Distortion of evidence-based medicine

Question 1

How is the evidence base distroted

Answer 1

• Missing data- publication bias
• Flawed clinical trials
• Others
  
  • Allowing politics to trump evidence
  • Regulatory capture

Question 2

Why does distortion of the evidence base matter

Answer 2

• Clinical decisions are based largely on published data
  
  • Systemic review/meta-analyses key tools
• If the published data are not an accurate reflection of reality then this may lead to
• Decisions that cause avoidable suffering/death
• Wasted resources
  
  • Where prescribers are misled into thinking that newer, more expensive treatments are more effective than older ones
  • Where healthcare funding is finite (e.g. everywhere), this deprives patients of other treatments

Question 3

What is publication bias

Answer 3

• Publication bias is the tendency on the parts of investigators, reviewers, and editors to submit or accept manuscripts for publication based on the direction or strength of the study findings

Question 4

How does publication bias happen

Answer 4

• Authors are more likely to submit positive (rather than negative or inconclusive) results
• Editors are more likely to accept positive results
• Pressure on academics to publish compounds the problem
• Negative or inconclusive results often remain unpublished

Question 5

Impact of publication bias on meta-analyses

Answer 5

Question 6

Publication bias: Reboxetine

Answer 6

• NA reuptake inhibitor
• Used in unipolar depression
• Marketed by Pfizer as Edronax
• Very common adverse events include Nausea and insomnia

Question 7

Reboxetine- Benefits

Answer 7

Question 8

Reboxetine- harms

Answer 8

Question 9

Publication bias in antidepressant trials

Answer 9

Question 10

Publication bias in reporting of adverse events as well as treatment outcomes

Answer 10

Question 11

Publication bias is compounded by industry funding of trials

Answer 11

Question 12

Outcome reporting bias

Answer 12

• The selective reporting of some outcomes but not others, depending on the nature and direction of the results

Question 13

Outcome reporting bias

Question 14

Flawed trials: external validity of RCTs in asthma

Answer 14

Question 15

Flawed trials: impact of atypical study populations on cost-effectiveness decisions

Answer 15

Question 16

Manipulation of trials: comparing your new drug with something rubbish

Answer 16

• Comparing your drug with placebo when effective treatments are already available
• Psychopharmacology
  
  • Paroxetine versus amitriptyline BD
  • Atypical antipsychotics versus haloperidol 20mg
  • Newer atypicals vs risperidone 8mg

Question 17

Flawed trials: Stopped to short

Answer 17

Question 18

Flawed trials: Use of surrogate outcome measures- Torcetrapib

Answer 18

Question 19

Flawed trials: Others

Answer 19

• Trials that are too small
• Trials that don’t measure drop-outs

Question 20

Tamiflu

Answer 20

• Oseltamivir
• Manufactured by Roche
• Neuraminidase inhibitor (Anti-viral) used for treatment and prevention of influenza A + B

Question 21

1997-99: Emergence of pandemic flu as a threat

Answer 21

• May 1997- 1st documented human cases of avian influenza H5N1 occurred in Hong Kong.
• April 1999- WHO publishes its first pandemic influenza plan
  
  • Recommends use of antivirals as prophylaxis
  • Written in collaboration with the European Scientific Working Group on Influenza (ESWI) a group ‘funded entirely by Roche and other influenza drug manufacturers’

Question 22

1999-2002: Approvals and calls to stockpile

Answer 22

• 1999-2000–FDA approvals of Tamiflu for treatment and prophylaxis of influenza
• 2002–EU approval for Tamiflu for treatment and prophylaxis of influenza
• May 2002–WHO calls for nations to stockpile influenza antivirals

Question 23

2003-05- stockpiling begins

Answer 23

• Aug 2003- the US begins stockpiling Tamiflu (est. spend to date = $1.3 billion)
• March 2005- UK government announces it will stockpile 14 million doses of Tamiflu (Est spend to date= £424 million)

Question 24

2006: Controversy about effectiveness of Tamiflu gathers pace

Answer 24

• July 2006–Cochrane review finds Tamiflu to be minimally effective with no comparative data regarding its effectiveness in treating avian influenza.“
• Because of their low effectiveness, NIs should not be used in routine seasonal influenza control. In a serious epidemic or pandemic, NIs should be used with other public health measures. We are unsure of the generalizability of our conclusions from seasonal to a pandemic or avian influenza.”

Question 25

Swine flu 2009

Answer 25

• April 2009–Outbreak of influenza A/H1N1 (‘swine flu’)
  
  • Originated in Mexico
  • Began to taper off in November 2009
  • Declared over in August 2010
  • Estimated 284,500 deaths
  • Kills 0.01-0.03% of those infected
    
    • 2-3% in 1918 ‘Spanish flu’ pandemic

Question 26

Late 2009- Roche withhold data from cochrane

Answer 26

• September 2009–Cochrane writes to Roche to ask for access to all the data on Tamiflu
• October 2009–Roche write back requesting that Cochrane authors sign a confidentiality agreement which included a clause stating that the signee was “not to disclose … the existence and terms of this Agreement”
  
  • Roche provides some extra data to Cochrane but all reports provided are incomplete