Peering into the “rabbit hole” of publication bias and inadequate

When patients seek medical care, they assume the treatment or advice they receive is based on a strong understanding of the human body and its processes. They also typically assume the care they receive is based on a strong understanding of the research literature pertaining to their well-being and any ailments for which they might seek care. However, publication bias and inadequate research transparency greatly threaten medical providers’ ability to practice evidence-based medicine in its truest form, and this in turn puts patients at unnecessary risk. The evidence of these issues existing is unequivocal. However, systematic reviews and other studies that present overviews of these issues – although certainly incredibly important in establishing the undeniable presence and pervasiveness of these issues – may inadvertently obfuscate the concreteness of these closely-related processes in action. Therefore, this article presents a “case series” of these detrimental issues in action in an effort to emphasize the tangibility of these issues and thereby help make their importance unmistakably clear.


Introduction
][6] The existence and persistence of these two closely-related issues carry profoundly detrimental implications for the evidence base from which researchers and medical providers operate.Importantly, these issues put patients at risk of receiving incomplete or inaccurate medical advice and/or an intervention that appears much more effective or advantageous than it really is, is less than ideal for the condition or situation in question, or is actually harmful.Such a claim should not be taken lightly.The systematic reviews and other studies aforementioned [1][2][3][4][5][6] collectively provide important and robust evidence of the incontrovertible existence and pervasiveness of these issues; however, these studies, although incredibly valuable, might still blur somewhat the concreteness of these issues.Therefore, it is instructive, and perhaps even crucial, to go deeper into the "rabbit hole," where one finds many well-documented specific examples that add unequivocal tangibility to the dire importance and relevance of these issues.To this end, this article presents a "case series" that demonstrates the very real effects publication bias and inadequate research transparency have on the medical literature, and in turn, the very real effects these issues can have on patient care and the practice and furthering of evidence-based medicine.

It breaks my heart to tell you…
After suffering a myocardial infarction (MI), some people develop dysrhythmias or aberrant heartbeats.Sometimes this is transient, but in other cases this can portend an increased risk for potentially lethal complications.Indeed, those who do develop persistent dysrhythmias have a higher risk of death than those who do not.Given this common medical knowledge, the historical question was: Should medical providers proactively administer drugs that act to suppress dysrhythmias after a patient has suffered a MI (post-MI antidysrhythmic prophylaxis)?
This is precisely what used to be done, but when Furberg completed his 1983 review assessing the impacts of this practice, there was no evidence of benefit from doing this (there was not even a trend suggesting possible benefit); in fact, Furberg even mentioned some emerging evidence that these agents might be harmful in this setting. 7However, he still concluded that the finding of no benefit seemed the least likely possibility, and instead, he concluded the most likely explanation was that the drugs did offer mortality benefit that was probably obscured by methodological shortcomings of the available trials. 7These agents continued to be used for almost an entire decade after his review.10] The harm amounted to the deaths of tens of thousands of people in the 1980s for every year they were used (especially later in the 1980s), with a contextual comparison of the annual number of deaths caused during the peak of their use quite possibly being greater than the number of U.S. military personnel killed in the entirety of the Vietnam War.The upper-level estimate is approximately 65,000 -70,000 excess deaths per year, and even the most conservative estimate still yields approximately 28,000 excess deaths per year of use.The total excess death estimate is in the hundreds of thousands. 11e story gets worse.In 1993, Cowley and colleagues published an article describing a randomized, double-blind, placebo-controlled trial conducted in 1980, prior to the publication of Furberg's 1983 review. 12In this study, there were nine deaths in the antidysrhythmic (lorcainide) group of 48 patients (18.75%; the abstract mistakenly indicates there were 49 patients in the lorcainide group, but there were actually 48), and only one death in the placebo group of 47 patients (2.13%).
Although the authors never conducted any statistical analysis on the mortality data, if one were to consider further the mortality event rates (in what is obviously a post hoc analysis), one would find an absolute increase in risk of death of 16.62% over the sixweek period of the study for those in the lorcainide group (95% confidence interval [CI], 4.21% to 29.93%), and by Fisher's exact test, the difference between the two groups would have a P value of 0.015 (rounded to three decimal places).Based on these results, one additional and unnecessary death was caused for about every six patients treated for six weeks with lorcainide for post-MI antidysrhythmic prophylaxis.
p166) Depressing, right?In 2008, Turner and colleagues published a striking review of 12 antidepressants where they compared all the phase II and phase III trials submitted to the FDA to the corresponding trials available in the peer-reviewed literature. 13The 12 antidepressants included selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, paroxetine CR, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine, venlafaxine XR, duloxetine), and agents with other mechanisms of action (bupropion SR, mirtazapine, nefazodone).Figure 1 shows the primary results graphically, along with several additional graphical representations of the study's data.How is this possible?Of the 38 positive studies, all but one were published, yielding 37 positive studies in the peer-reviewed literature.Of the 36 not-positive (24 negative and 12 questionable) studies, three were correctly published as negative, 22 were not published at all, and 11 were published in such a way as to make the results seem positive (a manner of reporting referred to as "spinning").Interestingly, Melander and colleagues published similarly disconcerting findings in 2003 when they found troubling issues with the SSRI literature compared to the data available at the Swedish drug regulatory authority. 14Out of 42 studies submitted to the drug regulatory authority, 21 showed a significant effect for the primary outcome (SEPO) and 21 found no significant effect for the primary outcome (NSEPO).However, in the peer-reviewed literature, there were 22 corresponding stand-alone publications finding SEPO; interestingly, three of the 21 studies finding SEPO were published as a stand-alone publication twice, with two of the 21 studies finding SEPO never appearing as a stand-alone publication (their data were pooled with other studies for a pooled-results publication).On the other hand, of the 21 studies finding NSEPO, only six were published as a stand-alone publication, the data from four never appeared in any fashion in the peer-reviewed literature, and the remaining 11 only had their data presented in a pooled-results publication incorporating data from other studies.All but one of the pooled-results publications had an amalgamation of studies finding SEPO and NSEPO, with one pooled-results publication being comprised of only two studies finding NSEPO.Additionally, the pooled publications were not always forthright about pooling.p2) If this were not already enough, Melander and colleagues also noted that only two of the stand-alone publications presented both an intention-to-treat (ITT) and per-protocol (PP) analysis.The remaining publications presented only one analysis, which tended to be the typically-more-treatment-favorable PP analysis (only 24% of the stand-alone publications reported an ITT analysis).Melander and colleagues rightly conclude:

