Drug Development

Liberation is a step the formulator _____; ADME is largely set by ______

controls; the molecule

Development runs ____ years; roughly ___ of drugs entering Phase I are ever approved.

10-15 years, 8%

Cost estimates range from about ____ (RAND median) to ____ (Deloitte per asset) — the method drives the number.

$708M
$2.23B

Retail prescriptions drugs are ___ of the $5.3 trillion US health bill, well behind hospital care at ____.

9%, hospital care at 31%.

1938 safety

1962 efficiacy

2007 Lifecycle

Patent and exclusivity is a response to a specific disaster; the ______ determines generic entry.

longer one

Pharmacognosy

Plant, marine and herbal sources

of drugs — the original

pharmacopoeia, and still a live

source of new scaffolds.

Pharmacology

Mechanism of action. What the

drug does to the body at

receptor and system level.

Medicinal Chemistry

Applying organic and inorganic

chemistry to design, optimise

and stabilise drug molecules.

Pharmaceutics

Turning a molecule into a

medicine a patient can actually

take — and getting it where it

needs to go
- the bridge discipline — it is where a chemical becomes a product

Clinical Pharmacy

Patient care, drug therapy

management, and the judgement

calls at the bedside

Pharmacy Administration

Business, policy and law as applied to pharmacy practice and

the medication supply chain.

What Pharmaceutics Actually Covers

1. Dosage Forms

2. Calculations

3. Industrial Pharmacy

4. Pharmacokinetics

5. Compounding & Dispensing

6. Physical Pharmacy

7. Biopharmaceutics

8. Pharmacodynamics

Solid orals must survive the GI tract and…

first-pass metabolism

Changing the dosage form changes the drug product and

requires its own approval

ADME

Disintegration: tablet breaks apart in the mouth

Dissolution: Drug particles dissolve in gastrointestinal fluids

Absorption: in the bloodstream

Distribution

Metabolism: in the liver

Excretion: by the kidneys

LADME

Liberation: Drug is released from its dosage form

Absorption: Drug crosses membranes into systemic circulation

Distribution: Drug partitions into tissues and fluids

Metabolism: Drug is chemically transformed, mostly hepatically

Excretion: Drug and Metabolites leave the body

What step can the formulator control in LADME?

Liberation

What are the two questions that matter clinically in absorption of the drug?

1. How much gets in (extent — bioavailability, F)

2. How fast (rate) , Bioequivalence testing

ADME is largely set by the

molecule

A drug helps in five ways

Diagnosis

Mitigation

Treatment

Cure

Prevention

How many years does it take to develop a drug?

10 - 15 years

What is the average cost to develop a drug?

$2.2 Billion dollars

__ of drugs entering Phase 1 are eventually approved

7.9%

Why does the cost per approved drug is so much larger than the cost per drug studied?

roughly 10,000 compounds screened yields about 250 worth preclinical testing, about 5 that enter human trials, and 1 that reaches patients

$467 Billion spent on retail prescription drugs in 2024.

9% of health spending

Who approves of the drugs and what is their mission? What is the balancing act?

FDA

Mission: To protect public health

Balancing Act: Make beneficial drugs available quickly

1848 Adulterated Drugs in the Mexican War

Crisis: Quinine used to treat yellow fever but was actually not a first line drug and was imported into the US

Response: required for all imported medications to be inspected for quality and purity

Formally recognized the USP

What was the first federal drug law?

1848 adulterated drugs in the mexican war

1901 Children Die from Contaminated Biologics

Biologics were regulated before small molecules were.

Crisis: Diphtheria antitoxin contaminated with tetanus killed 13 children in St. Louis.

The response: required government premarket approval — first such requirement US law

1906 The Pure Food and Drugs Act

Before 1906:

• no requirement to list ingredients on a label

After the act:

• prohibited misbranded or adulterated foods, drinks, and drugs

• CRITICALLY it did NOT require any proof of safety or effectiveness before marketing.

1937 The Elixir Sulfanilamide Disaster

Crisis: Antifreeze in a children’s medicine.

Response: Federal Food, Drug, and Cosmetic Act of 1938

• required sponsors to demonstrate SAFETY before marketing — the first premarket safety requirement for drugs

• Created the New Drug Application

1962 Thalidomide and the Efficacy Requirement

The crisis: thalidomide was marketed for morning sickness, but caused thousands of severe birth defects

Response: required government premarket EFFICIACY and Investigational New Drug (IND) application before human testing.

Orphan Drug Act of 1983

Problem: rare disease defined of affecting fewer than 200,000 people in the US. Rational companies did not develop these drugs.

Implemented Incentives:

1. Seven years of market exclusivity for the orphan indication, independent of patent status

2. Tax credits against qualified clinical trail expenses

3. Waiver of the PDUFA application fee — currently worth over $4.6 million

4. Grant funding and FDA assistance with protocol design

5. Administered by the Office of Orphan Products Developments; covers drugs, biologicals, devices and medical foods

Patent

Granted by the US Patent and Trademark Office, not the FDA

Runs roughly 20 years from the filing date of the application

The clock starts at invention — long before approval, so it includes development time eats into it.

Can cover the compound, the formulation, a method of use, or the manufacturing process

Exclusivity

Granted by the FDA on approval; entirely separate from patent law

New chemical entity: 5 years

New clinical investigation: 3 years

Orphan 7 years, Pediatric study adds 6 months, Biologicals 12 years

Runs from approval, so it never suffers the development-time erosion a patent does.

Whichever protection runs longer is the one that

actually controls when a generic can enter.
If a product reaches market early in its patent life, the remaining patent term will almost always outlast any exclusivity and exclusivity becomes irrelevant.

