Reading and exercises for preparation for Inglese IV

1. Today’s lesson
 Cochrane Collaboration
 TGN1412
 Clinical trials
 The Imperative to Share Clinical Study Reports:
Recommendations from the Tamiflu Experience
 True/false Vocabulary
 Side effects of Avandia
 Abstract The rosiglitazone decision process at FDA and EMA –
gap filling exercise and linking words
 Abstract Under-reporting of cardiovascular events in
rofecoxib - gap filling exercise
 Video Ben Goldacre What doctors don’t know about the drugs
they prescribe

2. VOCABULARY
MATCH THE WORDS WITH THEIR SYNONYMS
Claim solid/trustworthy
Harm promise
Pledge not objective
Set back affirm
Biased damage
Reliable problem/obstacle

3. TGN1412 was an experimental drug being investigated
for the treatment of multiple sclerosis, leukemia and
arthritis.
In its first human clinical trials, it caused catastrophic
systemic organ failure in the six subjects who were
given the drug
All six men have been told that they face "a lifetime of
contracting cancers and all the various auto-immune
diseases from lupus to MS, from rheumatoid
arthritis to ME”.

4. According to Sir Iain Chalmers, founder of the
Cochrane Collaboration, a trial on a single patient
using a substance similar to this molecule resulted in
the patient’s death.
This trial was not published

5. “We now have evidence that over 50% of trials go
unreported. What are patients who actually contribute to
these trials, participate in them, what are they to think of
this behaviour? I think it’s indefensible and it worries me
greatly that the medical establishment in my field has not
been more forthright in putting it right.”
Sir Iain Chalmers, founder of the Cochrane Collaboration on
BBC Radio 4 The Life Scientific
http://downloads.bbc.co.uk/podcasts/radio4/tls/tls_20120228-0930b.mp3
17 mins

6. Currently, some Phase 2 and the researchers also do not know
most Phase 3 drug trials are which treatment is being given
designed as to any given subject.
In a randomized trial each study randomized, double-blind,
subject is randomly assigned and placebo-controlled
When the trial is blind the subjects allows additional insurance against
involved in the study do not know bias or placebo effect.
which study treatment they receive,
If the study is double-blind, in alternating periods of time
during the study
A form of double-blind study called to receive either the study
a "double-dummy" design treatment or a placebo
In this kind of study, all patients are enables the researchers to isolate
given both placebo and active doses the effect of the study treatment
from the placebo effect
In a placebo-controlled trial the use thereby preventing biases
of a placebo

7. Read the following paper:
The Imperative to Share Clinical Study Reports:
Recommendations from the Tamiflu Experience
 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001201#

8. True or False [see paragraph number]
1.[3] There was international consensus that Tamiflu helped protect the
patient from more severe forms of flu
2. [4] The claims made about Tamiflu were based on a series of meta-analyses
3.[5] There are contradictions in the FDA’s response to claims about the
effectiveness of Tamiflu
4.[6] It is more important for regulators to assess clinical study reports than
journal publications of clinical trials
5.[7] Analysis of the Tamiflu clinical study report has given radical new
information about Avandia, Neurontin and Vioxx
6.[9] To ensure reliable evidence synthesis will require a change in the present
situation regarding manufacturers’ confidentiality
7.[10] The manufacturers give regulators access to all their trial reports when
a new drug is being approved
8.[11] It is not easy to gain access from the FDA to reviews, memos and other
correspondence

9. Find words or expressions in the text which mean:
Para 1 examination
2 believed
2 is greater than
3 welcomed
4 knew about
6 earnings/money
10 treatment
11 complete
11 access to
14 worries
15 move

10. Rosiglitazone (Avandia)may cause side effects.
Tell your doctor if any of these symptoms are
severe or do not go away:

11. More possible side effects of Rosiglitazone

12. Insert the following words into the abstract
The rosiglitazone decision process at FDA and
EMA. What should we learn?
introduction evidence associated
signs weight increased
evaluation overview

13. The rosiglitazone decision process at FDA and EMA. What
should we learn? Pouwels KB, van Grootheest K.
Abstract
In September 2010 the EMA decided to suspend the market authorisation
of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These
actions were taken approximately 10 years after the -----1----- of rosiglitazone,
because rosiglitazone might be associated with an increased risk of
ischemic heart disease. It is often stated that the first -----2----- of an increased risk
of ischemic heart disease were noticed in 2004, however already in 2001 the FDA
-concluded, based on data available to the EMA at the time of initial approval,
that rosiglitazone should not be used in combination with insulin, because this
combination therapy was -----3----- with an increased risk of cardiac failure and
ischemic heart disease. Remarkably, in 2007, when the -----4----- against this
combination therapy had -----5----- , the EMA made a decision that encouraged the
use of insulin in combination with rosiglitazone, while the FDA tried to restrict this
combination therapy. Despite the publication of several studies, including a large
randomized controlled study, the cardiovascular risk of rosiglitazone still has not
been definitively established. The -----6----- given to the benefits and the risks
seems mainly a subjective decision. To prevent new cases like rosiglitazone, more
attention should be given to -----7----- of study protocols of safety trials prior to their
starts. This paper gives a critical -----8----- of the decision making process at the
FDA and the EMA on the basis of public available information.