Study outcomes by total amount of patient data in
"[F]or anyone who relies on published data alone to choose a specific drug, our results should be a cause for concern.
Without access to all studies (positive as well as negative, published as well as unpublished) and without access to alternative analyses (intention to treat as well as per protocol), any attempt to recommend a specific drug is likely to be based on biased evidence."

C
6][17] These studies primarily surrounded treatment of painful conditions (migraine prophylaxis and neuropathic and nociceptive pain), but a smaller portion of the studies investigated use of gabapentin as an adjunctive agent in bipolar disorder.6][17] For instance, primary outcomes specified in protocols were sometimes not reported in the corresponding publication or were reported as secondary outcomes; likewise, primary outcomes that did not appear anywhere in the original protocol were added to publications.Proper disclosure of such changes in the primary outcome was variable (even though it should have been universal when it occurred).p10) Internal company documents provided in the Trials publication and associated additional file are also distressing (Figure 2). 16[17] Criticism and concern over celecoxib Adding insult to injury… The randomized, double-blind CLASS trial purportedly established the gastrointestinal safety advantage of celecoxib (Celebrex ® ), a cyclooxygenase-2 (COX-2) selective, non-steroidal, anti-inflammatory drug (NSAID), over other nonselective NSAIDs. 189][20][21][22][23][24][25] The stark difference is odd and should immediately give one pause and a desire to clarify the differences.Indeed, upon reviewing the FDA literature, one finds there were originally two protocols: N49-98-02-035 (dated January 26, 1998) and N49-98-02-102 (dated August 24, 1998). 20,21ollowing a total of eight protocol amendments (all of which took place with blinding preserved), the protocol pre-specified the trials were to run for the aforementioned durations of follow-up or until a pre-specified number of events had occurred (20 in each trial or 45 between the two trials). 20,21The protocol also pre-specified a plan to pool the data for the patients receiving celecoxib. 20,21The events accrued at rates lower than predicted, which affected the duration for which the trials ran; indeed, one of the amendments was to lengthen the study period of one of the trials by three months in order to reach the target number of events.I certainly am familiar with the Serpell study in detail.We have discussed the merits of publishing, republishing, and creating promotional campaigns around these results in the past.
We know that A wants to make sure that we align publication messages with your global marketing efforts.Our concern, not having seen any of P 's PR spin on the results as part of your promotional campaign on this manuscript, is that we make sure that we don't make up different ways of explaining away the results to different audiences.It is our understanding that you publicized the study as supporting the use of gabapentin for these difficult mixed NeP patients.
We can certainly say that these are very difficult patients to treat with this mixed bag of symptoms and that these are "good" results for this particularly difficult population.

