Drug Development Process

Original Arthur: Addie D. Anderson

CRB Consulting Engineers, Inc.

Overview
Important milestones establishing our current system of regulations Step-by-step overview of the drug development process Fast-track drug development More Information

Milestones
1800s U.S. became the worlds dumping ground for counterfeit, contaminated, diluted, and decomposed drug materials. U.S. Customs Laboratories were established to administer the Import Drugs Act of 1848.
Mission: Enforce purity and potency standards

State of Food and Drug Supply Late 1800s

Agricultural to industrial economy Principle means of refrigeration ICE Unpasteurized milk Cows werent tested for TB Pioneers of bacteriology just starting string of victories over infectious diseases Kick-a-poo Indian Sagwa Warners Safe Cure for Diabetes Opium, morphine, heroin, and cocaine no restrictions or labeling

Medicine Men vs Circus

http://www.fda.gov

Pure Food and Drug Act of 1906

Prohibited interstate commerce of misbranded and adulterated foods and drugs. Allowed for seizure and criminal penalties. Did not address:
Food or drug standards False advertising Inspection of food and drug facilities.

Enforced by Division of Chemistry

1937 Elixir of Sulfanilamide

Liquid form of Sulfanilamide produced using diethylene glycol as solvent. Diethylene glycol = Antifreeze Administered to mostly children to treat streptococcal infections. Existing laws did not require any kind of pharmacological studies demonstrating that a drug is safe. 107 people died.

1938- Food, Drug and Cosmetic Act

Extended control to cosmetics and therapeutic devices. Required new drugs to be demonstrated as safe before marketing. Eliminated requirement to prove intent to defraud in drug misbranding cases (fraudulent claims). Provided standards and safe tolerances. Authorized factory inspections.

1961- Thalidomide Crisis

Hailed as a wonder drug for sleeplessness. Relieved many morning sickness symptoms in pregnant women. Unknown that Thalidomide crossed the placental wall. Catastrophic results:
Peripheral neuritis nerve disorder Birth defects deafness, blindness, disfigurement, cleft palette, internal defects, phocomelia

1962- Kefauver-Harris Amendments

Drug Manufacturers were required to prove drug effectiveness and safety to FDA before marketing. Advertisements must show complete info on benefits and risks. Adverse effects must be reported to the FDA. Since 1962, thousands of drugs have been removed from the market because of these amendments.

Overview of Development Process

Drug Discovery Screening Pre-Clinical Testing IND Application Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials New Drug Application (NDA) / Biologics License Application (BLA) Phase IV and Beyond

Therapeutic Drug Discoveries

(R & D Careers: Scientists, Management, Finance, Accounting, HR)

Determine target disease. Develop hypothesis for a mechanism of treatment. Use CAD and 3-D modeling software to begin evaluating hypothesis. Determine feasibility of producing and evaluating the selected compound.

Screening
(Careers: Scientists, Management, Finance, Accounting, HR, Quality Assurance/Control, Regulatory)

Combination Chemistry
Make many possible compounds at one time. Focus on quantity of possible compounds, not purity of each.

High Throughput Screening

Test hundreds at a time for activity.

Process requires serious technology. 1 in 10,000 makes it to the market.

Pre-Clinical Testing
(Careers: Scientists, Management, Finance, Accounting, HR, Quality Assurance/Control, Regulatory, Vet Med)

Evaluate acute and short term toxicity in animals (one rodent, one nonrodent).
Dose at increasingly high levels to induce toxicity. Determine lethal dose. Dose at normal levels for short and long term.

Assess how drug is absorbed, distributed, metabolized, and excreted in animals.

Investigational New Drug (IND) Application

(Careers: Quality Assurance/Control, Regulatory people who love to write and document in detail, Legal)

Request submitted to FDA to allow human exposure to the experimental drug. IND is an ongoing file at FDA containing data on drug as it passes through the development process. Inexperienced companies often hire consultants to help.

Clinical Trials
Preclinical Years
3.5-6.5 Laboratory Test and Animal Population Studies

Phase I
1-1.5 20-80 healthy volunteers

Phase II
2 100-300 patient volunteers

Phase III
3-3.5 1,000-3,000 patient volunteers

FDA
1.5-2.5 15 Total

Phase IV

File Assess safety IND Purpose and biological with activity FDA Success Rate
5,000 compounds evaluated

Determine safety and dosage

Confirm effectiveness, Evaluate monitor effectiveness, adverse look for side reactions for effects long term use 5 enter clinical trials

File NDA Review process / with approval FDA

1 approved

Additional postmarketing testing

Phase I Clinical Trials

(Careers: Scientists, Management, Finance, Accounting, HR, Quality Assurance/Control, Regulatory, Medical)

Begin 30 days after submission of IND providing FDA has not placed a clinical hold on development. 20-80 healthy subjects Duration: 1 year Cost: $100,000 - $1,000,000 Determine bioavailability. Determine side effects associated with increasing doses. Gain early evidence on effectiveness.

Phase II Clinical Trials

(Careers: Scientists, Management, Finance, Accounting, HR, Quality Assurance/Control, Regulatory, Medical)

Not necessary to consult with FDA to begin Phase II. Assess a drugs effectiveness in treating a particular disease or medical condition. Safety and side effects are monitored. 100-300 patient volunteers Duration: 2 years Cost: $10-100 million Less than 1/3 of INDs survive Phase II.

Phase III Clinical Trials

(Careers: Scientists, Management, Finance, Accounting, HR, Quality Assurance/Control, Regulatory, Medical)

Company must consult with the FDA before beginning Phase III. 1,000-3,000 patient volunteers Multiple testing sites Duration: 3-3.5 years Cost: $10-500 million Confirm effectiveness and safety of drug.

New Drug Application (NDA) / Biologics License Application (BLA)

(Careers: Quality Assurance/Control, Regulatory people who love to write and document in detail, Legal, Pharmacists, Statisticians)

Formal proposal for the FDA to approve a new drug for sale in the U.S. Must provide sufficient evidence for the FDA to decide:
Drug is safe and effective. Benefits outweigh the risks. Proposed labeling is appropriate. Manufacturing methods and controls maintain drug identity, strength, quality, and purity.

NDA / BLA Review Process

(Careers: Quality Assurance/Control, Regulatory people who love to write and document in detail, Legal, Pharmacists, Statisticians)

Biologics
Center for Biologics Evaluation and Research (CBER)

All other drugs

Center for Drug Evaluation and Research (CDER)

NDA Review Process

(Careers: Quality Assurance/Control, Regulatory people who love to write and document in detail, Legal, Pharmacists, Statisticians)

Medical - clinical protocols, safety Biopharmaceutical - absorption, distribution,

metabolism, and excretion

Pharmacology - toxicity, therapeutic value Chemistry - chemical properties Microbiology - anti-infective drugs Statistical - results must be significant

Registration and Market Launch

(Careers: Marketing and Sales)

NDA must be approved. Must prove to FDA that you can safely produce drug.
Pre-approval inspection 3 production batches Development group justifies development process

For More Information

www.fda.gov

BioPharm Guide to Biopharmaceutical Development