HW Biology

1.1 Nature of Science

Summer 2021 1

BIOL 2110G CELLULAR & MOLECULAR BIOLOGY

1.1

Case Study #1 SCIENCE AND BIG PHARMA

David Jordan, CC BY-SA 3.0

Did you remember to complete the prep assignment?

From the prep assignment Types of trials ◦ Phase 1

◦ Phase 2

◦ Phase 3

Purpose and structure of each type of trial ◦ Why is it done, what are the ‘treatments”, how many people?

Key terms ◦ Placebo

◦ Blind study

◦ Double blind

Arthritis Pain Management NSAIDs

Non‐steroidal anti‐inflammatory drugs

Inhibit COX Enzymes NSAIDs inhibit COX enzymes

Cox enzymes prostaglandins

By NEUROtiker - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1972093

COX-2

with injury

 Prostaglandins that signal pain

COX-1

Always active

 Prostaglandins that protect stomach lining

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1.1 Nature of Science

Summer 2021 2

Inhibit COX Enzymes

So if you INHIBIT COX‐1, what will happen?

(clue – remember the function of the COX‐1 enzymes)

So if you INHIBIT COX‐2, what will happen?

(clue – remember the function of the COX‐2 enzymes)

Non‐specific NSAIDs E.g. ibuprofen (Advil), naproxyn (Aleve)

Inhibit COX‐2 and COX‐1

What is the intended effect of these drugs?

COX-2

with injury

 Prostaglandins that signal pain

COX-1

Always active

 Prostaglandins that protect stomach lining

Which produces intended effect?  COX-2 inhibition  COX-1 inhibition

Intended effect vs Side effect Side effect

Due to some other effect of drug

COX-2

with injury

 Prostaglandins that signal pain

COX-1

Always active

 Prostaglandins that protect stomach lining

Which produces side effects?  COX-2 inhibition  COX-1 inhibition

Non‐specific NSAIDs Predict and EXPLAIN the major side‐effect

How could you design a pain‐relieving drug to reduce this side‐effect?

Case Study Assignment Question 1

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1.1 Nature of Science

Summer 2021 3

COX-2

with injury

 Prostaglandins that signal pain

COX-1

Always active

 Prostaglandins that protect stomach lining

Enter Vioxx by Merck COX-2 specific inhibitor

Vioxx Small trials Effective

Fewer GI side‐effects

FDA approval in May 1998 

Vioxx becomes a blockbuster drug $1,000,000,000 annual sales

Millions of prescriptions

VIGOR study, November 2000, NEJM

Vioxx Naproxyn

8000+ patients

randomized

VIGOR No difference in intended effect

VIGOR Worksheet Question 2

0

1

2

3

4

5

0 1 2 3 4 5 6 7 8 9 10 11

C u m u la ti v e  I n d ic e n ce  ( % )

Months

GI Side-Effects

Vioxx na proxn

p<0.001

Data from Bombardier et al., 2000. NEJM 343:1520-1528.

Myocardial Infarctions (MI)  0.1% of 4029 in naproxyn group

0.42% of 4047 in Vioxx group

# of MIs in each group?

If 20,000,000 Americans took Vioxx

How many MIs would there be?

Worksheet Question 3a

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1.1 Nature of Science

Summer 2021 4

FDA meets with Merck Feb. 2001 Concern about myocardial infarctions (MIs) Internal company documents: 20 MIs in Vioxx group

Intentionally withheld in publication

How does this change the MI% in Vioxx group?

How does this change the # of MIs among 20,000,000 Americans?

Worksheet Question 3b

So, then what? FDA:

physicians must be told about the  VIGOR cardiovascular results

Merck:

Prohibited sales reps from discussing  VIGOR study with anyone

More investigation Vioxx (#) Naproxen (#) # Different

More or fewer on Vioxx?

Complicated GI Events

16 37

Serious Cardiovascular Events

47 20

Worksheet Question 4 APPROVe study: NSAIDS and colon polyp 

prevention

Vioxx Placebo

Randomized Double-blind

# polyps? # polyps? Dependent Variable

Experimental Control

APPROVe: Cardiovascular Events

0 0.5

1 1.5

2 2.5

3 3.5

4 4.5

5

0 6 12 18 24 30 36

C um

ul a

tiv e

In c

id e

nc e

( %

)

Months

Vioxx Placebo

p=0.008

Data from Bresalier et al. 2005. NEJM 352:1092-1102

Worksheet Question 5

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1.1 Nature of Science

Summer 2021 5

July & August 2005 1st Vioxx lawsuit (Texas)

Jurors awarded $253,400,000 to widow of man who had fatal heart attack in  2001 while taking Vioxx

November 2007 Merck pays $4.85 BILLION settlement fund to end lawsuits

Without admitting fault

Allowed Merck to avoid personal‐injury lawsuits 47,000 plaintiffs

265 class action suits

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