PDUFA, 1992

Solved: slow review and unpredictable, no management on timelines

Bargain:

• sponsors pay a fee, must be reauthorized by Congress every five year — currently PDUFA VII

What are the faster routes to Market?

1. Fast Track (1997)

2. Accelerated Approval (1992): most sought after

3. Requires preliminary clinical evidence of substantial improvement on a clinically significant endpoint. Adds intensive FDA guidance from Phase I onward.

4. Priority Review (1992): Shortens the review clock itself from 10 months to 6. Concerns the speed of FDA’s assessment not the evidence standard applied

What brought premarket safety?

Sulfanilamide event of 1938 at the cost of 107 lives

What brought efficiacy?

Thalidomide bought the efficacy requirement and the US was spared largely by Dr. Frances Oldham kelsey.

• created the Kefauver-Harris Amendments of 1962.

Kefauver-Harris Amendments of 1962

Required demonstration of EFFICACY in

addition to safety, via adequate and well-

controlled studies.

• Formalised the Investigational New Drug

(IND) application before human testing.

• Required informed consent from research

subjects.

• Required that labelling be truthful, not

misleading, and carry adequate directions

for use.

• Transferred prescription drug advertising

oversight from the FTC to the FDA.

What brought post-market authority?

GAO 2006, Grassley-Dodd, FDAAA 2007

• documented disputes between FDA’s Office of Drug Safety and Office of New Drugs that slowed evaluation.

• The Grassley-Dodd bull proposed mandatory post-market studies and an independent Drug Safety Oversight Board.

• mandate labelling changes, impose REMS.

What caused The Post Market Monitoring by GAO, FDAAA, and Grassley-Dodd

• Rezulin (troglitazone) causes life-threatening liver faliure

• Vioxx (rofecoxib) arthritis drug was linked to MI and stroke, withdrawn in 2004 after ten millions of prescriptions

What did the Inflation Reduction Act 2022 do?

Small molecules become eligible 7 years post-approval, biologics 11

What makes a drug “new”?

shape, form, route, excipient, process, manufacturer or molecule can trigger a new application.

Scientific Sense:

• pharmacologincally active ingredient not previously marketed

Regulatory Sense:

• 21 CFR 314.108 new chemical entity by its active moiety

505(b)(1) full NDA

A stand-alone application with full reports of safety and efficacy investigations conducted by or for the applicant.

The route for a genuinely new molecule. Everything in this lecture describes what it takes to fill one.

• safe & effective

• all brand name drugs

505(b)(2) - hybrid NDA

An NDA in which at least some information needed for approval comes from studies not conducted by or for the applicant — published literature or FDA’s findings of safety and efficacy for an approved drug.

• new dosage form, route, strength or combination of new drug

505 (j) — ANDA

abbreviated form for a duplicate of an already-approved drug: same active ingredient, dosage form, strength, route and labeling

bioequivalence, generics

351 (a) - BLA

biologics license application under the Public Health Service Act for products made in living systems

• licenses manufacturing process as well as the product

• abbreviated form: 351(k). biosimilar

1984 Hatch-Waxman Amendments created which applications?

505(b)(2) - hybrid and 505 j ANDA

patent term restoration and 30-month stay on one side, the ANDA pathway and 180-day exclusivity

New Chemical Entity/ New Molecular Entity / New Active Moiety are often used similarly, but the FDA focuses on what part of the drug?

active moiety

NCE

a drug molecule not previously marketed in the US

What does not count as an NCE?

a new salt or ester of an existing drug

CDER

Center for drug evaluation and research

FDA center that reviews and regulates most drugs for safety and effectiveness

What was the significance of Phenacetin vs. Tylenol

a single substituent separate a drug that was withdrawn for kidney damage and cancer

small molecules are

900 Da

cheap

oral

can cetner cell

Monoclonal antibodies (mAb)

highly specific antibodies that target proteins outside or on the surface of cells; usually given by injection and are expensive

Antibody-drug conjugates (ADCs)

antibody carries a toxic drug directly to cancer cells, help kill then while limiting damage to healthy cells

What is the importance of knowing the disease biology importance?

If the target is wrong, the drug can fail later even if the drug itself looks good

How to choose a lead in drug discovery based on the disease biology?

Select target (12-24 months) → understand normal before abnormal

• Understand normal → identify what changes in disease → choose the target

• Target validation: mkaing sure a target is actually worth developing a drug against

• A target isn’t truly proven until it works in patients

LEAD OPTIMIZATION: potency, selectivity, absorption, metabolic stability, safety margins, developability

What are the 3 questions behind every preclinical decision?

Will it be safe in humans?

Will it reach the target?

Will it be efficacious?

FDAMA act 2.0

no longer require animal testing before human trials (can use cell-based test) → due to 90% of drugs that clear in animal studies still FAIL in human trials

A drug with excellent potency can still show ____.

35% bioavailability

because you lose some during absorption and degradation

Toxicology studies

test whether a drug is safe and what harmful effects it may cause
ex: organ toxicity, DNA damage, reproductive effects, cancer risk before or during human trials

Acute (single dose) toxicity

testing the effects of high dose of a drug to see if it causes harmful or toxic effects

NOAEL

no observed adverse effect level

At what dose do we start with humans? Where do we get that dose?

1/10 of the NOEL
From the highest dose that caused no effects in animals

ex: NOEL 100 mg → human starting dose = 10 mg

Therapeutic index

the window between minimum effective dose and toxic dose

IND

Investigational New Drug application that allows a drug to be tested in humans

• nonclinical safety data, chemistry, manufacturing, controls

FDA can stop a trial before it starts or at any point later

What is the primary objective for Phase 1?

Safety and tolerability