How many of you have taken an antiviral drug after coming down with the flu?  It worse than nothing at all.   Regulatory approval of a drug is not guarantee of safe and effective.  First the hurdle in phase 3 trials is slightly better than a sugar pill and unless the side effects are major such as requiring hospitalization, they are not considered negative marks in the approval process.  Clairton was approved on a 4% improvement in symptom.  Some symptoms are considered positive and thus assure that the drug will be approved, such as sleeping better for sedatives (tranquillizers) based on the question in the Hamilton Inventor.  But sleeping better and longer doesn’t reduce depression.  Approval is based on a short trial of six weeks in a very select population of volunteers, and after running a washout period, in which a substantial number of volunteers are culled from the group—this is a standard procedure of industry funded studies that goes on reported.  After the washout period the trail starts and then results are recorded.  But many drugs are taken for years, and the evidence of delayed effects such as increased risk of heart attacks, osteoporosis, and cancer don’t show up in a trial.  The article below covers many key issues of an item that has made the news. 

http://www.worstpills.org/member/drugprofile.cfm?m_id=311  It was exposed that in the phase III trial, using the washout period that had removed “60% of volunteers”   http://www.cochrane.org/features/neuraminidase-inhibitors-preventing-and-treating-influenza-healthy-adults-and-children.  Since it is not in the interest of Roche to discover side effects are to report them, still towards the end of Tamiflu’s patent major side effects were uncovered:  “Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis, toxic epidermal necrolysis, abnormal heart rhythms, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome.^[38][39]”   

And it gets worse, the drug is sold as being effective if given within the first 2 days of symptoms, this precludes sending a blood sample to a lab, thus is given on the basis of symptom.  In the real world clinical situation that entails that most patients who get Tamiflu don’t have influenza, but just the common cold.  One study found under half of those treated with Tamiflu actually had influenza, and by March of that flu season the number went down to 1/6^th.  Left out also is a class example of scientific fraud that was exposed in Japan.   The following the government investigation into the fraud, Japanese press ran article on the case for nearly a year.  One could easily write a book on all the wrong doings associated with Tamiflu, how for example Rumsfeld on its board of directors promoted the stock-pilling of Tamiflu.  Several chapters could be written on the Cochrane Collaboration’s struggle to get the unpublished clinical trials, which were promised to be supplied to them by Roche.  Similar struggle was made by the British Medical Association.  Roche promised to supply them, but then didn’t delivery.  All this is the norm for how business is done.  It is as Prof. Marcia Angell states “There is a fundamental conflict between public and profits.”  Prof. Ben Goldacre, in Bad Pharma devoted 13 pages to Tamiflu, and it was of limited scope.  There is a national broadcast company of Australia 20 minute documentary exposing Tamiflu at https://www.youtube.com/watch?v=Wiqb9U3hup0.

Of course there are positive findings for the drug, Roche funded them.  Journal expert review prior to publishing an article is a sham.  Roche owns the raw data of the clinical trials and other details such as the trial protocol, and Roche wont share this with the reviewer.  If you doubt that favorable bias is the norm, then read the major study using raw data obtained by 4 professors through the Freedom of Information Action, from the phase 3 trials submitted to the FDA for approval of neuroleptic drugs.  The study found positive bias averages 32%.  Thus a drug which makes a condition worse by 10% will come out to be a 22% positive benefit.  The New England Journal of Medicine wanted the message widely desiminated and made the full version available for free—at http://content.nejm.org/cgi/content/full/358/3/252.   Given this is the norm, the positive results of a few hours less symptoms for Tamiflu are a result upon bias by design results.    

Below is the BMJ (British Medical Association) article on the UN’s decision to remove Tamiflu from their list of essential drugs.  Another example of the adage:  “It is amazing how quickly a good drug becomes a bad one once it goes off patent.”

http://www.bmj.com/content/358/bmj.j3266?utm_medium=email&utm_campaign_name=201707194&utm_source=etoc_daily

1.      Editorials  Mark H Ebell, professor of epidemiology

WHO downgrades status of oseltamivir

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3266 (Published 12 July 2017)

Important lessons from the Tamiflu story

Oseltamivir (Tamiflu) was approved by the US Food and Drug Administration in 1999 for the treatment of uncomplicated influenza within 48 hours of the onset of symptoms [many patients don’t get the drug until after this period of putative effectiveness]. The manufacturer’s press release stated that the drug was studied in two randomised trials enrolling a total of 849 patients with influenza and reported a 1.3 day mean reduction in the duration of symptoms.1 The drug was described as safe, with less than 1% of patients discontinuing it because of adverse effects. It was approved by the European Medicines Agency in 2002.2

