Exam 1

Why are most clinical trials in the US?

Because it is cheaper in the US and because the trials will be too difficult to observe in other countries

Why was thalidomide not approved in US?

Because of 1938 Drug act, the drug had to go through the FDA's approval and Dr. Kelsey would not let it in the country

Explain when bone resorption occurs in the bone remodeling cycle

Begins when osteoclasts remove a portion of the bone to be replaced later by the action of osteoblasts - vital step for signaling bone formaiton

A generic drug must be _________ to the patented drug

Bio-equivalent - generic drugs are the same chemically as their innovator counterparts and that they act the same way in the body

1902 = ________

Biological therapeutics

Mid risk, mid reward, mid cost

Biosimilars, drug repositioning, orphan drugs, drugs for rare, neglected Ind, life extnsion - indications

What can immune-mediated inflammation affect?

Bone density, induce synovial cell, proliferation, etc.

Phase II and phase III are usually __________ studies

Double blind studies

A finished dosage form that contains an active ingredient, usually classified as a drug substance or biologic

Drug Product

2. Novelty

Invention must be new. It must not have been previously known - new - not previously disclosed - no prior art

1. Utility

Invention must have at least one use - has some useful purpose

IND

Investigational New Drug

What did MRCK say about the hypothesis that naproxen protected the heart?

"It is scientificallt valid to make conclusions about one drug based on the results of another"

Pulmonary delivery

(aerosols, dry powder) - insulin - Dornase alfa (local) - Insulin

Drug life optimization: The three life periods

(discovery) Early: Pre clinical/ phase I, phase II, phase III (launch) (launch) Middle : Intro, growth, maturity, decline (loss of market exclusivity) Late: Generic competition

Occular delivery

(eye drops, injections) - VEGD- targeted fab and IgG1 mAb (injection) - VEGFR1-Fc-VEGFR2 fusion (injection)

Buccal delivery

(films,spray) - insulin - interferon

Vaginal delivery

(gels) - LHRH analogue

Transdermal delivery

(patches, creams, sprays) - PTH - insulin

Oral delivery

(pills, capsules_ - Calcitonin - insulin - exenatide - ocreotide

What is pannus

(spongy feeling) excessive growth of synoviocytes in RA

High risk, high reward, high cost

*Primary Care* - Novel NME's (new molecular entity) -NBE - follow on (duplicate action of existing drugs) NMEs

Explain how doctors used diphtheria anititoxin to treat diphtheria?

*Scientists learned to harness immune systems of some animals to produce antitoxin serums to use as medicines * 1. Scientists grow diptheria causing bacteria in the lab and harvest its toxin 2. Researchers then inject horses with the diphtheria toxin. As an immune response, the animals blood produces diphtheria's antitoxin 3. Scientists collect blood from horses and separate out of the antitoxin rich serum 4. Then, researchers purify the antitoxin serum for use as a medicine for people

Why didnt Rochester have a patent claim?

*They thought they did have a patent claim!* - after an 8 year review US patent and trademark office (PTO) gave university of rochester a sweeping patent for COX-2 inhibitors in 2000

VIOXX Gastrointestinal outcomes research study (VIGOR)

- total of 8076 patients were randomized to either rofecoxib 50mg daily or naproxen 1000 mg daily - median follow up time for trial was 9months( max = 13) - Patients visits were 6 weeks, 4months, and every 4 months until study termination - last patient exited trial in early 2000 and data was unblinded shortly after

What does the data collected in preclinical testing include?

- toxic and pharmacological effects - genetic toxicity - absorption, metabolism and excretion - identify metabolites and their potential toxicities

What are the two sources of origin of the pharmaceutical industry?

1. Apothecaries: moved into wholesale production of drugs like morphine, quinine and strychinine. 2. Dye and chemical companies: established research labs and discovered medical applicants for their products

NSAIDS that.. 1. Inhibit COX2 with 5-50 fold selectivity 2. Inhibit COX2 with a >50 fold selctivity 3. weak inhibitors of both isoforms

1. Celecoxib, etodolac, meloxican 2. Rofecoxib 3. 5-amino salicyclic acid, difunisal, sodium sallcytate, nabumetone, sulphasalazine

Describe the 4 steps that occur in bone remodeling

1. Damaged bone. Osteoclast move in to clear our space 2. Damaged bone is reabsorbed by active osteoclast (eat bone) 3. Osteoblasts move in to synthesize new bone (lay down bone) 4. Mineralization (calcification) of the new bone occurs

Describe the pathogenesis of diphtheria

1. Diphtheria toxin's receptor binding domain (B) binds host membrane 2. Membrane bound toxin (A +B) enters by endocytosis 3. Catalytic subunit A is cleaved but held to the B subunit by disulfide bonds. Endosome besicle acidifies; the disulfide bonds are then reduced 4. Transmembrane domain facilitates passage of the catalytic. A peptide through the vesicle membrane 5. The catalytic A domain ADP - ribosylates elongation factor 2 (EF2). This halts protein and kills the cell

What is the FDA's mission of history of drug regulation?

1. Ensure the safety and effectiveness of medicines 2. respond to public health disasters

What are the three requirements for obraining a parent

1. Utility 2. Novelty 3. Nonobvious

Describe pathway of drug development process

1.) Pre clinical research - synthesis and purification - Animal studies *IND submitted* 2.) Clinical testing - Phase I, Phase II, Phase III *NDA Review* *Post Market surveillance*

How did the Merck timeline begin?

1668, Merck acquires Angel pharmacy.... then went from a pharmacy trade to a research based industrial company... comparitive chemical analysis with guaranteed pure reagents in 1888, by 1900 company represente all continents. ...1920 first time non family joined executive management...2010 millipore acquisition * offset of a dye company * a lot of growth in end of 1800s and early 1900s*

What were some examples of early synthetic drugs?

1830s: justus von Liebig synthesized chloroform and chloral hydrate 1880's: Distillates of coal tar resulted in discovery of acetanilide as a fever reducing drug 1864: Barbituric acid was synthesized by Aldof von Baeyer 1890s: acetylsalicylic acid (aspirin) was synthesized in large quantities

When was the golden era of FIPCO?

1900s

What established minimum current good manufacturing practices for manufacturing, processing, packing, or holding drug products and medical devices ?

1978 GMPs final rules for drugs and devices

What was established after the tragedy of acetaminophen capsule poisoning by cyanide causing seven deaths and what was the result?

1982 Tamper- resistant packaging regulations issued for OTC products

What act was precipitated by illegal acts involving abbreviated new drug applications and what was the result?

1992 Generic Drug Enforcement Act Result: Creates debarment penalty

What year was searle/pfizers patent for celebrex?

