American Healthcare Giant J&J Stonewalling in Australia: Transvaginal Mesh

Exposed: how Johnson & Johnson cut its risk in vaginal mesh lawsuit.

July 20, 2017  FiDA highlight

* The world’s biggest healthcare group has quietly cut its exposure to victims in its vaginal mesh class-action lawsuit.

* Seven Johnson and Johnson subsidiaries are in breach of the Corporations Act.

* With no explanation, J&J and its auditor PwC reduced accounting disclosures and transparency.

The 700 women suing Johnson and Johnson for faulty vaginal mesh implants will not be pleased to hear that the healthcare giant has quietly reduced its exposure to medical negligence lawsuits.

Buried in Johnson and Johnson’s disclosures to the corporate regulator is a letter from the group’s lawyers King & Wood Malleson to the corporate regulator which shows a Deed of Cross Guarantee between seven of the group’s subsidiaries has lapsed. By allowing the Deed to lapse, the company has effectively reduced the pool of assets which creditors can access in a legal claim.

Previously, this Deed had ensured that the seven Johnson and Johnson companies had, until this year, guaranteed each others’ debts. This no longer appears to be the case. In the event therefore of a successful class action lawsuit, a claim potentially worth hundreds of millions of dollars, the 700 women may have less access to the assets of the world’s biggest healthcare company.

The company, whose market value in the US is $US370 billion, refused to respond to questions for this story. Communications director Meshlin Khouri claimed, “We are endeavouring to respond to your questions in the timeframe that you’ve requested …”.

We extended the timeframe and Khouri failed to respond to all questions. Gavin Fox-Smith, managing director of Johnson and Johnson Medical Australia/NZ was approached for comment but also declined to respond.

Johnson and Johnson is being sued in a class action lawsuit in the Federal Court. The plaintiffs claim faulty pelvic implants have caused them debilitating pain and that Johnson and Johnson failed to properly test the devices. The case is expected to run for six months. It follows a successful class lawsuit last year in which a $250 million settlement was struck with victims of faulty Johnson and Johnson hip implants.

An analysis of ten years of Johnson and Johnson financial statements shows a swathe of irregularities. Unlike its Big Pharma peers Abbvie and Gilead, Johnson and Johnson pays a reasonable amount of tax. Over ten years, the company racked up $12 billion in revenues and paid $238 million in income tax. In comparison to aggressive transfer pricing culprits Gilead and Abbvie, Johnson and Johnson showed gross margins of 40 per cent in Australia over the period; an indication that it is not pillaging the Australian tax base quite as aggressively as its peers.

However, enshrining the trend towards increasingly shoddy accounting and poor financial disclosure by multinational companies and their Big Four auditors – PwC, Deloitte, KPMG and EY – the financial statements of Johnson and Johnson are littered with faults.

For a start, its seven subsidiaries which had been covered by the aforementioned Deed of Guarantee, have failed to file accounts and are now two and a half months late. We can safely assume that the Australian Securities & Investments Commission (ASIC) has failed to fine the company for these myriad breaches.

Without any explanation by its directors or by its auditor PwC, Johnson and Johnson quietly changed from lodging General Purpose financial statements to the inadequate and skimpy Special Purpose variety in 2009.

Here is a company therefore which deems there are no other “users” of its financial statements than its parent company in New Jersey. Here is a company, the world’s largest healthcare group, an institution which has attracted billions of dollars in taxpayer support from Australia’s Pharmaceutical Benefits Scheme, but which deems that no other party apart from its parent company could be interested in its financial statements.

That is, directors and their auditors at PwC deem the victims of Johnson and Johnson lawsuits, the company’s staff, its creditors and the taxpaying public which subsidises the PBS – none of these stakeholders are deemed to have any interest in its financial statements.

PwC, which cooly picked up $6.6 million over the decade for audit and tax advice can’t even get its numbers straight. According to its “Auditors’ Remuneration” note, PwC earned $1.07 billion in audit fees over the past two years, rather than $1.07 million.

