Sidney Wolfe writes in the BMJ - AllTrials - Selective clinical trial reporting: betraying trial participants, harming patients

Reporting biases found in trials of cardiovascular devices

Reporting biases in published trials were first identified in 1986.1 Published randomized studies of combination chemotherapy compared with treatment with an alkylating agent as first line treatment for ovarian cancer showed a significant survival advantage for combination chemotherapy. Unpublished cancer trial registry data from the same studies, however, showed no such advantage.2 Similarly, in the treatment of multiple myeloma, registry data suggested a smaller survival advantage for combination chemotherapy (over prednisone and an alkylating agent) than the results of published studies. The author who reported the discrepancy concluded that his findings “demonstrate the value and importance of an international registry of all clinical trials.”1Subsequent evidence for biased and selective reporting included prompt or delayed publication depending on whether trial results were positive or negative3 and more favorable results and conclusions in published studies funded by industry than in those funded independently.4

The linked paper by Chang and colleagues (doi:10.1136/bmj.h2613) shows similar reporting biases in trials of medical devices.5 The authors found worrying differences between trial information submitted to the US regulator (the Food and Drug Administration) and trial information reported in medical journals. Among 177 studies of 106 high risk cardiovascular devices submitted to the FDA, fewer than half were published, and fewer than half the published studies (45%) reported primary results that precisely matched the results in submissions to the regulator. Among the published primary results, 11% (17) were judged to be “substantially different” from those submitted to the FDA. The authors concluded that “even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA.”5

Most studies of reporting biases have examined differences in efficacy between unpublished clinical trial data and journal publication data but evidence now exists of under-reporting of adverse events. A recent BMJ editorial cites “the growing body of research on reporting biases, which documents the gross under-reporting of adverse event data in such [medical journal] sources.”6

Unfortunately, selective reporting of clinical trial data in medical journals also extends to companies’ selective non-reporting of safety data to the FDA. In 2012, the US Department of Justice announced that “GSK [GlaxoSmithKline] has agreed to plead guilty to failing to report data to the FDA and has agreed to pay a criminal fine in the amount of $242,612,800 for its unlawful conduct concerning Avandia . . . The United States alleges that, between 2001 and 2007, GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends.”7

Efforts to increase the public availability of clinical trial data to prevent the serious public health consequences of overstating benefits and understating risks have triggered strong industry opposition. In 2012 the former executive director of the European Medicines Agency (EMA), Guido Rasi, committed the regulator to “proactive publication of clinical-trial data, once the marketing-authorisation process has ended.” He added “We are not here to decide if we publish clinical-trial data, but how.”8 Two pharmaceutical companies sued the EMA to prevent disclosure, and the EMA has watered down its original plans.9

Beyond adverse effects on patients of selective reporting in medical journals, the absence of publicly available data from clinical trials violates an important ethical principle of the Declaration of Helsinki: “Researchers have a duty to make publicly available the results of their research . . . Negative and inconclusive as well as positive results must be published or otherwise made publicly available.”10 Many people participate in research because they trust that the published results might improve the health of the general population.

Ignoring the Declaration of Helsinki, in 2013 the Pharmaceutical Research and Manufacturers of America (PhRMA) urged the US government to influence the European Union against the EMA’s data disclosure policy. In a letter to a US trade representative, PhRMA wrote that “Disclosure of companies’ non-public data submitted in clinical and pre-clinical dossiers and patient-level data risks damaging public health and patient welfare.”11

It is clear that the reverse is true. Non-disclosure is far more damaging. The letter of rebuttal from leaders of the high profile campaign for public registration and reporting of all trial results (AllTrials) reads,

 “The world is moving towards a recognition that hiding information about what was done and what was found in clinical trials is an abuse of trial participants’ trust and exposes patients to unnecessary harm.”12 

I, and many others, agree.

Notes

Cite this as: BMJ 2105;350:h2753

References

1. ↵

   Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986;4:1529-41.

   Abstract/FREE Full Text
2. ↵

   US Department of Health and Human Services: compilation of experimental cancer therapy protocol summaries. NIH publication, Government Printing Office, 1977-1983.

3. ↵

   Stern JM, Simes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997;315:640.

   Abstract/FREE Full Text
4. ↵

   Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2012;12:MR000033.

5. ↵

   Chang L, Dhruva SS, Chu J, Bero LA, Redberg RF. Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports.BMJ2105:350;h2613.

6. ↵

   Doshi P, Zito J, dosReis S.Digging for data on harms in duloxetine trials. It’s time for policy makers to get serious about drug related harms. BMJ2014;348:g3578.

   FREE Full Text
7. ↵
8. ↵
9. ↵

   Torjesin I. European Ombudsman ramps up action against European Medicines Agency over data transparency plans. BMJ2014;348:g3733.

