NEW DRUG DEVELOPMENT AND APPROVAL PROCESS

Presented by HYNDAVI MANYAM

CONTENTS
Introduction Drug

discovery and drug design Biologic characterization Early formulation studies The Investigational New Drug Application The New Drug Application Supplemental, Abbreviated & other applications References

INTRODUCTION:
The process and time

course from new drug discovery to approval is lengthy and complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups. The federal Food, Drug, and Cosmetic Act , as regulated through Title 21 of the U.S. Code of federal regulations, requires a new drug to be approved by the Food and Drug Administration(FDA) before it may be legally introduced in US market. The regulations apply to drug products manufactured domestically and those imported into the United States.

New chemical entity Sources : organic synthesis molecular modification isolation from plants

Preclinical studies including chemistry Physical properties Biological preformulation

Investigational new drug application (IND) submission FDA Review

Preclinical studies(contd) Plus: Longterm animal toxicity Product formulation Manufacturing and controls Package and label design Post marketing Phase IV clinical studies Clinical toxicology Additional indications Adverse reaction reporting Product defect reporting Product line extension

Clinical trials phase I phase II phase III

New drug application (NDA) submission FDA Review preapproval plant inspection FDA action

DRUG DISCOVERY AND DRUG DESIGN:

Irrespective of the country of origin, a drug may be proposed by its sponser for regulatory approval for marketing in the US and/or other countries. Sources of new drugs: Plants: After the isolation and structural identification of active plant constituents, organic chemists may recreate them by total synthesis or may develop semisynthetic compounds. Eg:Reserpine from Rauwolfia serpentina, vincristine and vinblastine from Vinca rosea Animals: Provide drugs that are mannered from their tissues or biologic processes. Eg: hormonal substances, vaccines,sera,antitoxins etc.,

Genetic

engineering: Yield purer vaccines, antibiotics etc., Recombinant DNA techniques: Involves manipulation of proteins Eg: human isulin, human growth hormone, hepatitis B vaccine, interferons etc., Monoclonal antibody production: This technique exploits the ability of cells with the potential to produce a desired antibody and stimulates a stream of pure antibody production. Eg:used to localize malignant cells of cancer

Human gene therapy:

Used to prevent, treat, cure, diagose, or mitigate human disease caused by genetic disorders. Eg: adenosine deaminase deficiency A Goal drug: In theory, a goal drug  Would produce the specifically desired effect  Be administered by the most desired route at minimal dosage and dosing frequency  Have optimal onset and duration of activity


Exhibit no side effects

    

It would be eliminated from the body efficiently and completely No residual side effect It would be easily produced at low cost Be pharmaceutically elegant Physically and chemically stable under various conditions of use and storage.

Methods of drug discovery: 1.Random or untargeted screening: Testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity

2.Nonrandom or targeted screens: To determine a specific activity. 3.Molecular modification: Chemical alteration of a known and previously characterized organic compound. 4.Mechanism based drug design: Molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process.

A Lead compound: It is a prototype chemical compound that has a fundamental desired biologic or pharmacologic activity. Prodrugs: It requires metabolic biotransformation following administration to yield the desired pharmacologically active compound. Prodrugs may be designed to modify solubility, absorption, biostability,prolonged release etc.,

FDAs definition of a New Drug: A new drug is any compound 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. Drug nomenclature: When 1st synthesized or identified from a natural source, an organic compound represented by an empirical formula. Systematic chemical name includes the positioning of different atoms. Nonproprietary or generic name is the shortened name.

Biologic characterization: Prospective drug substances must undergo preclinical testing for biologic activityto assess their potential as useful therapeutic agents. Pharmacology: It is the science concerned with drugs, their sources, appearance, chemistry, actions, and uses. It includes pharmacodynamics, pharmacokinetics and clinical pharmacology. In vitro cultures of cells and enzymes systems and in vivo models are used to define a chemicals pharmacologic profile. The primary objective of the animal studies is to obtain basic information on drugs effects that may be use to predict safe and effective use in humans.

Drug Metabolism: A series of animal studies of a proposed drugs ADME are undetaken to determine The extent and rate of drug absorption from various routes of administration, including the one intended for human use  The rate of distribution of the drug through the body and the site or sites and duration of the drugs residence  The rate, primary and secondary sites, and mechanism of the drugs metabolism in the body and the chemistry and pharmacology of any metabolites  The proportion of administered dose eliminated from the body and its rate and route of elimination


Toxicology: It deals with the adverse or undesired effects of drugs. Acute or Short-Term Toxicity Studies: 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. Subacute or Subchronic Studies: 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 administration of a single dose in human clinical testing. Chronic toxicity studies: For drugs intended to be given to humans for a week or more, animal studies of 90 to 180 days must demonstrate safety.

Carcinogenicity Studies: Data on the causes of animal death, tumor incidence, type and site, and necropsy findings are collected and evaluated Reproduction Studies: Included in these studies are fertility and mating behavior; early embryonic, prenatal, and postnatal development, multigenerational effects, teratology Genotoxicity or Mutagenicity Studies: Performed to determine whether the test compound can affect gene mutation or cause chromosome or DNA damage.