On the basis of these limited (and ultimately revealed as incomplete) data, governments acted. Concerned about a possible outbreak of avian influenza, as well as the H1N1 pandemic in 2009, the UK government stockpiled oseltamivir at a cost of over £600m (€680m; $770m) from 2006 to 2014. Similarly, the US government has spent over $1.5bn stockpiling the drug, based on recommendations from the Centers for Disease Control and Prevention (CDC).3And in 2010, in the wake of the worldwide pandemic of H1N1 influenza, oseltamivir was added to the World Health Organization’s list of essential medications.4 This list is intended to guide decisions on national formularies and should include only “the most efficacious, safe, and cost effective medicines for priority conditions.” As a result, oseltamivir has been described as “a nice little earner,” generating over $18bn in sales worldwide, half of it from governments stockpiling the drug.5

As recently as 2014, the director of the CDC stated that oseltamivir can “prevent serious complications; if you have influenza and get the medicine early, you may not need to be admitted to a hospital .... Antiviral flu medicines save lives, but they're unfortunately underutilized.”6 He even encouraged use in patients more than two days after the onset of symptoms. Yet, the FDA had long concluded that there was no evidence that oseltamivir reduced complications, hospital admissions, or mortality and actually prevented the manufacturer from making such claims in their promotional materials.  [This is one of many examples of regulatory capture, and subsequent industry reward.  The FDA allows their employs to moonlight for pharma.]

So, what is the truth? An editorial in The BMJ described a “multisystem failure,”7which is an apt description for the series of decisions based on flawed evidence made by the EMA, CDC, and WHO. These include the failure to publish all available evidence, to make the data available at the individual patient level, and to recognise the limitations of observational data [not flawed by regulatory captujre.]. Among the factors in play in these failures were Roche’s desire for profit, public fear of pandemic influenza, and politicians wanting to be seen as “doing something” to protect their constituents [and raised funds from industry].

Published data

To date, only three trials of oseltamivir in adults have been published in the medical literature.8910 These trials emphasised the per protocol analyses, which included only patients with a confirmed diagnosis of influenza, and reported a mean reduction of 30 hours in the duration of symptoms. Of course, what really matters is how the drug works for patients with influenza-like illness since near patient tests for influenza lack sensitivity11 and are little used in most European countries.12 After publication of their 2009 Cochrane review,13 Jefferson’s team was alerted to the existence of several unpublished trials.14 Following requests from The BMJ, the clinical trial reports [not the raw data of individual patients] were eventually made available to researchers [after a delay of 4 years, when the drug was about to go off patent].

A meta-analysis published in 2013 found only a 20 hour mean reduction in symptoms and no evidence of a reduction in the likelihood of pneumonia, hospital admission, or complications requiring an antibiotic.15 Jefferson’s Cochrane review, using an even larger set of unpublished studies, confirmed these findings and provided additional evidence of the drug’s harms, such as nausea (number needed to harm=28), vomiting (NNH=22), and psychiatric events (NNH=94) [these resulted in a number of juvenal death uncovered in Japan.]16 Individual patient data have still not been made available to researchers. Withholding these data was a serious breach of research ethics by Roche: suppressing information obtained from patients enrolled in trials of a then experimental drug, who thought that they were contributing to the medical knowledge base.

Observational studies

The CDC based its recommendation to stockpile oseltamivir largely on data from observational studies that showed a reduction in mortality for very sick hospital inpatients but are subject to confounding by indication, selection bias, and survivorship bias. The author of a recent systematic review of observational studies concluded that the findings were interesting but inconclusive because of the small sample size and flawed study designs.17

The manufacturer may not push back against the WHO decision, since the first generic version of oseltamivir was recently approved.18 Nevertheless, the story has several important lessons. Firstly, it is vital that all trials be published, and that individual patient data be made available for independent reanalysis. Efforts are under way (http://www.alltrials.net/) and deserve our support. Secondly, money spent stockpiling drugs that are minimally effective is money not spent on other public health priorities. Because diverting these funds causes direct harm to the public, we must demand better evidence to inform these decisions. Thirdly, belief in the efficacy of oseltamivir may have led to less research to find truly effective drugs for influenza, again harming the public.