   FREE Full Text

   http://www.bmj.com/content/350/bmj.h2753?

Doubts Raised About Off-Label Use of Subsys, a Strong Painkiller - NYT

Almost overnight, a powerful new painkiller has become a $100 million business and a hot Wall Street story.

But nearly as quickly, questions are emerging about how the drug is being sold, and to whom.

The drug, Subsys, is a form of fentanyl, a narcotic that is often used when painkillers like morphine fail to provide relief. The product was approved in 2012 for a relatively small number of people — cancer patients — but has since become an outsize moneymaker for the obscure company that makes it, Insys Therapeutics. In the last year, the company’s sales have soared and its share price has jumped nearly 270 percent.

Behind that business success is an unusual marketing machine that may have pushed Subsys far beyond the use envisioned by the Food and Drug Administration. The F.D.A. approved Subsys only for cancer patients who are already using round-the-clock painkillers, and warned that it should be prescribed only by oncologists and pain specialists. But just 1 percent of prescriptions are written by oncologists, according to data provided by Symphony Health, which analyzes drug trends. About half of the prescriptions were written by pain specialists, and a wide range of doctors prescribed the rest, including general practice physicians, neurologists and even dentists and podiatrists.

Photo

The drug is a narcotic often used when other painkillers don’t provide relief.

Interviews with several former Insys sales representatives suggest the company, based in Chandler, Ariz., has aggressively marketed the painkiller, including to physicians who did not treat many cancer patients and by paying its sales force higher commissions for selling higher doses of the drug.

Under F.D.A. rules, manufacturers may market prescription drugs only for approved uses. But doctors may prescribe drugs as they see fit. Over the last decade, pharmaceutical companies have paid billions of dollars to settle claims that they encouraged doctors to use drugs for nonapproved treatments, or so-called off-label uses, to increase sales and profits.

Drug-safety experts said the range of medical professionals who appeared to be prescribing Subsys was troubling, particularly given concerns about the widespread use — and abuse — of narcotic painkillers. In December, Insys disclosed that it had received a subpoena from the federal health department’s Office of the Inspector General for documents related to its sales and marketing practices. The company has said it is cooperating with the investigation.

Medicine aside, Subsys is, much as anything, a Wall Street story. The explosive growth of Insys was fanned first by Wall Street investors betting the company’s sales and share price would rise. Now, other investors are betting the stock will decline. Over the last week, shares of Insys have lost roughly a third of their value, after the arrest on federal fraud charges of a Michigan neurologist who was a top prescriber of Subsys. In a statement, Insys said it took patient safety seriously and was committed to working with doctors to ensure its products were used properly.

Drug-safety experts said it was crucial that products like Subsys be marketed responsibly because the drugs are powerful, and powerfully addictive.

“You’re essentially spreading the accessibility to a very potent, rapid-onset narcotic to a large number of people, and a number of them may get addicted,” said Dr. Sidney M. Wolfe, founder and senior adviser to the Public Citizen Health Research Group, a consumer organization.

Continue reading the main story

Oral fentanyl products like Subsys have a history of being broadly prescribed. In 2008, the drug company Cephalon pleaded guilty to a criminal charge and paid $425 million in fines for inappropriate marketing of its products, including Actiq, a fentanyl lollipop, which federal officials said was being promoted for a range of unapproved uses, including treatment of migraines.

In 2007, Cephalon sought approval from the F.D.A. to market a newer fentanyl product, a dissolving pill called Fentora, for use in people without cancer. At the time, F.D.A. officials cited data showing the product was already being widely used by noncancer patients and they later denied the company’s application. Cephalon was acquired by Teva Pharmaceutical Industries in 2011.

Dr. Margaret A. Hamburg, the F.D.A. commissioner, said the agency did not regulate how doctors practice medicine. Still, she acknowledged that the widespread prescribing of oral fentanyl products for off-label uses was troubling, especially given the agency’s efforts to restrict the use of fentanyl and other opioids in the face of painkiller abuse. In the case of products like Subsys, prescribers must undergo training about the drug’s risks, pass a test and register in a national database. Patients must sign an agreement with their doctor before being prescribed the drug.

“It is frustrating, and we are in a process of continually assessing how our approaches are unfolding in the real world,” Dr. Hamburg said.

Several doctors said products like Subsys, which is sprayed under the tongue, fill an important role for seriously ill cancer patients, who may need the drug if their condition worsens or if their standard painkiller regimen occasionally fails to work.

“You want it to work as quickly as possible,” said Dr. Joshua R. Wellington, a pain specialist at Indiana University Health University Hospital. He is a paid speaker for Insys and said he prescribed it only to cancer patients. “In my mind, that’s what sets it apart.”

