Today’s lessonCochrane CollaborationTGN1412Clinical trials

The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience

True/false VocabularySide effects of AvandiaAbstract The rosiglitazone decision process at FDA

and EMA – gap filling exercise and linking wordsAbstract Under-reporting of cardiovascular events

in  rofecoxib - gap filling exerciseVideo Ben Goldacre What doctors don’t know about

the drugs they prescribe

VOCABULARYMATCH THE WORDS WITH THEIR

SYNONYMS

Claim solid/trustworthyHarm promisePledge not objectiveSet back affirmBiased damageReliable problem/obstacle

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”.

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

“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 Scientifichttp://downloads.bbc.co.uk/podcasts/radio4/tls/tls_20120228-0930b.mp317 mins

Currently, some Phase 2 and most Phase 3 drug trials are designed as

the researchers also do not know which treatment is being given to any given subject.

In a randomized trial each study subject is randomly assigned

randomized, double-blind, and placebo-controlled

When the trial is blind the subjects involved in the study do not know which study treatment they receive,

allows additional insurance against bias or placebo effect.

If the study is double-blind, in alternating periods of time during the study

A form of double-blind study called a "double-dummy" design

to receive either the study treatment or a placebo

In this kind of study, all patients are given both placebo and active doses

enables the researchers to isolate the effect of the study treatment from the placebo effect

In a placebo-controlled trial the use of a placebo

thereby preventing biases

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#

True or False [see paragraph number]

1.[3] There was international consensus that Tamiflu helped protect the patient from more severe forms of flu2. [4] The claims made about Tamiflu were based on a series of meta-analyses3.[5] There are contradictions in the FDA’s response to claims about the effectiveness of Tamiflu4.[6] It is more important for regulators to assess clinical study reports than journal publications of clinical trials5.[7] Analysis of the Tamiflu clinical study report has given radical new information about Avandia, Neurontin and Vioxx6.[9] To ensure reliable evidence synthesis will require a change in the present situation regarding manufacturers’ confidentiality7.[10] The manufacturers give regulators access to all their trial reports when a new drug is being approved8.[11] It is not easy to gain access from the FDA to reviews, memos and other correspondence

Find words or expressions in the text which mean:

Para 1 examination2 believed2 is greater than3 welcomed4 knew about6 earnings/money10 treatment11 complete11 access to14 worries15 move

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

More possible side effects of Rosiglitazone

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

The rosiglitazone decision process at FDA and EMA. What should we learn? Pouwels KB, van Grootheest K.

AbstractIn 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.

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.

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.

GlaxoSmithKline to pay $3bn in US drug fraud scandal

Diabetes medication Avandia is one of the three drugs concerned in the fraud caseGlaxoSmithKline 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

Am Heart J. 2012 Aug;164(2):186-93. Epub 2012 Jul 3. Madigan D, Sigelman DW, Mayer JW, Furberg CD, Avorn J.

Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies. AbstractBackground; 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.

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

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

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.

1.[2] Strong sales are a good indication that a drug is safe F2.[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 F4.[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 F7.[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 F9.[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

1 reliable solid1 scrutiny examination2 assumed believed2 outweighs is greater than3 stockpiled bought/collected3 heralded welcomed4 was aware of knew about6 a revenue stream earnings/money10 handling use11 thorough complete11retrieval of access to12 pledged promised13 sets back is an obstacle to14 concerns worries15 shift move

The rosiglitazone decision process at FDA and EMA. What should we learn?Pouwels KB, van Grootheest K.AbstractIn 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.

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.AbstractBACKGROUND: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.