It is appropriate that WHO downgraded the status of this drug based on the concerted efforts of The BMJ, Jefferson and his team, and many others. A House of Commons report provides an excellent summary: “This longstanding regulatory and cultural failure impacts on all of medicine, and undermines the ability of clinicians, researchers, and patients to make informed decisions about which treatment is best.” Removal of oseltamivir from the essential medicines list is better late than never, but still comes far too late.

Footnotes

     Competing interests: I have read and understood BMJ policy on declaration of interests and declare that I received funding from Roche Diagnostics for a study of the impact of a point of care polymerase chain reaction test for influenza on clinical decision making and inappropriate use of antibiotics and oseltamivir. Roche had no role in study design, conduct, analysis, writing, interpretation, or decision to publish.

• Provenance and peer review: Commissioned, not externally peer reviewed.

References

1. ↵

Roche receives FDA approval of Tamiflu, first pill to treat the most common strains of influenza. Press release, October 1999. http://www.gilead.com/news/press-releases/1999/10/roche-receives-fda-approval-of-tamiflu-first-pill-to-treat-the-most-common-strains-of-influenza-ab.

2. ↵

European Medicines Agency. Tamiflu.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000402/human_med_001075.jsp&mid=WC0b01ac058001d124.

3. ↵

Abbasi K. The missing data that cost $20bn.BMJ2014;358:g2695doi:10.1136/bmj.g2695.

4. ↵

World Health Organization. WHO model list of essential medicines. 16th list (updated). 2010. http://apps.who.int/iris/bitstream/10665/70643/1/a95060_eng.pdf.

5. ↵

Jack A. Tamiflu: “a nice little earner.”BMJ2014;358:g2524.doi:10.1136/bmj.g2524 pmid:24811410.

6. ↵

CDC. Update on flu season 2014-15. Press briefing, 9 Jan 2014.https://www.cdc.gov/media/releases/2015/t0108-flu-update.html

7. ↵

Jefferson T, Doshi P. Multisystem failure: the story of anti-influenza drugs.BMJ2014;358:g2263. doi:10.1136/bmj.g2263 pmid:24721793.

8. ↵

Nicholson KG, Aoki FY, Osterhaus ADME, et al. Neuraminidase Inhibitor Flu Treatment Investigator Group. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet2000;358:1845-50. doi:10.1016/S0140-6736(00)02288-1 pmid:10866439.

9. ↵

Treanor JJ, Hayden FG, Vrooman PS, et al. US Oral Neuraminidase Study Group. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA2000;358:1016-24.doi:10.1001/jama.283.8.1016 pmid:10697061.

10. ↵

Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. [Clinical efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir in treating acute influenza--placebo-controlled double-blind multicenter phase III trial]Article in Japanese.Kansenshogaku Zasshi2000;358:1044-61.doi:10.11150/kansenshogakuzasshi1970.74.1044 pmid:11193557.

11. ↵

Hurt AC, Alexander R, Hibbert J, Deed N, Barr IG. Performance of six influenza rapid tests in detecting human influenza in clinical specimens. J Clin Virol2007;358:132-5.doi:10.1016/j.jcv.2007.03.002 pmid:17452000.

12. ↵

Howick J, Cals JW, Jones C, et al. Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA. BMJ Open2014;358:e005611.. doi:10.1136/bmjopen-2014-005611 pmid:25107438.

13. ↵

Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.BMJ2009;358:b5106. doi:10.1136/bmj.b5106 pmid:19995812.

14. ↵

Doshi P. Neuraminidase inhibitors—the story behind the Cochrane review.BMJ2009;358:b5164. doi:10.1136/bmj.b5164 pmid:19995813.

15. ↵

Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. Fam Pract2013;358:125-33.doi:10.1093/fampra/cms059 pmid:22997224.

16. ↵

Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ2014;358:g2545.doi:10.1136/bmj.g2545 pmid:24811411.

17. ↵

Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?BMJ2009;358:b5248.doi:10.1136/bmj.b5248 pmid:19995814.

18. ↵

US Food and Drug Administration. The FDA approves first generic version of widely used influenza drug, Tamiflu.