1995

In _______ vioxx was the drug with the largest direct to consumer advertising campaign in U.S at 160 million

2000 - more than budweiser (146 million, and pepsi 125 million) - MERCK recorded more than 11 billion in vioxx sales during drugs year on market (only on market for 5 years)

The cost of drug development in early 2000s, late 1990s and 1980s

2000s: 1.2 billion 1990s: 800 million mid 1980s: 320 million

A drug must be manufactured at ____ separate places that are geographically distinct

3 different places and 3 different sites

What happened to patients who were taking vioxx?

30,000 to 60,000 patients taking vioxx died from 1999 to 2004 - about 160, 000 patients were injured

NSAIDS that inhibit COX2 sigh a 5-50 fold selectivity vs >50 fold

5-50 selectivity: Celecoxib, etodalac, meloxican >50 fold: Rofecoxib *selective*

How is a drug administered?

A drug can be used in many different ways -inhalation: breathed into lungs - Nasal: Sprayed and absorbed through nasal membranes - Subcutaneous: Injection beneath skin - Intravenous: Injection into a vein - Intramuscular: /injection into a muscle

What happens to drug if not found to be manufactured according to cGMPS?

A drug is adulterated - A drug can meet its specifications, contain no detectible impurities, be both safe and effective and still be considered aldulterated if manufacturing was not in compliance with cGMP's *A company must establish procedures which assure drug is manufactured in a way to consistently meet specifications -FDA then approves procedures

ANDA

Abbreviated New Drug Application (generics)

Describe the host antibody response against diphtheria toxin

Antibody blocks toxin from binding to cell

Phase II clinical trials objective

Antitumor activity against specific tumor type (tumor response rate) - Short term side effects and risks Does not measure patient benefit(survival) - Tumor response is not direct measur of patient benefit - No internal control and small number of patients

The ______ name is developed by the company requesting approval for the drug and identifies it as exclusive property of that company

Brand name

Explain osteoimmunology: bone- immune interactions

Cells in the bone marrow are controlled by the immune systems in concert with other regulatory systems, such as endocrine and neural systems. - Bone system and immune system in bone-marrow microenvironment are regulated as if they were integrated in context of osteoimmune system.

Drug R&D

Certain small business (angel) high net worth individuals and have money to validate pre clinical trial

The _____ name is based on the molecular structure of the drug

Chemical name

Chondrocyte mediated - cartliage formation

Chondrocytes produce and maintain cartilage matrix, which consists mainly of collagen and proteoglycans - chondrocytes will be affected as well in RA because those cells respond to mediators in inflammed joints

______________ diphtheria infects and secretes toxin

Corynebacterium

Drug discovery phase last _____years Clinical trials last _____ years and FDA review last _____years

Drug discovery = 3-6 years Clinical trials = 6-7 years FDA review = 0.5 - 2 years

Compounds success rates by stage

Drug discovery: 5000 - 10000 screened Pre clinical: 250 compounds Clinical trials: 5 compounds FDA review: 1 compound

1962 = _________

Drug efficacy

1938 = ________

Drug safety

Patents

FDA grants each new drug a period of exclusivity - Patent protection lasts for 20 years - holder of new application receives limited protection from new competition in market place for innovation represented by approved drug product.

Describe the expansion of the FDA budget from 1930 - 2009

FDA needed to expand because it was not big enough. 1938: Complete revision of 1906 Food and Drugs Act 1949: FDA publishes first industry guide "Black Book" 1966: Fair packaging and labeling act 1970: EPA established, takes over pesticide programs 1973: Consumer product safety commission created by congress 1990: Nutrition labeling and education act 1995: FDA declares cigarettes to be "drug delivery devices 2000: Data quality act 2002: public health security 2003: FDA requires trans fat declaration on foods 2004: Food allergy labeling and consumer protection act 2009: FDA center for tobacco products established

In patients with RA treatment with refecoxib, a selective inhibitor of COX2, is associated with significantly ________ clinically important upper GI events than treatment with naprocen, nonselective inhibitor

FEWER

Which companies fit in with lead optimization and technologies, follow on drugs, clinical development, manufacturing, capital and resources, sales and marketing?

FIPCO and FIDDO = fits in both discovery and development categories *Large pharma*

Which companies fit in with preclinical studies, new technologies and clinical studies?

FIPN, NRDO *CRO's* (Contract research organizations)

How can solubility and permeability be addressed?

Formulation methods, BCS (Biopharmaceutics Classification system from FDA Pre formulation = Active pharmaceutical ingredient molecule, Excipient matrix constituting a formulation ---> Excipients and process,Prototype formulation = Proof of concept, exposure, toxicology qualifications, development decisions ---> Final market dosage form= Bio performance, long term shelf stability, Robust process, Regulatory approval, user/market acceptance

How did most of todays major pharmaceutical companies evolved?

From need to expand apothecaries to a scale of the 1800's dye and chemical industry

FIDDO

Fully integrated Drug Discovery and development - fits in all discovery and development

FIPCO

Fully integrated pharmaceutical company - fits in discovery, development, clinical phase

Patents are issued by ___________

Government, US patent and trademark office - to have a world wide patent you would have to go through every country in the world and go to the patent office - some countries make more sense to patent invention in and others *patent rights are limited by time and geography*

Before you submit an ________ all manufacturing must be done in preclinical research so you can get small number of products to begin clinical testing

IND

Phase II Clinical trials for oncology

Ideally conducted in patients with maximum performance status and min amount of prior chemotherapy - Larger sample size but sill less that 100 - Performed on specific tumor types in patients for which standard care has been ineffective - usually all patients receive same dose or regimen - sometimes compares diff schedules of administering same drug

Describe the history of thalidomide

In germany there was no prescription needed or regulations - no matter the dose the drug would not kill rats - used for morning sickness, sleep sedation,etc.

How were such results of cardiovascular damage "missed" by MERCK and FDA?

In their NDA, MERCk had manipulated some of their statistical analyses

What is rheumatoid arthritis?

Inflammatory condition, autoimmune disease, bodys immune system attacks tissue lining joints, no known cure

LCM

Life cycle mangement

Where can the first synthetic drugs and entire pharmaceutical industry be traced to?

Manufacture of textiles and synthetic dyes. - Dye industry became forefront - forerunner of modern pharmaceutical industry - molecules for dyes allowed some drugs to be developed and began to discover that some of those chemicals had physiological effects

Labeling drugs 1906

Manufacturers continue to sell unsafe food and drugs - industry quite corrupt at this time - Drug advertising had no standards

What does it mean in biologics. "The product is the process."?

Manufacturers that the manufacturing process remains substantially the same over time - Process is the end product! - cannot use mass spec to determine structure

What was the problem with vioxx?

March 30, 2000: Prelimanary info regarding an imbalance of serious cardiovascular thrombotic events was submitted by MERCK with original IND 46,894 submitted in 94. - MERCK suggested that there might be a small risk of cardiovascular effects, which were not previously reported in original application

When did the FDA approve VIOXX

May 20, 1999 approved for acute pain, dysemenorrhea and arthritis by the FDA

What were the financial consequences of taking VIOXX of the market?