Moreover the accounts are larded with completely spurious information about accounting policies relating to items which don’t exist. All this mirrors a systemic failure: a failure of the Australian Accounting Standards Board (AASB) a failure of successive governments and their Ministers for Finance, a failure of accounting peak bodies, a failure of ASIC to police the sector and above all a failure of the global accounting firms to which all these governments, agencies and peak bodies kow-tow.

If the government really had the backbone to fix this problem it could instruct ASIC to issue a guidance note requiring all foreign multinational companies to lodge General Purpose financial statements. This damaging failure of accountants to be accountable could be fixed in a week. Instead, the world’s largest companies operating in Australia, jagging billions in taxpayer subsidies, file inadequate financial statements which allow them to hide critical information and avoid tax.

michaelwest.com.au has been sponsored by GetUp! and the Tax Justice Network to conduct an investigation into the financial statements and tax affairs of 20 multinational companies. 

https://www.michaelwest.com.au/exposed-how-johnson-johnson-cut-its-risk-in-vaginal-mesh-lawsuit/

Surgical Mesh Lawsuits Proliferate as Industry Suppresses Patient Outcome Harm

The Truth Behind Transvaginal Mesh Litigation: Devices, Timelines, and Provider Characteristics.

Souders CP1, Eilber KS, McClelland L, Wood LN, Souders AR, Steiner V, Anger JT.

Female Pelvic Med Reconstr Surg. 2017 Jun 27. doi: 10.1097/SPV.0000000000000433. [Epub ahead of print]

Abstract

OBJECTIVES:

Following Food and Drug Administration communications about the safety of transvaginal prolapse, more than 73,000 patients with complications from treatment of pelvic organ prolapse (POP) or stress urinary incontinence (SUI) have filed product liability claims. This research analyzes the transvaginal mesh claims filed in the United States to identify key characteristics that may inform clinical decision-making.

METHODS:

We evaluated a 1% random sample from the Bloomberg Law Database: 2000 to 2014 and associated legal documents. Outcomes and measures used included annual rate of claim, mesh type, time interval between surgery and claim, defendants, and surgeon training.

RESULTS:

The search returned 76,865 results, and 2979 were excluded, leaving 73,915 claims. Of 739 claims (1%), 63.3% involved slings for SUI, 13.3% mesh for POP, and 165 (23.2%) involved both. The mesh named most often in claims was retropubic slings at 30.3% and transobturator slings at 27.1%. The number of cases filed increased significantly from 730 in 2011 to 11,798 in 2012, which then almost tripled in 2013 to 34,017. The interval from surgery to claim filing ranged from 4.8 to 5.3 years. Only 12% of implanting surgeons were or became board certified in Female Pelvic Medicine and Reconstructive Surgery. Only 4 cases named providers as codefendants.

CONCLUSIONS:

Most legal claims involved slings for SUI and began after the 2011 Food and Drug Administration communication about mesh for POP. The rise in lawsuits does not reflect the acceptably low complication rates for slings for SUI reported in the literature.

PMID: 28657986 DOI: 10.1097/SPV.0000000000000433

Pelvic Surgical Mesh: "Living in Hell"

Western Australian pelvic mesh victims criticise government response to scandal

Joanne McCarthy

21 Jul 2017, 1 p.m. FiDA highlight

• Women call on WA Health Minister to order investigation into mesh surgery research

Women allege they were used as guinea pigs in pelvic mesh trials in WA public and private hospitals

SUE Turner and Jeanette McKinnon are the Western Australian women implanted with pelvic mesh devices in public hospitals who refuse to be regarded as unfortunate statistics.

They have made submissions to a Federal Parliament Senate inquiry into pelvic mesh – with a public hearing in Perth on August 25 – listing serious, permanent and life-altering consequences of their surgeries more than a decade ago.

They want answers from WA Health Minister Roger Cook about mesh research allegedly conducted in public hospitals, and whether they are included in mesh trials for which they say they did not consent.

