Administration


oral peroral (per os, p.o.) gastrointestinal tract via mouth


parenteral intravenous intraarterial

under the tongue

other than GIT (by injection) vein artery



intracardiac heart intraspinal/intrathecal spine intraosseous bone intraarticular joint intrasynovial joint-fluid area intracutaneous/intradermal skin subcutaneous beneath the skin intramuscular muscle

Routes Of Drug Administration



epicutaneous (topical) transdermal

skin surface skin surface





intraocular intranasal aural intrarespiratory rectal vaginal urethral

eye nose ear lung rectum vagina urethra

Drug Product Labeling (Package Inserts)

1. Description of the product 2. Clinical Pharmacology 3. Indications and usage 4. Contraindications 5. Warnings


7.Adverse reactions
8.Drug abuse and Dependence 9.Over dosage

10.Dosage and Administration

11. How supplied

Some products, however, have been approved and later removed from the market for safety reasons, including the following: Grepafloxacin HCL (Raxar) Brofenac sodium (Duract) Cisapride (Propulsid) Alosetron HCL (Lotrovec) Fenfluramine HCL (Pondimin)

Dexfenfluramine HCL (Redux) Terfenadine (Seldane) Cerivastatin (Baycol) Mibefradil (Posicor) Astemizole (Hismanal) Troglitazone (Rezulin)

Preclinical Research and Development Initial synthesis and characterization


NDA Review Post Marketing Research and Surveillance Development Adverse reaction

Phase 1

Phase 2

Surveys/sampling testing Phase 3

Animal testing

Short term

Long term


Average 61/2 years

Average 7 years

Average 1 1/2 years

FDA 30-day safety review

NDA submitted

NDA approval

Average of approx. 15 years from initial synthesis to approval of NDA

Drug Discovery and Drug Design

- R and D activities on new Rx drugs for human - OTC drugs, generic drugs, biotechnology products, animal health care drugs, diagnostic products, and medical devices - development of new agents, such as vaccines to protect against poliomyelitis, measles, and influenza

New pharmacologic categories of drugs including oral hypoglycemic drugs effective against certain types of diabetes mellitus - Antineoplastic or anticancer drugs,

- Immunosuppressive agents to assist the bodys acceptance of organ transplant - Contraceptives to prevent pregnancy - Tranquilizers and antidepressant drugs to treat the emotionally distressed

New and Important Innovative Therapeutic Agents Approved by FDA

1. 2. 3. 4. 5. 6. 7. Efavirenz - Sustiva - to treat AIDS Didanosine - Videx EC - to treat AIDS Tenofovir - Viread - to treat AIDS Leuprolide acetate - Eligard prostate cancer Triptorelin pamoate - Trelstar - prostate cancer Lovastatin - Mevacor - hyperlipidemic Treprostinil sodium - Remodulin - pulmonary arterial hypertensive

8. Moxifloxacin HCl - Avelox - infectious disease 9. Montelukast sodium - Singulair - chronic asthma 10. Tegaserod maleate - Zelnorm - irritable bowel syndrome in women 11. Sodium oxybate -Xyrem - cataplexy in patient with narcolepsy 12. Galantamine HCl - Reminyl - dementia with Alzheimers disease 13. Fondaparinux sodium - Arixtra - deep vein thrombosis 14. Voriconazole - Vfend - infectious disease

Supplemental, Abbreviated, and Other Applications

Supplemental New Drug Application

Abbreviated New Drug Application

Biologics License Application Animal Drug Applications Medical Devices