Merck investors were not happy, their share price dropped when vioxx was withdrawn from market

What did retirement from MERCK include?

Monetary parachute

What did "Drug-lag" accomplish?

Motivated US based firms to diversify into fragrances, cosmetics, and other consumer products.

What was reported in NEJM vs. the truth regarding myocardial infractions

NEJM: Myocardial infractions were less common in naproxen group than in rofecoxib group (.1% vs .4%) Truth: There were 20 MIs (.494%) in the rofecoxib group and only 4 (.099%) in naproxen group **Data in NEJM excluded 3 MIs in rofecoxib group that several of Mercks authors were aware of prior to final revision of paper but chose not to include in paper.

What was MERCKS explanation for having a small risk of cardiovascular effects in vioxx

Naproxen (control group) had positive effects - All protocols were amended to allow use of low dose aspirin for patients who may be at risk for cardiovasuclar damage

Nasal delivery and sublingual delivery

Nasal: (sprays) - salmon calcitonin Sublingual: (Tablets) - Desmopressin

Legal drug or medicine

Natural or synthetic substance that when taken into a living body affects its functioning or structure and is used in diagnosis, mitigation, treatment or prevention of a disease or relief of discomfort

What needs to be done to make a biogeneric drug?

Need to prove the entire process is equivalent (bio similar)

NDA

New Drug Application (drugs)

Did MERCKs clinical data analysis showed any significant cardiovascular problems?

No

NRDO

No research development only - fits only in development phase of (Pre clinical, Phase 1, phase II, and phase III

What was the clinical data presented for NDA regarding vioxx

November 1998: Merck asks FDA approval for vioxx having tested the trug on 5400 subjects in eight studies - NDA included 5000 subjects exposed to rofecoxib from one dat to 8 weeks of whom 371 and 381 patients recieved 12.5 and 25 mg daily for one year or longer (daily dose for chronic pain), 272 patients recieved > 50 mg daily of more than 6 mnths (daily dose for acute pain) - NDA included two six week placebo and ibuprofen controlled studies. some patients participating in studies were involved in extension studies up to 86 weeks.

Who were the first ones to isolate clone and sequence COX 2 enzyme?

O'Banion, Winn, and Young in 1992

Phase I clinical trials

Objective is to determine a dose that is appropriate for use in phase II studies - Starts at does of 1/10 the median lethal dose, and gradually increased if no dose limiting toxic effects are observed. - Usually small sample size (15 to 30) - Metabolic and pharmacologic actions of drug - Side effects - Early evidence on effectiveness - Conclude is it safe? - Cardiovascular effects, neurological effects, things that alter fluid, respiratory problems, etc.

If patents give exclusive rights, than how can some drug manufacture generic versions of some drug?

Once the patent expires, manufacturers can apply to the FDA and submit an ANDA to sell generic versions

What was an example of ancient pharmacology?

Opium poppy plant dating from 3000 BC that contained the painkiller, morphine - Colchicine from autumn crocus - Quinine from cinchona tree - Digitalis from foxglove - Atropine from belladonna plant

What cells start laying down the bone?

Ostebolasts

Osteoarthritis vs RA

Osteo: Bone ends rub together, thinned cartilage RA: Bone erosion, swollen inflamed, synovial membrane

Explain what occurs during bone formation in the bone remodeling cycle?

Osteoblasts lay down collagen and mineral deposits over area previously remodeled by osteoclasts. Osteoblast activity is vital for maintaining bone mineral density and bone strength

placebo effect vs nocebo effect

Placebo effect = stems from a patients expectation or belief that the drug will do them good Nocebo effect = reverse of placebo effect, - patients have an expectation that a drug will not help them

Phase IV

Post marketing and safety monitoring continues after drug is approved - purpose is to catch any unexpected adverse rxn of approved drug

What is considered to be the last phase of drug discovery?

Preclinical development safety testing in animals - companies required to dest a drug candidate on at least 2 different animal species - governed by FDA good lab practices (GLP)

Develop adequate data to support a decision by the FDA that is reasonably safe to proceed with human trials of drug

Preclinical testing

1983 = _________

Rare diseases

Lymphocytes have _____ for antigens

Receptors

Formulation

Refers to different chemical substances including active drug, that are combined to product a final medicinal product - substances added may include stabilizing agents, bulking agents and solubilizing agents

Which companies fit in with novel targets, innovation, speciality products and technologies, hit and lead generation?

Research intensive FIDDO, FIPCO, RIPCO *Biotech*

RIPCO

Research intensive pharmaceutical company - only fits in discovery phase (target discovery, lead discovery, lead optimization)

What was the COX2 inhibitor used for vioxx?

Rofecoxib - no effect at doses for detection of GI in vivo of rat testing

Pharmacovigilance

Science and activities relating to detection, assessment and understanding and prevention adverse effects or any other drug related problem

The disovery of celebrex was done by _________

Searle research and development in 1997

When did MERCK get pulled by VIOXX?

September 30th, 2004

Single blind trial vs double blind vs triple blind trial

Single blind trial: The investigator is kept blind to the subjects assigned group Double blind trial: investigator and subject are kept blind to the subjects assigned group Triple blind trial: Investigator, subject and assigners are kept blind to the subjects assigned group *experimentation is based almost always in a double blind trial

Cytokines

Small proteins which are secreted by immune cells, especially T helper lymphocytes, macrophages, and dendritic cells - used by cells to "talk" with neighboring cells during an immune respone (letters of alphabet for immune cells) *interleikins, interferons, chemokines, tumor, necrosis factors, colony stimulating factors*

What produces synovial fluid and explain what it does?

Synoviocytes (pannus: excessive growth of synoviocytes in RA) - Type A synoviocyte (macrophage) - Type B ( fibroblastic) *Synovial fluid* 1.) Stop functioning to produce right kind of synovial fluid 2.) Inflammatory mediators start to make them proliferate and build up mostly type B

T lymphocyte receptor for antigen

T cell receptor (TCR) Th = T helper lymphocyte Tc = Cytotoxic T lymphocyte

T helper vs. T cytotoxic lymphocytes

T helper: express molecules which "help" other cells of immune system do their job. ex.) T helper lymphocytes can stimulate B lymphocytes to make more antibodie T cytotoxic: (killer cells) bind directly to other cells which are expressing foreign antigens and kill them

Meta analysis

Taking data from several clinical trials for same drug

What law was passed that gave authority to the FDA to oversee the safety of food, drugs and cosmetics?

The United States federal Food, Drug, and Cosmetic Act passed by congress in 1938

What is the only way to establish whether there are differences in a biogeneric drug?

To conduct clinical trials - FDA has stated that it has not determined how interchangeability can be established for complex proteins

What is happening if you are getting bone erosion?

There is too much osteoclasts but not enough osteoblasts

Why didnt FDA catch the problems in vioxx NDA?