They are scathing of Mr Cook’s commitment to “make some enquiries” about the alleged mesh research trials, in response to questions from Fairfax Media, and have called for a full investigation into whether women were used as “mesh guinea pigs” in public health facilities.  

“Something awful happened to me in 2004 and 2005 after I had mesh put into me. My world’s just so small now,” said Mrs McKinnon, who was 46 in 2004 when she was implanted with an Australian-developed pelvic mesh device at Bentley Hospital.

“It’s like living in hell. I’m dying a very slow and agonising death.”

Victorian Senator Derryn Hinch in February successfully argued for a Senate inquiry into how some pelvic mesh devices for women’s incontinence and prolapse problems after childbirth were cleared for use in Australia over the past two decades. He compared pelvic mesh products to Thalidomide, the drug that led to birth defects in babies in the 1960s.

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(Video on link.) Senator Derryn Hinch calls for a Senate inquiry into pelvic mesh.

The aggressive marketing of many mesh devices in Australia from 2003, without sufficient evidence of their safety and efficacy, led to “one of the greatest medical scandals and abuses of mothers in Australia's history,” Senator Hinch said in a speech to Parliament.

Nearly 200 Western Australian women have responded to a survey conducted by Victorian consumer health advocacy group, Health Issues Centre, for a submission to the inquiry representing the experiences of more than 2200 Australian women implanted with pelvic mesh devices.

More than 700 women are part of a current class action against major pelvic mesh manufacturer, Johnson & Johnson, in the Federal Court in Sydney.

Sue Turner, of Perth, has sought legal advice about a class action against an Australian manufacturing company, after she was implanted with an Australian-developed pelvic mesh device at Armadale Hospital in 2007.

“I was never told the device was high risk. I was never told about trials. I would never have consented to being part of a trial.

- Sue Turner, who had pelvic mesh surgery in 2007.

”

“I had a prolapse. I just trusted the doctor and our health system when he told me it would be a pretty easy fix,” Mrs Turner said.

“I was never told the device was high risk. I was never told about trials. I would never have consented to being part of a trial. If I was told there was a risk that if things went wrong I would never have a sex life again, or live a life of sometimes unendurable pain, or be left with mesh and anchors in my body that have moved and embedded into tissue very close to major blood vessels and nerves, I would never have consented. But I wasn’t told.”

In a statement to Fairfax Media Mr Cook said he would ask the Department of Health to “make some enquiries into the research undertaken, and the cases where the implants have been used”, after two senior Western Australian doctors released a series of papers from 2005 about trials in Western Australian public and private hospitals, including Armadale Hospital, using the Australian-developed pelvic mesh device.

In a statement by a WA Health Department unit, Fairfax Media was advised there are no records of research approvals for trials involving surgery on women at public hospitals using the Australian-developed pelvic mesh device.

Mrs Turner and Perth-based Australian Pelvic Mesh Support Group founder Caz Chisholm were angered by Mr Cook’s statements that the “WA Government understands the concern this has caused for some patients”, but “there have been very few complaints received by WA Health and the Health and Disability Complaints Office”.

“What are we? Guinea pigs?” Mrs Turner said.

“I want this stuff out of my body but my doctor’s told me the surgery could be life-threatening. This isn’t about numbers. It’s about how our health system allowed these devices onto the market, and how these doctors were allowed to do this surgery in public hospitals without telling us of the risks.”

Ms Chisholm said the lack of complaints was a consequence of women being told for years that their chronic problems, including often debilitating pain, repeated serious infections, and erosion of mesh into organs including the bladder and bowel, were not linked to mesh surgery, or not being told they were implanted with mesh.

“Many women who have presented to their doctors with pain and complications have been told it is not the mesh that is the cause.

- Australian Pelvic Mesh Support Group founder Caz Chisholm

”

“Many women who have presented to their doctors with pain and complications have been told it is not the mesh that is the cause. It is only because of recent media attention about stories of women's pain and complications that women are realising their own complications are identical to the media stories,” Ms Chisholm said.

“The minister says there have been very few complaints by women, but what about the doctors treating the women? Obviously doctors aren’t reporting complications either, and are they supposed to?”