“It is amazing how quickly a good drug becomes a bad one once it goes off patent.”

http://www.bmj.com/content/358/bmj.j3266?utm_medium=email&utm_campaign_name=201707194&utm_source=etoc_daily

1.      Editorials  Mark H Ebell, professor of epidemiology

WHO downgrades status of oseltamivir

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3266 (Published 12 July 2017)

Important lessons from the Tamiflu story

Oseltamivir (Tamiflu) was approved by the US Food and Drug Administration in 1999 for the treatment of uncomplicated influenza within 48 hours of the onset of symptoms [many patients don’t get the drug until after this period of putative effectiveness]. The manufacturer’s press release stated that the drug was studied in two randomised trials enrolling a total of 849 patients with influenza and reported a 1.3 day mean reduction in the duration of symptoms.1 The drug was described as safe, with less than 1% of patients discontinuing it because of adverse effects. It was approved by the European Medicines Agency in 2002.2

On the basis of these limited (and ultimately revealed as incomplete) data, governments acted. Concerned about a possible outbreak of avian influenza, as well as the H1N1 pandemic in 2009, the UK government stockpiled oseltamivir at a cost of over £600m (€680m; $770m) from 2006 to 2014. Similarly, the US government has spent over $1.5bn stockpiling the drug, based on recommendations from the Centers for Disease Control and Prevention (CDC).3And in 2010, in the wake of the worldwide pandemic of H1N1 influenza, oseltamivir was added to the World Health Organization’s list of essential medications.4 This list is intended to guide decisions on national formularies and should include only “the most efficacious, safe, and cost effective medicines for priority conditions.” As a result, oseltamivir has been described as “a nice little earner,” generating over $18bn in sales worldwide, half of it from governments stockpiling the drug.5

As recently as 2014, the director of the CDC stated that oseltamivir can “prevent serious complications; if you have influenza and get the medicine early, you may not need to be admitted to a hospital .... Antiviral flu medicines save lives, but they're unfortunately underutilized.”6 He even encouraged use in patients more than two days after the onset of symptoms. Yet, the FDA had long concluded that there was no evidence that oseltamivir reduced complications, hospital admissions, or mortality and actually prevented the manufacturer from making such claims in their promotional materials.  [This is one of many examples of regulatory capture, and subsequent industry reward.  The FDA allows their employs to moonlight for pharma.]

So, what is the truth? An editorial in The BMJ described a “multisystem failure,”7which is an apt description for the series of decisions based on flawed evidence made by the EMA, CDC, and WHO. These include the failure to publish all available evidence, to make the data available at the individual patient level, and to recognise the limitations of observational data [not flawed by regulatory captujre.]. Among the factors in play in these failures were Roche’s desire for profit, public fear of pandemic influenza, and politicians wanting to be seen as “doing something” to protect their constituents [and raised funds from industry].

Published data

To date, only three trials of oseltamivir in adults have been published in the medical literature.8910 These trials emphasised the per protocol analyses, which included only patients with a confirmed diagnosis of influenza, and reported a mean reduction of 30 hours in the duration of symptoms. Of course, what really matters is how the drug works for patients with influenza-like illness since near patient tests for influenza lack sensitivity11 and are little used in most European countries.12 After publication of their 2009 Cochrane review,13 Jefferson’s team was alerted to the existence of several unpublished trials.14 Following requests from The BMJ, the clinical trial reports [not the raw data of individual patients] were eventually made available to researchers [after a delay of 4 years, when the drug was about to go off patent].

A meta-analysis published in 2013 found only a 20 hour mean reduction in symptoms and no evidence of a reduction in the likelihood of pneumonia, hospital admission, or complications requiring an antibiotic.15 Jefferson’s Cochrane review, using an even larger set of unpublished studies, confirmed these findings and provided additional evidence of the drug’s harms, such as nausea (number needed to harm=28), vomiting (NNH=22), and psychiatric events (NNH=94) [these resulted in a number of juvenal death uncovered in Japan.]16 Individual patient data have still not been made available to researchers. Withholding these data was a serious breach of research ethics by Roche: suppressing information obtained from patients enrolled in trials of a then experimental drug, who thought that they were contributing to the medical knowledge base.

Observational studies

The CDC based its recommendation to stockpile oseltamivir largely on data from observational studies that showed a reduction in mortality for very sick hospital inpatients but are subject to confounding by indication, selection bias, and survivorship bias. The author of a recent systematic review of observational studies concluded that the findings were interesting but inconclusive because of the small sample size and flawed study designs.17

The manufacturer may not push back against the WHO decision, since the first generic version of oseltamivir was recently approved.18 Nevertheless, the story has several important lessons. Firstly, it is vital that all trials be published, and that individual patient data be made available for independent reanalysis. Efforts are under way (http://www.alltrials.net/) and deserve our support. Secondly, money spent stockpiling drugs that are minimally effective is money not spent on other public health priorities. Because diverting these funds causes direct harm to the public, we must demand better evidence to inform these decisions. Thirdly, belief in the efficacy of oseltamivir may have led to less research to find truly effective drugs for influenza, again harming the public.