There were 278 volumes, and they hid it where FDA did not catch it.

How do some NSAIDS work?

They bind to and inhibit cyclooxygenases

How is a drug typically manufactured?

Through chemical synthesis, means that it is made by combining specific chemical ingredients in an ordered process.

______ started prohibiting importation

USDA - Bayer was one of the first drugs that was blocked (heroine and aspirin) stoppped letting heroin in the country

What does inhibition of COX2 do?

limit osteoclast activity and may limit bone resorption in patients with RA

From what were the first pharmaceuticals obtained from?

Vegetable kingdom as the dried plants of herbs, and shrubs. Most cultures had some form of pharmacology, herbal therapies, et.

How does COX-2 inhibitors lead to heart attacks and strokes?

When COX-2 is blocked, prostacyclin may also be suppressed allowing platelets to stick together and blood vessels to constrict which can lead to heart attacks and strokes

Haematopoietic cells

White and red blood precursors

By who was the dye mauveine discovered by?

William Perkin in the 1850's

Who still distributed thalidomide in US as "investigational"?

William S. Merrell Co. 17 infants affected in USA

Can a drug manufacturer change the manufacturing process after a drug is made?

Yes, they analyze the finished product to establish that it is the same as before the manufacturing change

B lymphocte receptor for antigen

antibody or immunoglobulin

COX-2 inhibitors are drugs designed to ________ activity of COX-2 enzyme and _________ pain.

block, relieve

What was the primary endpoint regarding VIGOR study

confirmed upper gastrointestinal events adjudicated by blinded panel.

Irreversible non selective NSAID

ex.) Aspirin - cardioprotective at low doses - increased risk for GI side effects

Semi selective NSAIDS

ex.) Meloxican, dicofenac, etodolac, indomethacin, piroxican, nabumetone, sulinadac - Increased affinity for COX-2 but still retain activity for COX-1 - use with caution in patients at increased CV risk

COX-2 selective

ex.) Rofecoxib, celecoxib - increased risk for CV events - decreased risk for GI side effects

Non selective NSAIDs

ex.) ibuprofen, naproxed - decreased risk for CV events - increased risk for GI side effects

How did the structure activity theory emerged?

from interplay of experimental results from animal and human tests using vaccines, antitoxins and antibodies with chemical knowledge about dyes and their molecular structures. - resulted in ehlinch developing 1st systematically invented theory

The _____ name is assigned, in the US by an official body... the USAN council

generic

1848 = ________

imported drugs

How is a drug labelled?

info on external label of a drug vial is regulated by the FDA and is legally binding as well as the more extensive info in the package insert - legal contract between drug company and FDA

Where is a biologic manufactured?

inside a living system such as a microorganism or plant or animal cells - most are large and complex molecules or they are mixtures of molecules

What is the FDA's assessment on validity/reliability of data based on?

inspections at the time of marketing application submission - clinical investigators - sponsors - Contract Research Organizations (CROs)

Enablement

some proof that it works

Discovery of VIOXX

the development of COX 2 inhitor rofecoxib is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effects due to CXO1 inhibition

What were symptoms of the serum sickness?

*A systemic immune response against injected horse antibodies* - Vasculitis - Rash - Neuropathy - Acute renal failure - Glomerulonephritis - Anaphylaxis - Shock

Who sued pfizer over COX-2 research and won?

*BYU*(birgham young university) -BYU says its research was misappropriated to develop pfizers celebrex

Describe the development of RA

*autoimmune response = initiation* Normal: environment: smoking Genes: MHCII 1... Autoimmunity: RF, ACPA in blood join reactive ACPA, anti-CII 2... Subclinical arthritis (arthritis signs and symproms - Targeting joints Clinical arthritis: Diagnosis by doctor 2...Chronic destruction

Intellectual property basics (IP)

*one aspect = patent* = patent describes and "claims" an invention - patent "protects" an invention - patent gives an inventor certain rights to his or her invention (right to exclude others from making, using or selling invention)

VIOXX legal settlements

- 2005 Carol Ernst won first Vioxx state trial returned a $235 mill verdict for death of her husband. Texas law capped award at $26 mill. - in 2008, 14th court of appeals reversed finding and carol ernst got nothing. - Merck settled false advertising lawsuit for $23 million in September 2013 (patients could get $50 or more for having taken drug) - 2007: MERCK attempts to settle class action lawsuit patients that met criteria for having cardiovascular comp. 4.8 billion 2016: Merck agrees to pay $830 million to shareholders who sued company claining merk made misleading statements about safety of drug which results in stock price cash

How is a drug formulated?

- Active ingredient (drug itself) - need to decide what dosage of active ingredient, are fillers or excipients added in the drug, and what is the format for the drug will it be a pill capsule, etc. - All of the other stuff other than active ingredients in drugs is also part of the drugs (inactive = fillers)

What are some benefits of inhibiting cyclooxygeneases in arthritis

- Analgesis (reduces pain) - Reduction in inflammatory response (reduces pain and joint damage) - Reduction in bone resorption by osteoclasts (limit bone resorption) - Reduction in fibrosis of joints (helps maintain flexibitlity )

Biologics Control Act of 1902

- Annual licensing for manufacturers of anti-toxin - Regular inspections of production facilities First Act: Identify manufacture certainty and developed new agency

Describe the discovery of the first COX-2 inhibitor and what was the problem?

- Anti inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor Problem = this was first selective COX2 inhibito, but scientist and dupont did not know this since the COX2 enzyme had not been isolated or cloned yet *did not know mechanism of action (what it was inhibiting)

Prior Art Novelty (mechanism)

- Are there prior patents which describe part of your invention? - Are their publications that describe part of your invention? - Did you disclose any aspect of your invention in a manuscript, grant application, talk, poster session, etc. before filing your patent application

Good COX-1 vs. Bad COX-2 hypothesis

- Aspirin, ibuprofen, and naproxen are non-selective inhibitors of both Cox-1 and Cox-2 enxyme - Cox-1 inhibition is associated with small increased risk of gastrointestinal bleeding (ulcers). known in middle of 1990s. - Vioxx is one of a class of drugs that are selective Cox-2 inhibitors. only inhibit COx-2 enzyme that is involved in inflammation and pain, reducing risk for gastrointestinal problems. *MERCK*

Rheumatoid Arthritis Autoantigens

- CCP (cyclic citrullinated peptide) - rheumatoid factor - an antibody against the Fc region of immunoglobulin G - collagen - GP39 - human cartilage glycoprotein 39

What starts occurring to joints when rheumatoid arthritis occurs?

- Cartilage begins to thin - bone erosion -swelling

What are some factors that determine how long it takes for a drug candidate to become eligible for testing in human patients?