Mrs McKinnon has spent more than a decade on antibiotics.

“I came out of hospital not very well in 2004 and had my first urinary tract infection shortly after that. Then it was one urinary tract infection after another. If I come off the antibiotics I get a urinary tract infection,” she said.

She had another four major surgeries over the following year to relieve the pain and address mesh erosion into organs. 

In 2009 Mrs McKinnon was diagnosed with the auto immune condition lupus, requiring steroid treatment.

“I was normal, healthy and fit before I had that surgery. I’m only 59 and I feel like a 100-year-old. I thought all these years it was just me. It’s just the nightmare that you live.”

In a statement in June the Royal Australian College of Obstetricians and Gynaecologists said the majority of women treated with mesh for incontinence or prolapse had “a good long-term result” but “in a small number of cases the complications have been very serious”.

In a submission to the Senate inquiry Victoria’s Health Issues Centre chief executive Danny Vadasz has criticised mesh debate “framed in terms of the good outcomes of the many outweighing the unfortunate experiences of a few”.

“Our health system is built on values such as equity and a universal duty of care, not on a cost/benefit analysis that accepts the unavoidability of collateral damage,” he said, in a Health Issues Centre submission arguing Australian regulators have been “asleep at the wheel” on pelvic mesh.

Do you know more? Email jmccarthy@fairfaxmedia.com.au

http://www.theherald.com.au/story/4804268/its-like-living-in-hell/

FDA and Pharma/Device Industry: Where is the Integrity? The BMJ Inquires!

Big data’s big bias: bringing noise and conflicts to US drug regulation

Published 18 July 2017 (FiDA highlight)

• Jeanne Lenzer, associate editor, The BMJ, USA

• jlenzer@bmj.com

A little known private foundation to support FDA’s “regulatory science” takes money out of the FDA’s coffers to support analyses using levels of evidence recommended by industry; many of the foundation’s directors have financial links to the drug and device makers that the FDA regulates. 

Big data can be used cautiously to examine real world outcomes and to improve surveillance of drug safety. For example, it has been used to identify overuse of some interventions and can show drug and device complications in real world settings rather than idealized controlled trials.12 However, big data are a noisy mess, and analyses by entities with profit motives may identify spurious associations that support fast track approvals and indication creep (broadening the indications for drugs and devices).

The Reagan-Udall Foundation curates real world evidence or “big data” derived from routinely collected health data from insurance claims, electronic health records, voluntary registries, and social media. The US drug and device regulator, the Food and Drug Administration, says that such data can speed up research, “saving time and money” for “therapeutic development, outcomes research [and] safety surveillance.”3

In January, Robert Califf, then FDA commissioner, announced the launch of Innovation in Medical Evidence Development and Surveillance (IMEDS), a foundation project that he said would collect and analyze big data to identify “important safety issues.”4

However, critics of the move say that big data are poor for identifying adverse events and the system may expose patients to overtreatment and associated harms. Financial conflicts of interest, they worry, could influence the way big data are used, including exploitation of the weaknesses inherent in observational data to win FDA approval for new uses of drugs and devices and to exonerate drugs of previously detected harms. There is evidence and precedent to support both concerns (box).

No drug risks identified

IMEDS aggregates data from millions of patients mostly through the FDA’s Sentinel system, which was set up to identify and analyze safety problems.5 Public and private researchers can access these data to search for safety signals and other information.4

But claims data and routinely collected electronic health record data are not structured for research purposes, and researchers report that recognition, collection, reporting, and reproducibility of adverse events are unreliable at best.5678910

In 2015, drug safety experts reviewed various big data projects, including the FDA’s Sentinel. They reported that the projects have “proved largely unable to provide credible evidence of new, unsuspected drug adverse effects” and that six years after Sentinel was launched it “has not yet been the primary data source in identifying a single new drug risk that led to a significant regulatory action such as a drug withdrawal, boxed warning, restriction or contraindication.”11

Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, confirmed in January 2017 that Sentinel has not identified any important safety signals to date. “What it has done,” she emphasized to The BMJ, “is evaluate signals from the spontaneous reporting system (for example, excess bleeding with dabigatran) and shown that it was due to stimulated reporting, not a real increase in bleeding. This type of study would have taken a long time using traditional methods.”