Photo

Insys Therapeutics reported first-quarter sales of Subsys of $40.7 million, up from $9.7 million a year ago. CreditSamantha Sais for The New York Times

Still, Subsys has sold surprisingly well given the drug is approved only for cancer pain, and given that only a small number of oncologists, who are typically responsible for treating their patients’ pain, appear to be prescribing it. In addition to pain specialists and anesthesiologists, who together made up about half of all prescriptions, a significant number were written by neurologists and physical medicine and rehabilitation specialists, who often treat patients with a variety of pain conditions.

The former sales employees said that while the company targeted some oncologists, it placed more focus on high prescribers of competing products like Actiq and Fentora, regardless of whether those doctors treated cancer patients. They also said they were trained to mention the restriction to cancer pain at the beginning of the sales pitch and then to move on to a more general discussion of “breakthrough pain” in the doctors’ other patients.

Dr. Wellington said while he did not prescribe the drug off-label, he understood why some colleagues did. “Cancer pain is not a unique pain syndrome,” he said. “Pain is pain.”

Others disagreed.

Dr. Lewis S. Nelson, a medical toxicologist at the New York University School of Medicine, said such drugs might be appropriate for a terminally ill cancer patient, but fentanyl, like other opiates, carries a high risk of dependency. It can also cause respiratory distress — and death — if it is taken by people who are not using painkillers regularly.

“If you’re waiting to die, you should die in comfort and dignity,” Dr. Nelson said. “It’s very different than if you’re attempting to have a functional life, because these drugs are relatively incompatible with having a functional life.”

Continue reading the main story

At least part of Insys’s business strategy appears to rely on the assumption that patients will eventually need more of the drug, along with higher doses. Higher doses are more expensive than lower doses.

Comments from a Wall Street analyst underscore that view. “As Subsys grows more mature, we expect the number of experienced patients to grow,” Michael E. Faerm, an analyst for Wells Fargo, wrote last year in a note to investors. “As the experienced patients titrate higher, the average dose per prescription should increase.”

The former Insys sales representatives said they were paid more for selling higher doses.

Pratap Khedkar, who oversees the pharmaceutical practice at ZS Associates, a global sales and marketing firm, said such a practice was highly unusual because “most companies feel that is the doctor’s decision because it is very patient-specific.”

Many of the sales representatives were new to the pharmaceutical industry and were paid low base salaries, about $40,000 a year, compared with the industry standard of about $80,000, as an added incentive to rack up higher sales commissions, they said. Some said they were told they could make hundreds of thousands by selling aggressively.

Michael L. Babich, the chief executive of Insys, has attributed his company’s sales to its ambitious compensation structure. “We believe this is the most effective way to motivate our sales team,” he told analysts during an earnings call last fall.

On Tuesday, the company reported that Subsys sales continued to grow in the first quarter of this year, to $40.7 million, from $9.7 million a year ago.

Meanwhile, the company’s plans for Subsys are only just getting underway: Earlier this year, Insys announced that it intended to seek approval to market the product for a broader range of uses, including for children and burn patients, and to treat acute pain in emergency rooms.

http://www.nytimes.com/2014/05/14/business/doubts-raised-about-off-label-use-of-subsys-a-strong-painkiller.html?partner=socialflow&smid=tw-nytimesbusiness&_r=0

GSK Poland - Shelley Jofre writes in the BMJ

1. Shelley Jofre, BBC Panorama correspondent

1. shelley.jofre@bbc.co.uk

The company may have broken US and UK laws on bribery, says Shelley Jofre

GlaxoSmithKline (GSK) recently announced that by 2016 it will end direct payments to doctors for promotional talks and stop setting individual targets for its sales reps.1 The announcement by GSK, which last year made profits of £6.6bn (€7.9bn; $11.0bn), was broadly welcomed in an industry that has long been tarnished by accusations of corruption and aggressive marketing.

But just as Britain’s largest drug company attempts to rebuild its image, it has emerged that the company is now facing new allegations of bribery in Poland and Iraq.2 A BBC Panorama report, entitled “Who’s paying your doctor?,” has found that GSK is under investigation in Poland for allegedly bribing doctors there.

It’s alleged that GSK sales reps in the region of Lodz, Poland’s third largest city, paid doctors as recently as 2012 to boost prescriptions of some of the company’s best known drugs.

A spokesman for the Lodz public prosecutor’s office, Krzysztof Kopania, toldPanorama that one GSK regional manager and 11 doctors have been charged in connection with corruption allegations for offences committed in 2010-12.

One doctor has already admitted guilt, been fined, and given a suspended sentence. He told Panorama he took money but only under pressure from a GSK drug rep. The investigation is ongoing.