- Complexity of disease - chemical characteristics of drug candidate *solubility in water can affect ability to develop them - resources in money and manpower that company invests

Phase III Clinical trials

- Conducted in 100s to 1000 patients at multiple institutions around the country - Objective = determine whether new therapy is more effective or less debilitating than standard treatment - Focuses on specidic types of cancer - Endpoints focus on patient benefit: *survival time *symptom control *Quality of life * long term side effects and risks * progression free survival *Disease free survival

How is a patent a contract?

- Contract with the government - inventor discloses how to make and use invention in written patent application - in return, inventor receives right from government to exclude others from making, using, and selling his or her invention for 20 years.

The controlled Substances Act of 1970

- Control over the coding of drugs and the enforcement of these codes given to the FDA and the Drug enforcement Agency (DEA) - 5 different classifications of controlled substances were established 1. Substances have high potential for abuse, no medical use in treatment in U.S. and have lack of accepted safety. ex.) MDMA, heroin, marijuana,etc. 2. High potential for abuse, may lead to sever psych or physical dependence and have accepted medical use with severe restrictions ex.) hydro, oxycodone, morphine, cocaine, etc. 3. Have less potential for abuse but may lead do moderate or low physical dependence or high psych dependence ex.) Hydrocodone, tylenol with codeine, anabolic steroids, ketamine, etc. 4. Have low potential for abuse relative to substances in 3 5. low potential for abuse relative to substances in 4, and consist limited quantities of narcotics - Regulations regarding the prescription, distribution, storage, and use of these drugs was defined

1951 Durham - Humphrey Amendment

- Defines a prescription drug - identifies what is a refillable prescription

What was the problem with the anti-diphtherium serum (antitoxin)?

- Dosage was a real problem, did not know how much to inject - doctors did not use gloves or take any sanitary measures causing chances of getting infected to be very high Manufacturing problems: - standard procedures for immunization of horses - contamination of collected horse sera - handling of sera so that anti-toxin did not degrade - effective dose of anti toxin needed for injection

What did Biologics control act of 1902 and pure food and drugs act of 1906 accomplish?

- Established standard operating procedures for manufacturing anti-toxin - established procedures for collection and storage - established assays for determining dosing - licensed pharmaceutical companies who could manufacture anti-toxin - established labelling standards for biologics

What are the steps in patenting process

- File application - file info disclosure statement - publication of application - receive office action - office action contains rejections relating to one or more novelty obviousness, utility, written description, best mode, et. - prepare and file response to office auction, either amending claims of application or disputing position of patent examiner - notice of allowance - issuance of patent

What did John K smith found?

- Founded a pharmaceutical company in 1841 - Brought in his bookeeper Kline then merged company with perfume factory of Harry B. French to form smith, kline and french company

1906 Pure Food and Drug Act

- Harvey Wiley, head of chemistry USDA - prohibited interstate commerce of unsafe drugs - required proper labeling - identified official standards for drug

In the 1938 drug safety, what were some shortcomings found of the 1906 Act?

- Lack of inspections - inability to control false claims - failure to regulate medical devices - inability to control what could be marketed - sulfanilamide disaster

Explain the saw suit that occured between Rochester and searl?

- Law suit claims that university is entitled to royalties on celebrex made my G.D Searle and pfizer Co. Which generated nearly 1.5 billion in 1999 - Rochester's claim could eventually expant to cover vioxx, a merck product - Searle attorneys argued that the patent was "overly broad" - Supreme court decline to review a federal circuit decision on Rochester patent involving discovery of separate COX-2 gene - in 2004, lower court ruling declared university's patent invalid

What were the problems with the two RA treatments in the 1980s?

- Long term steroid use resulted in litany of side effects (immunse suppression, osteoporosis, dependence development, cardiovascular effects,etc.) - Non steroidal anti - inflammatory drugs, the mechanaism of action unknown, not very effective in some patients, some significant side effects (gastric bleeding in some patients)

Post- Marketing Surveillance

- Monitor ongoing safety of marketed drugs - Some adverse effects may only be discovered once a product is widely used - Manufacturer files periodic reports to FDA (report adverse reactions, submit quality control records) - FDA may require additional (phase IV) trials to evaluate long term side effects

Explain the lawsuit between BYU and pfizer?

- Monsanto entered a contract with BYU and Dr. Simmons in 1991 to partner on development of drugs that targeted COX-2, but left COX-1 unaffected - Simmons and BYU claim that Monsanto used their research methodologies and data to develop celebrex outside of parntership with pfizer in order to avoid having to share the profits - Requested actual and punitive damages in 2006 - A long delayed COX2 issue gets settled for $450 million in 2012

Imported drugs (1848)

- Most US drugs were imported - Education and standards were established - prohibited importation of unsafe or adulterated drugs

What problems resulted in late 1800's to early 1900's?

- No safety regulations - no efficacy standards in place - no proper labeling - no dosage information - no standard operating procedures for manufacturing - Anyone could make and sell drugs - What drugs treat what diseases?

Modern FDA organization and structure

- Office of external affairs - Office of management and systems - office of operations - office of policy

___________ originated in Detroit in 1866 and ______ was formed in germany by Frederic Bayer and Johannn Westoctt

- Park, Davis and Co. (Codrenin :cocaine and adrenaline) - Bayer AG (Aspirin and heroin)

What does the FDA require before advancing to clinical testing?

- Pharmacological profile of the drug - Determination of the acute toxicity of the drug in at least two species of animals - Short term toxicity studies ranging from 2 weeks to 3 months

Describe the FDA responsibilities

- Protecting the public health by assuring the safety, effectiveness, and security of: * human and vet drugs, vaccines, and other biological products, medical devices, our nations food supply, cosmetics, dietary supplements, and products that give off radiation - Advancing the ph by helping to speed product innovations - helping public get accurate, science based info they need to use medicines and foods to improve their health

What was the truth from the VIGOR study safety results

- Reported in NEJM: mortality rate was .5% in rofecoxib and 0.4% in the naproxen group - TRUTH: incidence of death in VIGOR was 22/4047 (.54%) for rofecoxib and 15/4209 (.37%) for naproxen

The food, Drug and Cosmetic Act of 1938

- Required proof of drug safety (NDA) - Expanded labelling to include warnings - authorized factory inspections - outlawed false claims for drugs - covered medical devices

Kefauver-Harris Amendments of 1962

- Required proof of effectiveness - Gave FDA control over clinical trials - gave FDA authority to regulate advertising of prescription drugs - established good manufacturing practices

Investigational New Drug Application (INDA)

- Required to advance a test compound to clinical trials - Provides info to FDA about Animal pharmacology and toxicology studies, manufacturing info, and clinical trial protocols and investigator information. - Becomes effective if FDA does not disapprove it whithin 30 days

What is done during the research and development stage?