But the analysis cited by Woodcock conflicts with the results of other studies that would be unaffected by “stimulated reporting,” some of which found excess bleeding events with dabigatran compared with warfarin, especially at higher doses. Nor was the finding supported by a later FDA analysis.12

Reagan-Udall Foundation

Congress established the Reagan-Udall Foundation in 2007 in response to a damning report by the Institute of Medicine (IOM), which found that the FDA was seriously underfunded and understaffed, with “serious scientific deficiencies.”13 The institute concluded that “product dangers are not rapidly compared and analyzed” and that performance measures used by the FDA, “such as time to review a new product application,” can create pressures that “lead to unintended consequences, such as worse drug safety.”

The IOM recommended that Congress double its funding of the FDA and increase staffing to reduce workload and time pressures. However, the FDA’s budget rose just 19% in inflation adjusted dollars from 2006 to 2016.14 In addition, Congress stipulated that the FDA must contribute $500 000 to $1 250 000 annually to the newly formed foundation, which also receives industry funding.

The foundation was controversial at the outset15161718: critics warned that allowing a quasi-regulatory agency to receive funding from companies regulated by the FDA poses a threat to its integrity; some called it “little more than a front” for industry.16

Watchdog organizations such as Public Citizen, Science in the Public Interest, Health Care Renewal, and the Union of Concerned Scientists warned that mixing industry interests with a regulatory agency would tend to promote the interests of funders and could weaken protections for the public.

Woodcock told Associated Press in 2007 that although the FDA will suggest various research projects, “as with any foundation, the donors will have the primary say over how the funds are used.”15

Directors’ ties to industry

Mark McClellan, FDA commissioner under the George W Bush administration and the first chair of the Reagan-Udall Foundation’s board, promised that strict conflict of interest rules would protect against bias: the foundation’s bylaws state, “No more than four members of the 14 member board of directors shall be representatives of FDA regulated industries.”19

However, there are currently 13 board members, and nine have or had financial ties to industry at the time of their appointment to the board. For example, many of the members hold or held leadership and top scientific positions at industries regulated by the FDA. These include Mark B McClellan, director at Johnson & Johnson; Pamela G Bailey, former chief executive of AdvaMed, the medical device industry’s trade association, and current chief executive of the Grocery Manufacturers Association; Kay Holcomb, senior vice president for science policy at the trade association BIO (Biotechnology Industry Organization); and Garry Neil, chief scientific officer for the drug company Aevi Genomic Medicine.

Board members file conflict of interest forms with the foundation, but the forms are not available on the foundation’s website, and the posted profiles don’t always reveal members’ financial ties. For example, the profile for Mark B McClellan, who serves as the board’s liaison to IMEDS, mentions his academic ties but not that he is a director at Johnson & Johnson and Renova.

Panel stacking

In addition to the number of board members with current or former financial ties to industry is the problem of “panel stacking,” in which the composition of the body seems likely to predispose it toward a particular outcome.20 Ellen Sigal, the foundation chair, has urged deregulation21 and has praised President Donald Trump’s choice of Scott Gottlieb to head the FDA. Gottlieb has long supported deregulation of the FDA and was paid at least $413 000 from multiple drug and medical device companies, largely for consulting and speaking fees, between 2013 and 2015.22

Another director, Allan Coukell, is also vice chair of the board of the Medical Device Innovation Consortium, a public-private entity that has a goal of “collaborating on regulatory science to make patient access to new medical device technologies faster, safer, and more cost-effective.” Coukell testified in a 2015 FDA hearing that industry funding of the FDA through the Prescription Drug User Fee Act “has been a success” by shortening review times and increasing the agency’s capacity to evaluate new medicines. He called for more investment in “regulatory science” and recommended that this be part of future user fee agreements.23

Panel stacking generally occurs when a panel chair or officer with financial conflicts appoints panelists who are not representative of the scientific community but instead are known to espouse a position favored by industry. Former FDA commissioner Andrew von Eschenbach appointed the Reagan-Udall Foundation’s original board members in 2008, when he also triggered controversy by intervening on behalf of industry regarding FDA scientists’ objections to the collagen meniscus implant Menaflex.2425 After leaving the FDA, von Eschenbach became a director at the drug companies BioTime and Viamet.