It is appropriate that WHO downgraded the status of this drug based on the concerted efforts of The BMJ, Jefferson and his team, and many others. A House of Commons report provides an excellent summary: “This longstanding regulatory and cultural failure impacts on all of medicine, and undermines the ability of clinicians, researchers, and patients to make informed decisions about which treatment is best.” Removal of oseltamivir from the essential medicines list is better late than never, but still comes far too late.

Footnotes

     Competing interests: I have read and understood BMJ policy on declaration of interests and declare that I received funding from Roche Diagnostics for a study of the impact of a point of care polymerase chain reaction test for influenza on clinical decision making and inappropriate use of antibiotics and oseltamivir. Roche had no role in study design, conduct, analysis, writing, interpretation, or decision to publish.

• Provenance and peer review: Commissioned, not externally peer reviewed.

References

1. ↵

Roche receives FDA approval of Tamiflu, first pill to treat the most common strains of influenza. Press release, October 1999. http://www.gilead.com/news/press-releases/1999/10/roche-receives-fda-approval-of-tamiflu-first-pill-to-treat-the-most-common-strains-of-influenza-ab.

2. ↵

European Medicines Agency. Tamiflu.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000402/human_med_001075.jsp&mid=WC0b01ac058001d124.

3. ↵

Abbasi K. The missing data that cost $20bn.BMJ2014;358:g2695doi:10.1136/bmj.g2695.

4. ↵

World Health Organization. WHO model list of essential medicines. 16th list (updated). 2010. http://apps.who.int/iris/bitstream/10665/70643/1/a95060_eng.pdf.

5. ↵

Jack A. Tamiflu: “a nice little earner.”BMJ2014;358:g2524.doi:10.1136/bmj.g2524 pmid:24811410.

6. ↵

CDC. Update on flu season 2014-15. Press briefing, 9 Jan 2014.https://www.cdc.gov/media/releases/2015/t0108-flu-update.html

7. ↵

Jefferson T, Doshi P. Multisystem failure: the story of anti-influenza drugs.BMJ2014;358:g2263. doi:10.1136/bmj.g2263 pmid:24721793.

8. ↵

Nicholson KG, Aoki FY, Osterhaus ADME, et al. Neuraminidase Inhibitor Flu Treatment Investigator Group. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet2000;358:1845-50. doi:10.1016/S0140-6736(00)02288-1 pmid:10866439.

9. ↵

Treanor JJ, Hayden FG, Vrooman PS, et al. US Oral Neuraminidase Study Group. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA2000;358:1016-24.doi:10.1001/jama.283.8.1016 pmid:10697061.

10. ↵

Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. [Clinical efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir in treating acute influenza--placebo-controlled double-blind multicenter phase III trial]Article in Japanese.Kansenshogaku Zasshi2000;358:1044-61.doi:10.11150/kansenshogakuzasshi1970.74.1044 pmid:11193557.

11. ↵

Hurt AC, Alexander R, Hibbert J, Deed N, Barr IG. Performance of six influenza rapid tests in detecting human influenza in clinical specimens. J Clin Virol2007;358:132-5.doi:10.1016/j.jcv.2007.03.002 pmid:17452000.

12. ↵

Howick J, Cals JW, Jones C, et al. Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA. BMJ Open2014;358:e005611.. doi:10.1136/bmjopen-2014-005611 pmid:25107438.

13. ↵

Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.BMJ2009;358:b5106. doi:10.1136/bmj.b5106 pmid:19995812.

14. ↵

Doshi P. Neuraminidase inhibitors—the story behind the Cochrane review.BMJ2009;358:b5164. doi:10.1136/bmj.b5164 pmid:19995813.

15. ↵

Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. Fam Pract2013;358:125-33.doi:10.1093/fampra/cms059 pmid:22997224.

16. ↵

Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ2014;358:g2545.doi:10.1136/bmj.g2545 pmid:24811411.

17. ↵

Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?BMJ2009;358:b5248.doi:10.1136/bmj.b5248 pmid:19995814.

18. ↵

US Food and Drug Administration. The FDA approves first generic version of widely used influenza drug, Tamiflu.