- Research team formed and objective set - Chemicals synthesized - Chemicals tested for efficacy and safety in test tubes and animals, results are used to choose drug candidate - Formulation, stability scale-up synthesis, chronic safety in animals

Describe the 1937 Sulfanilamide disaster

- S.E. Massengill company created an elixir of antibiotic sulfanilamide by dissolving it in diethylene glycol because sulfanilamide did not dissolve good tasked bad - Diethylene glycol is a great solvent but very toxic, but there was no legal requirement to test the toxicity of formulation *More than 100 people killed by this elixir (most were children)

What happened during the drug efficacy period in 1962?

- Senate hearings for revisions of drug laws, senator Kefauver (tenn) - FDA blocks US NDA for thalidomide - Thalidomide disaster in europe - concept on how to do phase 1 (safety) trial

The orphan drug act

- Serious diseases affecting less than 200,000 (orphan disease) - not enough patients for pharm companies to make profit - incentive government grants - marketing exclusivity - FDA assistance, company tax credits

What did diphtheria cause?

- Significant mortality especially in children - toxin inactivates protein synthesis and kills cells and can be very deleterious - found out that if you can develop anitbodies then they can block binding of toxin from receptor - mistake that caused us to create rules

What were possible problems with manufacturing diphtheria anti-toxin?

- Standard procedures for immunization of horses - contamination of collected horse sera - handling of sera so that anti-toxin does not degrade - effective dose of anti - toxin needed for injection

What steps are required for FDA approval?

- The IND (investigation New drug) - Phase II trials - Phase III trials - Late stage Acts - Phase IV studies - The NDA (New drug application)

What form of data is collected in Preclinical Testing?

- Toxic and pharmacological effects - Genetic toxicity - Absorption, metabolism, and excretion - Identify metabolites and their potential toxicities

What patent documents are available to be searched online?

- U.S. Patents and US published applications - Foreign patent documents (EPO and JPO) - Non-patent literature (any published documents publicly available other than patents or published patent applications) *Internet searches such as google *Trade publications and databases(IEE, CHEMnetBASE, etc.

Biological therapeutics 1902

- Unregulated production of tetanus anitoxin (was being made in horses) - illness and death from contaminated products

What were some of the shortcomings of the 1938 Act FDA?

- What exactly is a prescription - prescription vs non prescription drugs - lack of sufficient oversight of some drugs (some drugs had to be sold or dispensed through a physician but no clear rules - Doctors tole in prescribing not clear - illegal sale and distribution of drugs - following WWII concept of prescription wasnt laid out yet

Antigen

- anything that can trigger immune response - foreign molecules which immune system reacts against

What did the Biologics control act of 1902 and Food and Drugs Act of 1906 establish in regards to anti toxin?

- established standard operating procedures for manufacturing anti-toxin - established procedures for collection and storage - established assays for determining dosing - licensed pharmaceutical companies who could manufacture anti toxin - established labelling standards for biologics * once rules were in place they were also in place for chemical drugs

What things does the FDA regulate?

- foods except for most meat and poultry products (reg by US department of Agriculture) - food additives - infant formulas - dietary supplements - human drugs - vaccines, blood products, and other biologics - medical devices - electronic products that give off radiation (microwaves, etc.) - cosmetics - animal feeds and drugs - tobacco products

Inflammation

- localized or tissue - centric activation of immune response - protective and destructive - pain, heat, redness and swelling *self antigen in RA*

Immune system

- network of cells, tissues, and organs that work together to defect the body against attacks by "foreign" invaders - protective and destructive

Benefits to patients in clinical trials (medical care network)

- no cost membership - receive excellent medical care - receive study related medical care and tests at no cost - may receive compensation, travel and inconvenience for study participation - updated on clinical trial results, etc.

The patent as a contract

- patents are a contract with the government - inventor discloses how to make and use the invention in written patent application - in return, inventor recieves the right from government to exclude others from making, using, and selling his or her invention for 20 years

Before advancing to clinical testing what does the FDA require?

- pharmacological profile of the drug - determination of the cute toxicity of the drug in at least two species of animals - short term toxicity studies ranging from 3 weeks to 3 months

Explain the VIGOR study safety results

- safety of both rofecoxib and naproxen was similar to that reported in previous studies - mortality rate was .5% in the rofecoxib and 0.4% in naproxen - myocardial infractions were less common in naproxen than in rofecoxib group (.1% vs. .4%) - rate of death from cardiovascular causes was .2% in both groups

What are some side effects of inhibiting cyclooxygenases in arthritis?

- stomach problems (bleeding, ulcers, etc.) - Kidney problems - Cardiovascular disease (myocardial infraction MI, stoke, fluid retention, increased blood pressure) - possible neurological problems = allergy to NSAIDS in a small percentage of individuals

MERCK VIOXX fines for breaking the law

-2011, Merck, sharp and dohme agreed to pay $950 mill to resolve criminal charges and civil claims related to promotion and marketing of painkiller Vioxx (rofecoxib) - Merck will plead guilty to a one count info charging a single violation of FDCA for introducing a misbranded drug - Merck will plead guilty to a misdemeanor for its illegal promotional activity and will pay $321,636,000

What were some things that were accomplished in the golden era? (1930-1960)

-Deaths in infancy were cut in half -maternal deaths from infections declined by more than 90% - tuberculosis, diphtheria and pneumonia could be treated and cured for the first time in human history - wartime support for research accelerated development of certain therapies -X ray crystallography UV, and infrared spectroscopy initiated gradual shift from wet chemistry of solution to dry chemistry. (molecular structure and bioactivity)

What were two methods to treat RA in the 1980s?

1.) Injected oral steroids 2.) Non - steroidal antiinflammatory

What act creates one of the first government regulatory agencies not known as FDA, and makes it illegal to sell "aldulterated" or "misbranded" food or drugs?

1906 Pure Food and Drug Act - culmination of 25 years of lobbying

What Act created the FDA?

1906 Pure food and drug act

Describe the Good Manufacturing Practices (GMP) regulatory timeline

1. 1906 Pure Food and Drug Act 2. 1938 Federal Food, Drugs and Cosmetic Act 3. 1962 Kefauver- Harris Drug Amendments 4. 1978 GMPs Final rules for drugs and devices 5. 1982 Tamper - resistant packaging regulations issued for OTC products 6. 1992 Generic Drug Enforcement Act 7. 1996 Proposed Revision to US CGMPs for Drugs and Biologics

What are the factors that must be considered by the DEA before a drug can be scheduled

1. Drugs actual or relative potential for abuse 2. Scientific evidence of its pharmacologic effect 3. State of current scientific knowledge regarding drug or other substance 4. History and current pattern of abuse 5. Scope, duration, and significance of abuse 6. What risk there is to public health 7. Its psychic or physiological dependence liability 8. Whether substance is an immediate percursor of a substance already controlled

Investigators conducting phase I trial use one of 2 different statistical designs..

1. Single Ascending dosage (SAD) -small groups of subjects are given a single dose of drugs, if no adverse effects are observed new group of subjects get higher dose until max tolerable dose is determined 2. Multiple Ascending Doses (MAD) - Small groups of subjects are given multiple low doses of drug with subsequent dose escalation for further groups based on safety data

What are the 2 main reasons for some clinical trials to enroll patients instead of healthy volunteers?

