Drug Development Process

Exam 1

What is a drug?

a chemical substance that interacts with a part of the body and alters existing physiological processes.

What does API stand for? What is an excipient?

active pharmaceutical ingredient

• Drug product includes API and excipients

Excipient

• include anti-adherents, binders, lubricants, sweeteners, vehicles, etc.

What is pharmacodynamics and pharmacokinetics?

• Pharmacodynamics: what the drug does to the body

• Pharmacokinetics: what the body does to the drug

How long does drug development take?

10-20 years

For every 10,000-15,000 new compounds screened, how many get approved?

Only 1 approved as market drug, 5 considered safe for testingafter extensive clinical trials.

What is an IND?

investigational new drug

• submitted to FDA before clinical trials begin, a request to test a new pharmaceutical in humans

What does NDA stand for?

New Drug Application

• vehicle through which drug sponsors formally propose that the FDA approves a new pharmaceutical for sale and marketing in the U.S. Data gathered during animal studies and human clinical trials of an Investigational New Drug become part of the NDA

What does ANDA stand for?

Abbreviated New Drug Application

• contains data which is submitted to FDA for review and potential approval of a generic drug product

What does BLA stand for?

Biologics License Application

• a request for permission to introduce, or deliver for introduction, a. biologic or a biosimilar product into interstate commerce.

Who was Martin Shkreli?

• Founded Turing pharmaceuticals in Feb 2015

• Launched Turing with one drug in development and two already approved (intranasal version of ketamine for depression, intranasal version of oxytocin, Vecamyl for hypertension)

• Acquired Daraprim (pyrimethamine approved in 1953), on Aug 10, 2015. Used for anti-malarial/antiparasitic, in conjunction with leucovorin and sulfadiazine to treat patients with AIDS related and AIDS unrelated toxoplasmosis

Drastically raising the price of the life-saving drug Daraprim by over 5000%. His actions led to widespread public outrage and scrutiny regarding drug pricing in the pharmaceutical industry.

ANDA approval barriers

• Scientific/Bioequivalence challenges: complex formulations or sameness issues

• Legal/Market: patents and exclusivity, user free compliance

• Regulatory/Filing Hurdles: refuse to receive, chemistry/manufacturing/controls, drug master file errors

Solutions for off-patent single-source monopolies

• Creates act of 2019: authorizes generic developers to sue brand companies that refuse to self samples of RLDs at fair market value

• FDA Hatch-Waxman Guidance on Citizen Petitions: allows FDA to summarily deny petitions filed primarily to delay ANDA approvals

Solutions for Drug Pricing

• Inflation Reduction Act of 2022: imposes financial penalties on drug manufacturers, that increase drug prices above the rate of inflation for Medicare beneficiaries

What is included in drug discovery?

• Target identification and validation: predicted molecular target of a small molecule is identified and verified

• Lead generation: hits from a high throughput screen are evaluated and undergo limited optimization to identify promising lead compounds

• Lead Optimization: determine structure activity-relationship of analogs, optimization of properties (solubility, lipophilicity, permeability), Tox/ADME screens

What is included in in vitro assays?

• Primary: does drug interact with target (enzyme, receptor, etc.)

• Secondary: does drug active/inhibit target

• Aqueous solubility

• LogD (lipophilicity)

• Permeability: predicts intestinal absorption

• Microsomal stability

• CYP P450 inhibition/induction

• Hep G2 hepatotoxicity

• Cytotoxicity in suitable cell line

• hERG: human ether-a-go-go-gene

What are ex vivo assays?

study performed on tissue, cells, or organs extracted from living organism and studied under controlled conditions outside body, typically maintaining natural structural organization

What are examples of in vivo assays?

• Disease efficacy models

• Oral pharmacokinetics

• PK/PD correlations

• early safety and toxicity studies

• Pre-clinical safety and toxicity studies

What are species used to determine toxicology?

• rodents: rat, mouse, rabbit, guinea pig, hamster

• Dogs

• Non-rodent mammal

• non-human primate: marmosets, rhesus, monkeys)

Routes of administration for toxicology?

• oral

• Subcutaneous

• Intravenous

• Intramuscular

• Intraperitoneal

• Topical (pigs used for this route)

What is included in clinical trials and its phases?

Phase 1: 20-100 healthy volunteers

• Safety most important

Phase 2: 100-500 volunteers with condition

• Safety and efficacy

Phase 3: 1000-5000

• Confirm overall benefit and safety

Phase 4: post-marketing studies

• Monitor long-term safety in real-world use

What is cGMP and some principles of it?

Current Good Manufacturing Practices

• regulations enforced by FDA as legal requirements for the manufacturing of drug products and the IND submissions

• Found in Title 21 of Code of Federal Regulations

• cGMP includes materials, buildings, equipment, records, procedures, and people