Funding the foundation

Between 2009 and 2013 the Reagan-Udall Foundation reported $6 429 028 in revenue. About 22% was from the FDA, 39% from “industry,” and 38% from not-for-profit entities.26 However, the not-for-profit organizations include industry trade associations such as the Pharmaceutical Research and Manufacturers of America (PhRMA) and the PhRMA Foundation, which are wholly or partially funded by industry.

One major not-for-profit contributor, the Bill and Melinda Gates Foundation, has attracted criticism for its investments in the agricultural biotechnology company Monsanto and ties to pharmaceutical companies; its lack of accountability to the public; and for hiring Tadataka “Tachi” Yamada, who was then the head of research and development at GlaxoSmithKline (GSK).27282930 Yamada was one of von Eschenbach’s first appointments to the Reagan-Udall Foundation board, and a US Senate committee investigation concluded in 2007 that, while at GSK, Yamada played a key role in intimidating and silencing the prominent diabetes researcher John Buse, who reported excess cardiovascular events associated with the GSK drug rosiglitazone (Avandia).31

Although the Reagan-Udall Foundation is a public charity, partially funded by taxpayer dollars, June Wasser, its executive director, told The BMJ that the foundation is “an independent non-governmental non-profit [that] does not fall under the jurisdiction or authority of any government agency.” This means it is not subject to US Department of Health and Human Services requirements that users of public data must use the data in the public interest, and that the data must not be used primarily for commercial purposes.32

Nor is access to the data free. Wasser said the cost of IMEDS queries “depends on the size and complexity of the study and typically costs hundreds of thousands of dollars,” a price that will be within the budgets of industry but not feasible for community doctors or independent academics.

Funding IMEDS

The Reagan-Udall Foundation’s IMEDS project was separately funded exclusively by nine drug companies, which jointly contributed $3.2m in 2013, the project’s first year of development before official launch in 2017; from 2014 through 2016, drug companies contributed an additional $7.17m, Wasser told The BMJ via email. As it is a non-profit foundation, manufacturers can write off their contributions as charitable donations.

The IMEDS steering committee has six voting and two non-voting members; the steering committee chair, Marcus D Wilson, is also president of HealthCore, a for-profit corporation that describes itself on its website as a “subsidiary of Anthem, Inc, with a first of a kind, large, integrated database and deep understanding of the complexities and nuances of big data.” HealthCore partners with Pharmaceutical Product Development, a global contract research organization, to “help biopharmaceutical clients demonstrate more quickly and cost-effectively how their products will perform and benefit patients in the real world.”

Wilson indicated that he has no financial interests related to any business regulated by the FDA on his conflict of interest form. However, HealthCore is an IMEDS “data partner,” and as such, IMEDS pays for HealthCore’s services. Wilson’s simultaneous roles as chair of IMEDS and president of HealthCore might seem then to pose a conflict of interest.

Elizabeth Andrews, cochair of the IMEDS steering committee, serves as a consultant to “multiple pharmaceutical companies” through her contract research organization, RTI International, and previously was “vice president of worldwide epidemiology at a large pharmaceutical company.”33 Patrizia Cavazzoni, senior vice president for development operations at Pfizer, has held “leadership positions within the R&D organizations at Eli Lilly and Sanofi.”33 Michael Rosenblatt, who served on the IMEDS steering committee from its inception in 2013 until late last year, was chief medical officer at Merck during his tenure with IMEDS.33

Reagan-Udall has issued statements that it protects against “conflicts of interest and undue influence” by ensuring that “an employee or director does not participate in matters in which such a conflict would or could exist,” and that they will be “transparent” in all matters.