1. Some drug candidates (oncology drugs) are too potentially toxic for administration to healthy patients 2. Patients suffering from serious disease, no available treatment may benefit from durg

What are the 10 principles of GMP?

1. Step by step procedure 2. Follow procedure 3. Document work 4. Validation work 5. Integrate productivity, quality and safety into facilities and equipment 6. Maintain facilities and equipment 7. Define, develop and demonstrate job competence 8. Make cleanliness a daily habit 9. Build quality into processes 10. Conduct compliance and performance audits

What were the problems with apothecaries (1600's to 1800's)?

1. Where did you get your stock from? 2. Distribution problems - need to scale up in distribution for more people will have access to drugs

What act was created due to the sulfanilamide tragedy with poisonous solvent that caused 107 deaths and what was the result?

1938 Federal Food, Drug and Cosmetic Act Result: requires manufacturers to prove safety of products before marketing

Legislation in ____ and in _____ was enacted to test and approve drugs and to require appropriate labeling

1938 and 1966

What amendments was created due to the tragedy of thalidomide that caused birth defects in thousands of European babies and what was the result?

1962 Kefauver-Harris Drug Amendments Result: Manufacturers must prove efficacy of products before marketing them and ensure stricter control over drug testing

What added detail for validation, blend uniformity, prevention of cross - contamination, and handling out of specification results?

1996 Proposed Revision to US CGMPs for Drugs and Biologics

By ______ MERCK knew for certain there were cardiovascular effects to vioxx

2000

What is prostacyclin and what is it produced by?

A prostaglandin produced by COX-2 in blood vessel walls, it opens blood vessels and prevents platlets from clumping.

ISO 9000 Series Standards

A set of guidelines issued by the international organization for standardization (ISO) that describes standards for quality systems ( for all industries not just pharmaceuticals)

Food Laboratory Practices (GLP)

A set of regulations governing the methods used in conducting nonclinical laboratory studies intended to support applications for research or marketing permits for FDA regulated products

Good Manufacturing Practices (GMP; also cGMP or CGMP)

A set of regulations governing the methods used in manufacture, quality control, and quality assurance for the preparation of drug or medical device products - FDA doesnt really worry about synthesis but about what the product will be like

NASAIDS that can completely inhibit both COX1 and COX2 but have little selectivity

Aspririn, diclofenac, fenoprofen, fluriprofen, idomethacin, ibuprofen, ketoprofen, mefnamic acid, naproxen, piroxicam, sulindac sulphide

What are some non steroidal anti inflammatory drugs (NSAIDS) that complete inhibit COZ 1 and COX2

Aspirin, tylenol, acetaminophen, ibuprofen, naproxen, aleve, fenoprofen

Aspirin marketed by Bayer since ________, Naproxen (alleve) and ibuprophen (advil ) marketed since _______, and Diclofenac (numerous) marketed since early ______

Aspririn = 1860s for its analgesic and anti inflammatory effects Naproxen and ibuprophen = 1970s Dicofenac = 1980s

A blood product or an active drug ingredient which is generally a protein isolated from a biomass produced by a natural or recombination organism

Biologic

BLA

Biologics Licensing Application (biologics)

Brand Drugs vs. Generic drugs

Brand drugs: - Protected by a patent - supplied by a single company - Marketed under a brand name - Brand drugs are priced by pharm company and regulated by the federal patented medicine prices review board Generic Drugs: - low cost version of brand drugs - Produced by generic companies once patents expire on brand name drug - Are as safe and effective as brand drugs - Price includes manufacturing cost and rebate paid to pharmacies to stock their drug

What allows the brand drug to still stay on the market after the generic drug comes out?

Brand recognition allows the more expensive brand to stay on the market even though it is much more expensive, marketing also helps.

Low risk, low reward, low cost

Branded combintns, LCM, generics, supergenerics Three life

Physiologic stimulus.....________

COX-1 constitutive - stomach, kidney, intestine, platelets, endothelium - PGE2 TxA2 PGI2 = physiologic functions

Inflammatory stimuli ... _________

COX-2 inducible - inflammatory sites (macrophages, synoviocytes) - inflammatory PGs, proteases, O2 - inflamation

What inhibitor was used to synthesize celebrex and vioxx?

COX-2 inhibitor *NS-398* - synthesized two compounds

What is COX-2, and how does it manufacture?

COX-2 is an enzyme that is activated at sites of injury. Manufacturers hormone-like substances called prostaglandins which trigger painful inflammation

CSD

Committee on safety of drugs - not a regular agency and did not police physicians or industry behavior or during clinical trial (1968 medicines act) - national licensing authority, and put control of market access of new drugs

What occurs after the three phases are complete?

Company files New Drug Application (NDA) - the FDA reviews NDA and the drug is finally approved for marketing

What occurs right after the research and development stage?

Company files investigational new drug (IND) application with FDA

Describe a phase I clinical trial for oncology

Conducted in patients with advanced disease that is resistant to standard therapy - small sample size (15 to 10 patients) - Not performed separately by tumor type - Not designed to compare different treatment regimens (not randomized)

VIOXX investigational new drug application (IND)

December 20, 1994 - Merck opens IND 46,894 (VIOXX) for osteoarthritis and acute pain in division of anti-inflammatory, analgesic and ophthalmic drug products

Where does the brand name come from?

Developed by the company requesting approval for the drug and identifies it as the exclusive property of that company

What does Preclinical testing do?

Develops adequate data to support a decision by the FDA that is reasonably safe to proceed with human trials of the drug

Generally, but not limited to, a manufactured instrument or mechanical object used for medical purposes

Device

What was not stated in the patent for vioxx?

Did not have the compound stated

Who was the poster child for vioxx?

Dorothy Hamill

An active drug ingredient which is generally but not limited to a well defined, characterized chemical entity prepared by controlled synthesis

Drug Substance

Why didnt dupont (DUP-697) or taisho (NS-398) have a patent claim?

Dupont did not know that this was a COX-2 inhibitor because COX-2 enzyme had not been isolated and cloned. Taisho did not know either that it was an inhibitor because the enzyme had just been isolated and cloned in 92.

What did the early and late 19th century see as well as the start of the 20th century?

Early: chemist able to extract and concentrate plant based remedies giving rise to treatment like morphine and quinine. End of 19th: Saw development of important vaccines including tetanus arised Early 20th century: animal systems resulted in isolation of epinephrine as 1st hormone that could be used as medicine

Why was the imported drugs of 1848 ineffective?

Enforcement challenges and domestic patent medicines - middle 1800s most drug companies were in germany, few in britain but rarely any standards in US

Who funds drug development?

Entrepreneurs, companies, and taxpayers.

FIPN

Fully integrated pharmaceutical network

What did War production Boards accomplish?