B
9][20][21] Table 1 below provides the CSUGIE incidence rate data from the FDA literature for the entire study period and for the untenable six-month truncation point.9][20][21] Nevertheless, the inappropriately truncated six-month data for this post hoc altered primary outcome are saluted by the authors in their publication. 18Table 2 below provides the incidence rate data from the FDA literature for the post hoc altered primary outcome of CSUGIEs plus GDUs.It is also important to note that GDUs are a clinically weaker and logistically more problematic outcome to use as part of a primary outcome measure compared to the relatively much more robust composite outcome of CSUGIEs.Goldkind gives a succinct and telling overview of the problems inherent in including GDUs as a part of the primary outcome measure on page 22 of his review for the FDA. 20so of interest is FDA documentation indicating that the sponsor specified original intent to compare the event rate in the group receiving celecoxib (n = 3,987) to each of the groups receiving   BID indicates twice a day; CR, crude rate; pt-yrs, patient-years; TID, three times a day.
diclofenac (n = 1,996) and ibuprofen (n = 1,985) separately as long as the outcome data for the pooled celecoxib group were significantly different from the pooled NSAID group (this stepwise approach was employed to prevent type I error). 19,20However, if one reads the JAMA article, one only finds data for the celecoxib group versus the pooled NSAID group, even though the authors noted a significant difference for the celecoxib group versus the pooled NSAID group for the post hoc altered primary outcome. 18his too is peculiar, and it is troubling to note that in the data available in the FDA documents, celecoxib repeatedly failed to separate significantly from diclofenac. 19-21p9) ) The failure of celecoxib to demonstrate significant benefit compared to diclofenac in the aforementioned analyses should again give one pause.Indeed, as Witter noted in his review for the FDA: "Therefore, particularly for making drug class (i.e.p76) There is still more to the story.p8113) In the trial data discussed above, the dosing regimen of the medications was as follows: celecoxib, 400 mg twice a day; diclofenac, 75 mg twice a day; and ibuprofen, 800 mg three times a day.While the doses of diclofenac and ibuprofen are at the higher end of officiallyrecommended doses for treatment of pain caused by osteoarthritis and rheumatoid arthritis, the dose of celecoxib used in the trials was two to four times higher than the doses officially recommended for the same indications, respectively.p10) Unfortunately, instead of providing a rigorous and reassuring assessment, comparing the FDA literature and internal company documents to the official CLASS publication leaves one with little more than profound disillusionment and considerable uncertainty.
Might doses such as 100-200 mg twice daily -the doses typically used in clinical practice -fare differently for similar outcomes?Unfortunately, there is no reliable answer to this question.Some might cite SUCCESS-I, CONDOR, and GI-REASONS (the other major trials of celecoxib versus nonselective NSAIDs) as providing the answers, but doing so is mistaken.For example, the SUCCESS-I trial was a randomized, double-blind trial studying celecoxib at two doses -100 mg twice daily (n = 4,393) and 200 mg twice daily (n = 4,407) -versus the nonselective NSAIDs naproxen at 500 mg twice daily (n = 905) and diclofenac at 50 mg twice daily (n = 3,489); however, amidst limitations to the study, perhaps most notably for the discussion at hand is the fact that exposure to the medications only lasted 12 weeks, thus precluding any conclusion about long-term effects. 29CONDOR was a randomized, doubleblind trial that studied celecoxib 200 mg twice daily (n = 2,238) versus diclofenac slow release 75 mg twice daily plus omeprazole 20 mg once a day (n = 2,246). 30The CONDOR trial ran for six months, which, although better than 12 weeks, is still a disappointing and questionable duration given the aforementioned discussion Worse case: we have to attack the trial design if we do not see the results we want.
Best case: Data is all we want and we go forward; will need to justify our trial design.
If other endpoints do not deliver, we will also need to strategize on how we provide the data. of the CLASS trial data.This trial has other limitations, but again foregoing such considerations for the discussion at hand, it is still instructive to appraise the actual event rates and the components of the primary composite outcome for the six-month duration of the trial.Notably, the rates of gastroduodenal hemorrhage; gastric outlet obstruction; gastroduodenal, small-bowel, or large-bowel perforation; small-bowel hemorrhage; and large-bowel hemorrhage were identical between the two groups.As shown in Table 3 below, the statistically significant difference reported for the primary composite outcome was driven predominantly by the study-defined outcome of clinically-significant anemia of presumed occult gastrointestinal origin, including possible small-bowel blood loss, with a smaller contribution from clinically-significant anemia judged to be from a visualized gastrointestinal lesion.Similar findings are seen in the GI-REASONS trial, although it had a smaller difference in the primary composite outcome. 31GI-REASONS was another randomized trial that ran for six months, but it was open-label with blinded endpoint assessment and assessed celecoxib (n = 4,035) versus freely-chosen nonselective NSAIDs (n = 4,032).It too has other limitations, but setting those issues aside again to consider the six-month event rates, we again see a statistically significant difference reported for the primary composite outcome (the composition of which was very similar, but not identical, to the primary composite outcome seen in the CONDOR trial).However, as seen in Table 4 below, the difference in the primary composite outcome was again mostly due to differences in clinically-significant anemia of presumed occult gastrointestinal origin, including possible small bowel blood loss, and in this trial, the difference in clinicallysignificant anemia judged to be from a visualized gastrointestinal lesion was notably smaller, differing by only two events between the groups.Although CONDOR and GI-REASONS had similar durations and outcomes (thereby perhaps tempting some to compare the event rates for the primary composite outcomes to one another), one must note there were differences in methodology (e.  *The primary composite outcome included: gastroduodenal, small-bowel, or large-bowel hemorrhage; acute gastrointestinal hemorrhage of unknown origin, including presumed small-bowel hemorrhage; gastroduodenal, small-bowel, or large-bowel perforation; gastric outlet obstruction; clinically significant anemia with a defined gastrointestinal lesion judged to be the cause; and clinically-significant anemia of presumed occult gastrointestinal origin, including possible small-bowel blood loss.
^Clinically-significant anemia was defined in the protocol as a decrease in hemoglobin by 2 g/dL or more or a drop in hematocrit of 10% or more.
# One patient in the diclofenac slow release plus omeprazole group was found to have bleeding angiodysplasia in the colon.
celecoxib and/or financial relationships with the parent company for celecoxib, up to and including working exclusively for the parent company.Although this is not necessarily an incorrigible flaw by default, one is prudent to be cognizant of such conflicts of interest, and given the mishandlings of the CLASS trial, some might reasonably be left with additional uncertainties about the integrity of the conduct of the SUCCESS-I, CONDOR, and GI-REASONS trials.