Nonetheless, Wilson declined to answer any questions from The BMJ about the financial relations between HealthCore and IMEDS. For Reagan-Udall, Wasser said that details about payments from the foundation or IMEDS to HealthCore “are confidential under the terms of our contract.”

Despite its status as a public charity, supported in part by taxpayer money, the foundation is not subject to Freedom of Information Act requests. The FDA responded to a freedom of information request from The BMJ, stating that it was “unable to locate any records” in relation to contract information between IMEDS and HealthCore.

Light touch FDA

President Trump and the new FDA commissioner, Gottlieb, have promised to slash regulations for drug and device makers. Gottlieb has asserted that “The FDA’s caution is hazardous to our health” and said that the agency should stop burdening businesses with lengthy, expensive clinical trials that require control arms and clinical outcomes. Instead, he has recommended more use of surrogate endpoints and sometimes dropping control arms.34

Industry support of the 21st Century Cures Act, which allows the use of observational data and case reports to support regulatory decisions, represents a profound shift in FDA policy; now, instead of corporate influence being exerted on an individual product basis, the very nature of “scientific evidence” itself is under siege. Big data analyses promoted by a foundation so deeply enmeshed with industry, and by the industry backed 21st Century Cures Act, seems likely to worsen—not improve—drug safety.

Big data: inadequate and inaccurate

Many randomized controlled trials are too small to pick up relatively rare but serious adverse events, so it might seem logical that “big data” could provide better recognition. However, a recent study found that big data were less likely to yield adverse events than large randomized controlled trials with 4000 or more participants.35 This seems at least partly because of the unstructured nature of routinely collected data.

Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic, told The BMJ, “Claims data as a source for truth in science has been shown over and over again to be inadequate and inaccurate. The use of big data for regulatory purposes ignores unmeasured confounders and is no substitute for a well designed randomized controlled trial.”

Safety signals aren’t the only issue at stake: industry is promoting applications of real-world analyses for “precision medicine” and comparative effectiveness research.36 Yet, analyses of observational data often yield spurious associations—a problem that may be increased by orders of magnitude with big data because they allow researchers readily to test multiple hypotheses, increasing the likelihood of finding one or more associations to be “positive” simply because of the play of chance (that is, false positives).37

In a study involving 17 275 patients and 835 deaths that compared treatment effects on mortality using routinely collected data and subsequent randomized controlled trials, the authors reported that “real world data” analyses “showed significantly more favorable mortality benefits by 31% than subsequent trials (summary relative odds ratio 1.31 (95% confidence interval 1.03 to 1.65; I2=0%)).” The difference was apparent even with statistical attempts to reduce confounding bias in each of the observational studies.38

The overly optimistic results of real world data in effectiveness studies may stem from confounding by indication, publication bias, and immortality bias. John Ioannidis, professor of medicine and of health research and policy at the Stanford University School of Medicine and one of the authors of the study, told The BMJ that routinely collected data are more likely to yield “biased results,” and he is “very skeptical about using real world evidence to make licensing or guideline decisions.”

A pertinent example is the “Take 3” flu campaign by the Centers for Disease Control and Prevention, which urged the public to seek treatment with a neuraminidase inhibitor because, according to CDC director, Thomas Frieden, it can “saves lives.”39 The Take 3 campaign was funded by Roche, the manufacturer of the neuraminidase inhibitor oseltamivir. However, in 1999, the FDA had written to Roche telling the company to refrain from claiming the drug “saves lives” since randomized controlled trials had not proved that it reduced mortality or even the incidence of pneumonia. When questioned about his claim, Frieden said the CDC discounted a Cochrane meta-analysis that showed no benefit because Cochrane “limited” to RCTs only; instead, Frieden said observational data and case reports supported his claim that oseltamivir saves lives.394041

Footnotes

• Provenance and peer review: Commissioned; not externally peer reviewed.
• Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

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