Gave US firms a leading position after WWII - Produced in 1940's over half of worlds pharmaceutical and accounted for 1/3 of international trade in medicines

The discovery of the COx-2 inhibitor NS-390, what was the problem

Gen pharmacol, 1993, research center taisho pharmaceutical Co. Japan NS-398= novel non steroidal anti inflammatory drug with potent analgesic and antipyretic effecs which causes minimal lesions Problem = scientist at taisho did not know that this was a COX2 inhibitor since COX2 enzyme had just been isolated and cloned in 1992 - structure of NS-398 was used to direct synthesis of celebrex and vioxx - did not look at compound to see if it was a selective inhibito

What occurs if ANDA is approved?

Generic drug is approved for 180 days exclusivity period (Where other generic manufacturers may commence other generic versions) - because of this competition, price of generic drugs is significantly reduced.

Dye companies started to scale up production creating a _______ industry

Global such as: - BASF chemical company Germany 1860s - Hoechst dyeworks, Germany 1870's

How is drug manufactured?

Good manufacturing practices (GMP) - implemented by FDA to ensure that drug products are manufactured in an appropriate and safe way

BCS classes

I: solubility= high, permeability = high, % of products on market = 35%, % of drug candidates = 5-10%, Formulation Approach = Tablet or capsule II: Solubility = low, permeability = high, % of products on market = 30%. % of drug candidates = 60-70%, Formulation approach = Particle size reduction, salt formation, self emulsifying systems, nanoparticles, solid dispersions, surfactants III: solubility = high, permeability = low, % of products on market = 25%. % of drug candidates = 5-10%, Formulation approach = Absorption and permeability enhancers, lipids IV: solubility = low, permeability = low, % of products on market = 10%. % of drug candidates = 10-20%, Formulation approach = Combination of Class II and III approaches

All clinical trials must be reviewed and approved by what board?

Institutional Review Board (IRB), where trials will be conducted

All clinical trials must be reviewed and approved by ________where trials will be conducted

Institutional review board (IRB)

What causes RA?

Interaction between immune system and bone system - come of the same mediators that are flammatory and have ability to affect function of bone cells, that can affect immune response - initially flammatory response

3. Nonobvious

Invention must not be "obviousness" over what is already known ("prior art") - not obvious to someone skilled in art

What were the grounds that the federal court declared the University of Rochester's patent invalid?

It did not include the precise chemical formula for such an inhibitor of COX-2 (2004)

Where does the generic name come from?

It is assigned in the US by an official body... the United States Adopted Names (USAN) council

Where does the chemical name of a drug come from?

It is based on the molecular structure of the drug

What must a generic drug contain?

It must have the same active ingredient, strength, dosage form and route of administration as the reference (patented) drug.

What is included in the joints, bone, cartilage, and synovial fluid

Joints: - connects bones, provides support, allows movement Bone: - Osteocytes (bone cells) Osteoblasts (cells that stimulate bone formation) Osteoclasts ( cells that deconstruct bone formation) Cartilage: Chondrocytes Synovial fluid: Synoviocytes

How long does each stage of clinical trials usually last?

Lab studies: (preclinical) several years Human safety: (phase I) days or weeks (tens of people) Expanded safety: (phase I/II) weeks or months (hundreds) Efficacy and safety: (phase III) several years (thousands)

1906= ______

Labeling drugs

What application is submitted after clinical trials? and what does it do?

New Drug Application (NDA) - Seeks approval to market drug in US - Provides info to FDA reviewers regarding: *Drug safety and efficacy *Risk vs. benefits of drug *Proposed labeling *Manufacturing methods to maintain drugs identity, strength, quality and purity - 100,000 pages or more

NBE

New biological entity

NME

New molecular entity

Does being issued a patent give one the right to practice ones invention?

No. Need a freedom to operate - an opinion given after a patent is issued to assess the right to practice ones invention - Must defend patent legally when challenged in court of law

Bone absorbing cells that clean space are known as ________

Osteoclasts

What was the broke conflict of interest regulations

Panel members had been associated with MERCK or being paid by MERCK

What is the main difference between brand drug and generic drug?

Patent rights

Pharmacokinetics, and pharmacodyanamics

Pharmacokinetics (PK) - measures what the body does to a drug, how drug is absorbed, distributed, broken down and excreted Pharmacodynamics (PD) - describes what drug does to body - how increasing concentrations of drug influence potential toxicity *Both are important in establishing safety and appropriate dosage

What occurs after the company files the IND application?

Phase 1 occurs: clinical trials, studies in healthy humans (toleration) Phase II: Studies in patients (efficacy) Phase III: Large clinical trials in many patients

What are some adverse events in clinical trials?

Phase III you make sure there are non - no equal events - which events are more concerning? (dont want to see Cardiovasuclar, respiratory problems, etc. Rashes on the other hand are not a big deal)

Who discovered injected and oral steroids, and what was the problem with these?

Prednisone in the 1950s and noted for its immediate and dramatic analgesic and anti inflammatory effects - problem was that some individuals could not take these because it would either cause gastrinal intestinal propblems or others so there was a need for non steroidal inflammatory drugs, also long term steroid use results in osteoporosis (bone and joint destruction

1951 = _________

Prescriptions

Who was the president of Merck research vioxx, the V.P clinical research of Merck in 1997

President: Dr. Edward Scolnick V.P: Dr. Alise Reicin

Orphan drugs

Products developed to treat a patient population of less than 200,000 and receive a 7 year exclusivity period

Process of clinical trials

Protocol approval --> selection of co-workers ---> approval process --> Patient recruitment and participation ---> Data entry ---> Statistical process ---> Presentation and publication of report ---> Data filled registration obtained

What did the orphan drug act do?

Provided incentives for researchers to develop drugs for treating rate diseases - introduced the tax breaks and an extra two years of market exclusivity, making it a more attractive investment - Prior to the orphan drug act fewer than 10 drugs received approval for marketing

Which companies fit in with novel mechanism for unmet needs including orphan, rare and neglected diseases, speciality technologies?

Research intensive RIPCO, start - ups *Academic institues*

What does the FDA's determinations on drug approval depend on?

Submission of reliable data from clinical trials - Regulatory review of the data is multidisciplinary approach (clinical, pharmacology/toxicology, clinical pharmacology, drug quality (chem) and statistics)

Rational design

Substrates or receptors for enzymes, hormones or neruotransmitters known to be involved in particular disease is selected on basis of knowledge of bodys biochemical and physiological processes - chemist investigate compounds that block function of chosen target molecule - search is done among natural sources that might have desired biochemical effect - researchers modify the lead candidate from this process to turn it into a pill or injection tolerated by humans *became a real possibility in 1970s* *predict how molecules structure will affect behavior through physical models *

What was the theory regarding COX-1 and COX -2?

That COX I was good and COXII was bad, not correct

Bioavailability

Total amount that reaches target tissue and time taken to get there after administration