14. According to a scientist for the U.S. Food and Drug Administration (FDA), Avandia
is linked to as many as 100,000 heart attacks. Clinical studies show that the
drug increases the risk of heart attack by 43 percent and can double the risk of
heart failure after one year of treatment.
GlaxoSmithKline is to pay $3bn (£1.9bn) in the largest
healthcare fraud settlement in US history.

15.  In September 2010 the EMA decided to suspend the market authorisation of
rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These
actions were taken approximately 10 years after the introduction of rosiglitazone,
because rosiglitazone might be associated with an increased risk of ischemic heart
disease. It is often stated that the first signs of an increased risk of ischemic heart
disease were noticed in 2004, however already in 2001 the FDA concluded, based
on data available to the EMA at the time of initial approval, that rosiglitazone
should not be used in combination with insulin, because this combination therapy
was associated with an increased risk of cardiac failure and ischemic heart disease.
Remarkably, in 2007, when the evidence against this combination therapy had
increased, the EMA made a decision that encouraged the use of insulin in
combination with rosiglitazone, while the FDA tried to restrict this combination
therapy. Despite the publication of several studies, including a large randomized
controlled study, the cardiovascular risk of rosiglitazone still has not been
definitively established. The weight given to the benefits and the risks seems mainly
a subjective decision. To prevent new cases like rosiglitazone, more attention
should be given to evaluation of study protocols of safety trials prior to their starts.
This paper gives a critical overview of the decision making process at the FDA and
the EMA on the basis of public available information.

16. GlaxoSmithKline to pay $3bn in US drug fraud scandal
Diabetes medication Avandia is one of the three drugs concerned in
the fraud case
GlaxoSmithKline is to pay $3bn (£1.9bn) in the largest
healthcare fraud settlement in US history.
The drug giant is to plead guilty to promoting two drugs for
unapproved uses and failing to report safety data about a diabetes
drug to the Food and Drug Administration (FDA).
GSK, one of the world's largest healthcare and pharmaceuticals
companies, admitted to promoting antidepressants Paxil and
Wellbutrin for unapproved uses, including treatment of children
and adolescents.
The company also conceded charges that it held back data and
Made unsupported safety claims over its diabetes drug Avandia.
BBC News 2 July 2012

17. Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease
studies.
Abstract
Background; In September 2004, rofecoxib (Vioxx) was removed from the market
-----1----- it was found to produce a -----2----- doubling of cardiovascularthrombotic (CVT)
events in a placebo-controlled study. Its manufacturer stated that this was the first clear
evidence of such risk and criticized -----3----- analyses of earlier CVT risk for focusing on
investigator-reported events. We studied contemporaneously adjudicated CVT events to
assess the information on cardiovascular risk available -----4----- the drug was in
widespread use.
Methods: -----5----- an intention-to-treat analysis of adjudicated CVT deaths, we analyzed
detailed patient-level data collected -----6----- 3 randomized placebo-controlled trials
of rofecoxib versus placebo that had been designed to define the drug's possible role in
the prevention or treatment of Alzheimer disease. All trials -----7----- completed by April
2003.
Results: In the 3 studies combined, the data indicated that rofecoxib -----8----- tripled
the risk of confirmed CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding
reached the P < .05 level of significance by June 2001.
Conclusion: Intention-to-treat analysis of placebo-controlled studies of rofecoxib for
Alzheimer disease demonstrated that the drug produced a significant increase in
confirmed CVT deaths nearly 40 months before it was removed from the market.-----
9-----, published analyses of these trials -----10----- restricted to on-treatment analyses
(ending 14 days after cessation of treatment) that did not reveal this risk. Intention-to-
treat analyses of clinical trial data can reveal important information about potential drug
risks and -----11----- performed routinely and reported in a -----12----- manner.