Remonstrance and reproach regarding rosiglitazone
3][34][35][36][37][38][39][40][41][42][43] When John Buse (a physician researcher from the University of North Carolina at Chapel Hill) raised concern over the cardiovascular risk of rosiglitazone starting in 1999, the parent company of the drug took considerable efforts to try to silence him, including complaining to his superiors and threatening legal action.
This ultimately ended in the U.S. Senate Committee on Finance (USSCoF) getting involved.The USSCoF eventually determined the actions of the parent company amounted to "intimidation," and the USSCoF review of the matter is indeed telling: "The effect of silencing this criticism is, in our opinion, extremely serious.At a July 30, 2007, safety panel on Avandia, FDA scientists presented an analysis estimating that Avandia caused approximately 83,000 excess heart attacks since coming on the market.p2) Furthermore, additional internal company documents show more duplicitous behavior surrounding rosiglitazone (Figure 4). 33,34*The trial allowed dose titration in each group and unrestricted medication selection and switching within the nonselective NSAID group (switching between the groups was not allowed, however).The celecoxib dose most commonly prescribed initially was 200 mg daily (90%).The nonselective NSAIDs included meloxicam (average dose 13.0 mg), naproxen (average dose 819.8 mg), nabumetone (average dose 1,089.0mg), diclofenac (average dose 124.4 mg), ibuprofen (average dose 1,453.2mg), and etodolac (average dose 709.2 mg).
^The primary composite outcome included: gastroduodenal, small-bowel, or large-bowel hemorrhage; acute gastrointestinal hemorrhage of unknown origin, including presumed small-bowel hemorrhage; gastroduodenal, small-bowel, or large-bowel perforation; gastric outlet or small-bowel obstruction; symptomatic ulcers; clinically significant anemia with a defined gastrointestinal lesion judged to be the cause; clinically-significant anemia of presumed occult gastrointestinal origin including possible smallbowel blood loss.
# Clinically-significant anemia was defined in the protocol as a decrease in hemoglobin by 2 g/dL or more or a drop in hematocrit of 10% or more.