Early Formulation Studies: 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. 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.

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 Comprise all dosage formulations used in the clinical evaluation of a new drug
This includes the

Phase 2,

proposed new drug, placebos (inert substances for controlled studies) and drug products against which the new drug is to be compared (comparator drugs or drug products)

The Investigational New Drug Application: It has to be filed by the sponsor prior to giving to the human subjects. It should include the following data  Full description of new drug  Where and how it is manufactured  All quality control information and standards  Stability  Analytical method  Pharmacology  Toxicology  Efficacy in animals  Persons who will do the clinical studies

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 FDA-1571):  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

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

Comparison of Clinical trials: Phase I Phase II Phase III Phase IV

OBJECTIVES:

metabolic and pharmacological actions and the maximally tolerated dose

effectiveness, determine the short-term side effects and identify common risks for a specific population and disease

additional information about the effectiveness on clinical outcomes and evaluate the overall risk-benefit ratio in a demographically diverse sample

Monitor ongoing safety in large populations and identify additional uses of the agent that might be approved by the FDA

DURATION:

Up to 1 month

Several months

Several years

Ongoing (following FDA approval)

Phase I

Phase II

Phase III

Phase IV

POPULATI ON:

Healthy volunteers or individuals with the target disease (such as cancer or HIV)

Individuals with target disease

Individuals with target disease

Individuals with target disease, as well as new age groups, genders, etc.

SAMPLE SIZE:

20 to 80

200 to 300

Hundreds to thousands

Thousands

DATA FOCUS:

-Vital signs -Plasma and serum levels -Adverse events

-Dose response, tolerance -Adverse events -Efficacy

Laboratory data -Efficacy -Adverse events

-Efficacy -Pharmacoeconomics -Epidemiology -Adverse events

Clinical study controls and designs: Phase 2 and some phase 3 studies are controlled i.e., the effects of the investigational drug are compared with another agent( placebo or an active drug). Blinded studies:  The identities of the investigational drug and the control are not revealed to certain participants to decrease bias.  In preparing dosage forms for blinded studies, all of the agents administered must be indistinguishable to the blinded individuals. Single blind studies: The patient is unaware of agent administered Double blind studies: Neither the patient nor the clinician is aware of the agent administered.

Drug Dosage and Terminology: The safe and effective dose of a drug depends on different factors:
  

Characteristics of the drug substance The dosage form and its route of administration Variety patient factors - age, body weight, general health status, pathologic conditions 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. Under dosage / Over dosage -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

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

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 Concomitant Drug Therapy Time and conditions of administration Dosage form and route of administration

Treatment IND: A treatment IND permits the use of an investigational drug in the treatment of patients not enrolled in the clinical study but who have a serious or immediately life- threatening disease for which there is no alternative therapy. IND for an Orphan Drug: Orphan disease is defined as a rare disease or condition that affects fewer than 2,00,000 people in the US and for which there is no reasonable expectation that costs of R&D for the indication can be recovered by sales of the product in US.

Withdrawal or termination of an IND:  A sponsor may withdraw an IND at any time.  The FDA may terminate an IND and related clinical investigations for reasons safety, efficacy, or regulatory compliance. THE NEW DRUG APPLICATION: General content of the NDA submission:  A NDA contains a complete presentation of all of the preclinical and clinical results that the sponsor has obtained during the investigation of drug.  The applicant submits three copies of the NDA: 1.An archival copy- maintained by the FDA as the reference document 2.A review copy- used by the FDA review division 3.A field copy- used by the FDA district office and field inspectors

          

Drug Product Labeling (Package Inserts) Description of the product Clinical Pharmacology Indications and usage Contraindications Warnings Precautions Adverse reactions Drug abuse and Dependence Over dosage Dosage and Administration How supplied

Phase IV studies and post marketing surveillance:  Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold.  Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons.  The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.  Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses

Supplemental, Abbreviated, and Other Applications

    

Supplemental New Drug Application Abbreviated New Drug Application Biologics License Application Animal Drug Applications Medical Devices

Conclusion: The process of drug development is the transformation of the chemists compound through the pharmacists formulation and production of the product to become marketable merchandise. This long involved process requires the input of large resources and a myriad of professional and technical expertise. The process consists of several distinct but overlapping and interlinked phases, which have a range of milestones to gauge progress. Careful coordination throughout the process is necessary to ensure that the development of any adverse results is acted upon and decisions to either progress or drop the compound are taken before expenditure is excessive.

REFERENCES :
1.

2.

3. 4. 5.

Loyd V. Allen, Jr. Nicholas G. Popovich, Howard C. Ansel, drug dosage form and drug delivery system design in Text book of Ansels pharmaceutical dosage forms and drug delivery systems 8th edition Remington, The Science and Practice of Pharmacy 21st edition volume1, The New Drug Approval Process and Clinical Trial Design en.wikipedia.org/wiki/drug_development New Drug approval process- Richard.A.Guarino The Textbook of Pharmaceutical Medicine-Fourth edition-John Griffin, John O Grady