18. Insert the following words into the abstract
Under-reporting of cardiovascular events in
the rofecoxib Alzheimer disease studies.
near more than using
after had been were
while previous by contrast
timely during should be

20. Watch this TED talk by epidemiologist Ben
Goldacre in which he explains why negative or
inconclusive findings in clinical trials go
unreported.
http://www.youtube.com/watch?v=RKmxL8VYy0M

21. Currently, some Phase 2 and most Phase 3 drug trials are
designed as randomized, double-blind, and placebo-controlled.
In a randomized trial each study subject is randomly assigned to
receive either the study treatment or a placebo.
When the trial is blind the subjects involved in the study do not
know which study treatment they receive, thereby preventing
biases
If the study is double-blind, the researchers also do not know
which treatment is being given to any given subject.
A form of double-blind study called a "double-dummy" design
allows additional insurance against bias or placebo effect.
In this kind of study, all patients are given both placebo and active
doses in alternating periods of time during the study.
In a placebo-controlled trial the use of a placebo enables the
researchers to isolate the effect of the study treatment from
the placebo effect.

22. 1.[2] Strong sales are a good indication that a drug is safe F
2.[3] There was international consensus that Tamiflu helped protect the
patient from more severe forms of flu T
3.[4]The claims made about Tamiflu were based on a series of meta-analyses F
4.[5] There are contradictions in the FDA’s response to claims about the
effectiveness of Tamiflu T
5.[6] It is more important for regulators to assess clinical study reports than
journal publications of clinical trials T
6.[7] Analysis of the Tamiflu clinical study report has given radical new
information about Avandia, Neurontin and Vioxx F
7.[9] To ensure reliable evidence synthesis will require a change in the present
situation regarding manufacturers’ confidentiality T
8.[10] The manufacturers give regulators access to all their trial reports when
a new drug is being approved F
9.[11] It is not easy to gain access from the FDA to reviews, memos and other
correspondence T
10.[12] Roche have not kept their promise to give reviewers access to
information T

23. 1 reliable solid
1 scrutiny examination
2 assumed believed
2 outweighs is greater than
3 stockpiled bought/collected
3 heralded welcomed
4 was aware of knew about
6 a revenue stream earnings/money
10 handling use
11 thorough complete
11retrieval of access to
12 pledged promised
13 sets back is an obstacle to
14 concerns worries
15 shift move

24. should we learn?
Pouwels KB, van Grootheest K.
Abstract
In September 2010 the EMA decided to suspend the market authorisation
of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These
actions were taken approximately 10 years after the introduction of rosiglitazone,
because rosiglitazone might be associated with an increased risk of
ischemic heart disease. It is often stated that the first signs of an increased risk of
ischemic heart disease were noticed in 2004, however already in 2001 the FDA
concluded, based on data available to the EMA at the time of initial approval,
that rosiglitazone should not be used in combination with insulin, because this
combination therapy was associated with an increased risk of cardiac failure and
ischemic heart disease. Remarkably, in 2007, when the evidence against this
combination therapy had increased, the EMA made a decision that encouraged the
use of insulin in combination with rosiglitazone, while the FDA tried to restrict this
combination therapy. Despite the publication of several studies, including a large
randomized controlled study, the cardiovascular risk of rosiglitazone still has not
been definitively established. The weight given to the benefits and the risks seems
mainly a subjective decision. To prevent new cases like rosiglitazone, more
attention should be given to evaluation of study protocols of safety trials prior to
their starts. This paper gives a critical overview of the decision making process at
the FDA and the EMA on the basis of public available information.

25. Am Heart J. 2012 Aug;164(2):186-93. Epub 2012 Jul 3.
Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies.
Madigan D, Sigelman DW, Mayer JW, Furberg CD, Avorn J.
Abstract
BACKGROUND:
In September 2004, rofecoxib (Vioxx) was removed from the market after it was found to produce a
near doubling of cardiovascularthrombotic (CVT) events in a placebo-controlled study. Its
manufacturer stated that this was the first clear evidence of such risk and criticized previous
analyses of earlier CVT risk for focusing on investigator-reported events. We studied
contemporaneously adjudicated CVT events to assess the information
on cardiovascular risk available while the drug was in widespread use.
METHODS:
Using an intention-to-treat analysis of adjudicated CVT deaths, we analyzed detailed patient-level
data collected during 3 randomized placebo-controlled trials of rofecoxib versus placebo that had
been designed to define the drug's possible role in the prevention or treatment of Alzheimer disease.
All trials had been completed by April 2003.
RESULTS:
In the 3 studies combined, the data indicated that rofecoxib more than tripled the risk of confirmed
CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding reached the P < .05 level of
significance by June 2001.
CONCLUSION:
Intention-to-treat analysis of placebo-controlled studies of rofecoxib for Alzheimer disease
demonstrated that the drug produced a significant increase in confirmed CVT deaths nearly 40
months before it was removed from the market. By contrast, published analyses of these trials were
restricted to on-treatment analyses (ending 14 days after cessation of treatment) that did not reveal
this risk. Intention-to-treat analyses of clinical trial data can reveal important information about
potential drug risks and should be performed routinely and reported in a timely manner.