D
Once again, the story does not end there.p6) What exactly did the Nissen and Wolski meta-analysis find?Compared to the control group (defined in their meta-analysis as those who received either placebo or other medications used to treat diabetes), those who received rosiglitazone experienced significantly more myocardial infarctions (MIs), with an odds ratio (OR) of 1.43 (95% confidence interval [CI], 1.03 -1.98; P = 0.03). 36Nissen and Wolski also assessed death from cardiovascular causes, finding an OR of 1.64 (95% CI, 0.98 -2.74; P = 0.06). 36K and the FDA had also conducted their own meta-analyses, both of which were consistent with the findings in the Nissen and Wolski meta-analysis. 35In a concerned email to company executives on May 8, 2007, Moncef Slaoui, the head of research at GSK, spoke of the meta-analyses: p173) This press release is in rather obvious contrast to internal discussions.
Also of note, 27 of the 42 studies included in the Nissen and Wolski meta-analysis were unpublished but available to them as a result of litigation surrounding another drug manufactured by GSK (one of the 27 unpublished studies is also available through the FDA, as it was submitted to the FDA as part of the approval process for rosiglitazone). 368][39][40][41][42] The 2010 meta-analysis included 36 unpublished trials (again with one trial also being available through the FDA) and 20 published trials. 41The effect estimate for MI (OR, 1.28; 95% CI, 1.02 -1.63; P = 0.04) was similar, albeit somewhat less than that seen in the 2007 metaanalysis; with exclusion of the RECORD trial, the effect estimate increased (OR, 1.39; 95% CI, 1.02 -1.89; P = 0.04) and more closely approximated the 2007 findings. 36,37,41iefly, interim results from the RECORD trial (which was originally planned to run until 2009) were published in 2007 shortly after Nissen and Wolski's 2007 meta-analysis. 35,37However, it appears GSK made this decision unilaterally, as opposed to leaving that decision in the hands of the steering committee (SC). 35A GSK employee is also on record reiterating the force with which GSK would pursue the matter with the SC if necessary: p184) The SC was convinced, however, and the unplanned interim analysis was published.However, as the pre-publication manuscript was being sent amongst the primary authors, one author noted: "The HR ratio [sic] (and 95% CI) for MI in RECORD is not inconsistent with Nissen's -and he had more events; what's to stop him adding the events from RECORD to his meta-analysis and re-enforcing his view?" 35(p197) (note this is exactly what happened in the updated meta-analysis published in 2010).This same author also wrote in the same email: "[m]anuscript looks to me to play down 239% INCREASE in HF.p197) Though one is glad to see the concern about downplaying an increase in heart failure, the tone of the manuscript was still far too strong, as evidenced by the pre-publication editorial and peer review process.Though there is unavoidable uncertainty that accompanies interpretation of an unplanned interim analysis, the published data were not inconsistent with the 2007 Nissen and Wolski meta-analysis. 35,37,38However, the interim analysis was too underpowered to determine anything robustly, a fact that USSCoF documents suggest GSK knew. 35,37,38e peer reviewer plainly noted that the data "are inconclusive about the question of increased risk in the rosiglitazone arm," 35(p201) and an editor for NEJM noted: "This reviewer, along with other reviewers, asks that you modify the language in multiple locations in the manuscript to tone down your conclusions.This is especially important given that this is an unplanned interim analysis of an ongoing trial, a fact that introduces additional uncertainty.[39][40] A purportedly independent reevaluation of the RECORD trial cardiovascular outcomes data was also recently published by a team from the Duke Clinical Research Institute (DCRI). 42Although it essentially upheld the interim RECORD analysis, one notes that GSK was allowed to prepare the materials for the reanalysis, and "[d]espite a concerted effort to obtain additional information, only a modest amount of additional person-years of follow-up was obtained (328 person-years)" by the DCRI team, which was mostly "about vital status and not nonfatal MIs or strokes." 42(247)To give context, there were a total of 25,833 person-years of follow-up for mortality and 23,692 person-years of follow-up for the composite of cardiovascular death, MI, or stroke. 42e aforementioned role that GSK had in the DCRI team's analysis raises difficult questions.The DCRI team can only operate on the data to which they had access, which was overwhelmingly prepared and provided by GSK.Since Buse first raised concerns in 1999, the above seems to make it clear that GSK's history with rosiglitazone does not reflect one of scientific integrity or transparency.In its concluding remarks, the 2010 USSCoF document notes: "The totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public.Several years prior to Nissen's study, it can be argued that GSK was on notice that Avandia may have problems.Based on this knowledge, GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner.Instead, GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk.p15) Additionally, even if one were to accept the RECORD trial results, the 2010 meta-analysis by Nissen and Wolski that included the RECORD trial still stands, and there is still the concern over the increased incidence of heart failure in the RECORD data, so it remains clear the RECORD data ultimately do not resolve concerns about rosiglitazone.
In 2012, GSK officially pled guilty to, among other things, failing to report safety data about rosiglitazone to the FDA. 43e off-putting case of oseltamivir Feel sick yet?On July 14, 2009, Japanese pediatrician Keiji Hayashi astutely pointed out a problem with the then-current Cochrane review on oseltamivir (Tamiflu ® ) in healthy adults. 445][46] Hayashi requested the Cochrane group analyze all the data independently.][54][55][56][57][58][59][60] The BMJ's website also has extensive details, including a timeline and catalogued correspondence. 44,47,48Fiona Godlee (Editor-in-Chief of The BMJ), Tom Jefferson and Peter Doshi (two authors of the Cochrane review, with Jefferson as lead author), and others fiercely pursued the issue.As a result of this endeavor, The BMJ also ultimately started the "Open Data" campaign on October 29, 2012, with the first campaign being the "Tamiflu campaign." 47,48 late 2013, Roche finally made 77 minimally-redacted CSRs available to Jefferson and his colleagues, and they were subsequently able to undertake an unprecedented review of CSRs that required herculean effort.Their updated review on the effects of oseltamivir in healthy adults and children was finally published in 2014 (their designation of "previously healthy" allowed chronic illnesses such as asthma, diabetes, or hypertension, but did not allow conditions with greater potential to impact immune system functioning, such as malignancy or HIV). 59The review now summarizes 23 oseltamivir trials with 9,623 patients in total, and the results were not terribly flattering. 59 what almost seems to be an insultingly brief overview of the review, oseltamivir was found to reduce symptom duration by about 16.8 hours in adults (95% CI, 8.4 -25.1 hours; P < 0.0001), amounting to roughly 0.7 days (95% CI, 0.35 -1.05 days).In children, no beneficial effect was noted overall.When stratifying children by presence of asthma, children with asthma did not benefit, but otherwise healthy children experienced a reduction in symptom duration by about 29 hours (95% CI, 12 -47 hours; P = 0.0011), amounting to roughly 1.21 days (95% CI, 0.5 -1.96 days); however, the results in healthy children are based on a single trial with 669 participants, and the results in children with asthma are based on two trials with a total of 660 participants between the two trials.
The authors found no beneficial effect of oseltamivir on hospitalizations, serious complications (pneumonia was considered individually and will be discussed below), bronchitis, sinusitis, or otitis media.
Pneumonia was considered as an individual outcome.Noteworthy issues with pneumonia as an endpoint included it being a self-reported, investigator-mediated, unverified diagnosis, and the documentation was at times weakly regimented.However, with this understanding, the authors found that 100 adults would have to be treated with oseltamivir to prevent one case of pneumonia (number needed to treat to benefit one person [NNTB], 100; 95% CI, 67 -451; P = 0.02).
However, in the analysis limited to more detailed documentation of pneumonia (which had just over one-third the amount of patient data that the less specific documentation method had), no statistically significant benefit was found for prevention of pneumonia.No study reported the effects of oseltamivir on pneumonia confirmed by radiography (a rather notable shortcoming of the available trial data), and there was no apparent effect on pneumonia in children whatsoever.
For adult prophylaxis, the review found that oseltamivir helped reduce symptomatic influenza with an NNTB of 33 (95% CI, 26 to 55; P = 0.000091).Effects of prophylaxis specific to children are not reported.
Most admirably, those wishing to scrutinize the data for themselves have open access to the entirety of the data. 61The full Cochrane review is now freely available (in 2013, the Cochrane Collaboration committed to making its reviews open-access one year after they are published), and an abridged version of the review has openaccess availability as a separate article published in The BMJ. 59,62 An individual-patient-data meta-analysis (IPD MA) of nine Rochesponsored oseltamivir trials including 4,328 patients was published in The Lancet not too long after the updated Cochrane review was published. 63The primary outcome was reduction in time to alleviation of symptoms, and for the full intention-to-treat population, this outcome was a median of 17.8 hours (95% CI, 9.3 to 27.1 hours), which is quite similar to the respective findings of the Cochrane review.An intention-to-treat analysis limited to those with laboratory confirmation of influenza infection showed a slightly earlier time to relief of symptoms (reduction in time to alleviation of symptoms of 25.2 hours; 95% CI, 16.0 to 36.2 hours).Although this primary outcome was largely consistent with the findings of the Cochrane review, two other analyses were emphasized by the study's authors, and these findings were not consistent with those of the Cochrane review.First, in the intention-to-treat analysis limited to those with confirmation of influenza infection, lower respiratory tract infections "requiring" antibiotics were lower among those receiving osteltamivir, with an absolute risk difference of 3.8% (95% CI, 2.2% to 5.0%), translating to an NNTB of 27 (95% CI, 20 to 46).[66] (Acute exacerbations of chronic bronchitis sometimes do require antibiotics, but this is not what the authors reference in their metaanalysis.)Furthermore, given the aforementioned issues surrounding "pneumonia" as an outcome, one also has to question the rigor with which acute bronchitis was assessed.The same can be said for lower respiratory tract infections "requiring" antibiotics in general; indeed, there is no clear definition for this outcome, and there appear to have been no criteria met to confirm a bacterial infection or the "need" for antibiotics.Also in the population with confirmed influenza infection was an approximate 1.1% absolute risk difference (95% CI, 0.3% to 1.4%) for being admitted to the hospital for any reason, translating to an NNTB of 91 (95% CI, 72 to 334); however, the reasons for admission were reportedly too varied to detect any pattern.Here again, we seem to be lacking a desirable granularity in data (in spite of the IPD MA approach) and clarity in reporting.This IPD MA also found an increase in nausea (NNTH, 27; 95% CI, 16 to 55) and vomiting (NNTH, 21; 95% CI, 13 to 37), but no increase in neuropsychiatric outcomes.
Although IPD MA is a powerful analytical modality, this review is not as thorough or transparent as that of the Cochrane group.Additionally, one notes the Lancet IPD MA was, on the surface, funded by the independent Multiparty Group for Advice on Science (MUGAS) foundation (for example, this is the funding source reported in the abstract on PubMed); however, an unrestricted grant from Roche really funded the study.Although not transparently reflected on PubMed, this is admitted within the body of the meta-analysis (see the "Acknowledgements" section at the very end of the article and the "Role of the funding source" subsection at the end of the "Methods" section).The authors claim Roche merely provided funding and had no other involvement, but this still introduces an unavoidable degree of uncertainty, and this is not ameliorated by discovering that two of the four authors have significant conflicts of interest (with one of the authors being on the Board of Directors of Gilead Sciences, which, although not specified in the disclosures, holds the patent on oseltamivir).
Although the current Cochrane review on oseltamivir is unprecedented in scale and even some of its methodology (i.e.reviewing individual CSRs), it represents a collective concerted effort to summarize the best-available research literature on oseltamivir in an unbiased manner, and it unequivocally represents the most robust, complete, and transparent assessment of the clinical trial evidence on oseltamivir.
Putting that aside, the deeply troubling and more important observation -which is seen in the research providing an overview of these issues [1][2][3][4][5][6] and which speaks to the core of this entire writingis the utter lack of full publication and transparency.Hayashi made his critique in 2009.The updated review could not be published until 2014 despite continual intensive efforts to gain access to the requisite data.
This is a problem.
2][3][4][5][6] These symptoms signify a grave illness in medicine, one that can only be corrected with a unified effort to provide the remedy.

Conclusion
8][69][70][71][72] Similarly, ClinicalTrials.gov4][75][76][77][78][79][80][81][82][83][84][85][86] On the surface, the changes are desirable, as they call for an expansion in what exactly must be reported.[75][76][77][78][79][80][81][82][83][84][85][86] On the other hand, the AllTrials initiative (www.alltrials.net)8][89] It is being led in the U.S. by Dartmouth's Geisel School of Medicine and the Dartmouth Institute for Health Policy and Clinical Practice, with the official launch in the U.S. occurring just this year in late July. 87][92] The Institute of Medicine (IOM) and World Health Organization (WHO) also recently made explicit calls to improve these issues. 93,94he remedy is long overdue, and we owe it to patients to come up with that remedy.Although this "case series" focuses heavily on industry (and with due cause), it must be noted that industry is not the only party at fault here; indeed, although not a novel finding, even the most recent appraisal of the failure of ClinicalTrials.govand the FDAAA of 2007 shows that studies funded by governmental or academic institutions also suffer greatly from publication bias. 82mportantly, the AllTrials initiative, the activities of The BMJ, the RIAT initiative, and the calls of the IOM and WHO are not simply glittering generalities that ultimately lack substance -they all make concerted efforts to meaningfully address the issues, and contained within these efforts are suggested remedies.However, in order for these issues to be resolved, we still desperately need a unified voice from those within the scientific and medical community, and those outside the medical and scientific community should be a part of this as well.Publication bias and inadequate research transparency are scientifically and medically reprehensible and in violation of the basic ethical principles set forth in the World Medical Association's Declaration of Helsinki. 95These issues have existed and gone unfettered for far too long.It is time to change that.

Competing interests
Truly none, but in the interest of full disclosure, I am a current member of the U.S. Board of BMJ Fellows.I do not receive any compensation from The BMJ or anyone else as a result of this.I disclose this here since this article cites works published in The BMJ and ultimately draws attention to their efforts in combating issues with publication bias and inadequate research transparency.

Grant information
The author declared that no grants/funding were involved in supporting this work.The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias You can publish traditional articles, null/negative results, case reports, data notes and more The peer review process is transparent and collaborative Your article is indexed in PubMed after passing peer review Dedicated customer support at every stage For pre-submission enquiries, contact research@f1000.com

3 AFigure 1 .
Figure 1.Graphical representations of studies and study data concerning antidepressants as submitted to the FDA versus studies and study data appearing in the peer-reviewed literature.All graphs were created using data from Turner and colleagues' 2008 publication.Percentages are rounded to nearest tenth of a percentage point.13 21

Figure 2 .
Figure 2. A sampling of internal company memos and emails concerning gabapentin (Neurontin ® ) that became available to the public as a result of litigation over fraudulent sales practices in the marketing of gabapentin.These and other documents are provided in the open-access Trials article and the associated additional file.Page numbers provided with the images shown here are for the supplemental file. 16 you want to describe the results and we'll incorporate this into the poster.

Figure 3 .
Figure 3. Sampling of internal company documents that are now a matter of public record after being unsealed by a federal judge as part of a securities fraud case against the parent company of celecoxib.The items above show content regarding strategic planning on what would be done with the celecoxib data based on the favorability of the results and a research director's response after learning that a symposium offered during a medical conference claimed the CLASS trial demonstrated celecoxib's superior gastrointestinal safety profile compared to nonselective NSAIDs. 27,28 27(p8507)AThanks.They swallowed our story, hook, like and sinker... Samuel H. Zwillich Clinical Research / CRAII B 28(p9041) /2001 08:08:18 (GMT-05:00) Marty There was no Avandia v Actos study performed in exSB.Study 175 was an Actos only study performed to give us enough info using historical comparison to make a decision about large scale H-H.This was done for the US business, way under the radar and we lost both in terms of LDL and Tgs.Per Sr Mgmt request, these data should not see the light of day to anyone outside of GSK.

AFrom:BFigure 4 .Forwarded
Figure 4. Sampling of internal company documents that are now a matter of public record (after being released by the U.S. Senate Committee on Finance) discussing rosiglitazone (Avandia ® ). 34H-H indicates head-to-head trial; RSG, rosiglitazone.The images from pages 21 and 22 are from a consecutive email chain.

Table 2 . Crude incidence rates for clinically-significant upper gastrointestinal event (CSUGIE) plus symptomatic gastroduodenal ulcer not resulting in a CSUGIE (GDU) seen in the FDA documentation for the pooled data from N49-98-02-035 and N49-98-02-102. 19-21
g. double-blind in CONDOR versus open-label with blinded outcome assessment in GI-REASONS, fixed-dose and fixed-drug comparison in CONDOR versus clinician-determined dosing and allowance for use of and switching between different nonselective NSAIDs in the nonselective NSAID group in GI-REASONS) and patient population (e.g.exclusion of patients who tested positive for Helicobacter pylori in CONDOR versus allowance of such patients in GI-REASONS).Still, perhaps the most salient and troubling feature is that no trial has ever continued long enough to resolve lingering uncertainties raised by the full dataset behind the CLASS trial regarding the long-term assessment of celecoxib compared to nonselective NSAIDs, and simply meta-analyzing the available trials cannot resolve this uncertainty, either.Finally, all of these trials had significant conflict of interest with respect to trial funding from the parent company for

Table 4 . Event rates from the GI-REASONS trial for the primary composite outcome and its components. 31
Identical rates for the following components of the primary composite outcome: SB hemorrhage; SB obstruction; GD, SB, or LB perforation Data presented are number (percentage) of patients in each group and come from Table1from the GI-REASONS trial.

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