A former sales rep for GSK in Lodz, Jarek Wiśniewski, told Panorama that money from the company’s £1m annual marketing programme for GSK’s blockbuster asthma drug, fluticasone (which it markets as Seretide), was used to bribe doctors to boost sales of the drug.

“There is a simple equation,” Wiśniewski told Panorama. “We pay doctors, they give us prescriptions. We don’t pay doctors, we don’t see prescriptions for our drugs.”

Educational services

The whistleblower explained that the bribes were disguised as fees for “educational services.”

“We cannot go to doctors and say to them, ‘I need 20 more prescriptions’,” said Wiśniewski. “So we prepare an agreement for them to give a talk to patients—we pay one hundred pounds, but we expect more than a hundred prescriptions for this drug.”

Wiśniewski confirmed that the doctors understood clearly that they must produce a certain number of prescriptions in return for the money. It’s a bribe, he said.

The Polish investigation has established, independently of former employees, that contracts were signed and payments made to doctors in at least a dozen different health centres across the region of Lodz where there was no evidence that “patient education” had taken place.

The payments were often small by UK standards—according to the prosecutor most were for several hundred zloty, but some were for several thousands (100 zloty = £20 (€24; $33)). But for Polish doctors, who earn around £700 a month, the sums are considerable.

Another former GSK rep in Poland, who spoke to Panorama on condition of anonymity, confirmed the payments influenced doctors’ prescribing:

“This worked on the principle of a kind of obligation. The doctor feels obliged and he tries to a greater or lesser degree to fulfil that obligation. I think that—as with many colleagues—my feelings were very negative and unpleasant but such was the working culture. It is not easy to find a job.”

In response to Panorama’s questions about the case, GSK confirmed that it ran a programme in Poland in 2010-12 to help improve diagnostic standards and medical training for the benefit of patients with respiratory disease.

“[Some] sessions were delivered by specialist healthcare professionals who, based on contracts signed with GSK, received payments appropriate to the scope of work as well as their level of knowledge and experience. The provision of sessions under this programme was agreed with the Polish healthcare centres.

“Following receipt of allegations regarding the conduct of the programme in the Lodz region, GSK has investigated the matter, using resources from both inside and outside the company,” the company added. “The investigation found evidence of inappropriate communication in contravention of GSK policy by a single employee. The employee concerned was reprimanded and disciplined as a result. We continue to investigate these matters and are co-operating fully with the CBA [the anti-corruption bureau in Poland].”

GSK said it agreed that “there is a need to modernise interactions between the pharmaceutical industry and healthcare professionals to ensure patients’ interests are always put first and to eliminate even a perception of a conflict of interest. This is why we have made, and will continue to make, fundamental changes to our business such as opening up access to our clinical trial data, changing how we pay our sales representatives and stopping payments to healthcare professionals for speaking engagements and for attendance at medical conferences.”

Meanwhile, in Poland, doctors face jail sentences of six months to eight years if they are found guilty of giving or accepting bribes, and GKS’s Lodz manager faces one to 10 years if found guilty of bribery.

Wiśniewski first raised his concerns with his bosses at GSK in Poland in May 2011. He says they carried out an investigation, then he was moved to another department. In September 2012 he was eventually fired for “poor performance” even though he says he had been singled out as a high flier in previous years. He is now unemployed.

GSK did not respond to questions about how the Polish whistleblower was treated.

Cases in US and China

The details of the case emerge as GSK attempts to rebuild its image after pleading guilty in 2012 to criminal charges in the United States and paying $3bn (£1.8bn) in fines for promoting some of its best selling antidepressants for unapproved uses, bribing doctors, and failing to report safety data about its drug for the treatment of diabetes.3 The allegations dated to the mid-2000s, and Andrew Witty, who took over as chief executive in 2008, claimed the behaviour dated from a different era.

Similar allegations emerged last year in China, where authorities have accused GSK of funnelling substantial sums in expenses to doctors and officials in 2007-10 to encourage them to use its drugs. GSK’s funding for all advertising, promotional, and training activity in China during the relevant period was around ¥3bn (£288m; €350m; $483m). The extent to which this funding was used fraudulently remains under investigation. The company again said such behaviour was not sanctioned at a corporate level and that claimed senior executives of GSK China had “acted outside of our processes and controls.”4 GSK has said it is “cooperating fully with the investigation in China.”

The head of GSK China was replaced in 2013, and GSK has reportedly just sacked more of its Chinese staff.5

GSK confirmed recently that it is also investigating bribery accusations in Iraq.

Views from Public Citizen

But Sydney Wolfe, founder of US campaign group Public Citizen, is sceptical of GSK’s recent pledge to change its ways. He recently analysed all the fines paid out by the drug industry in the US over the past 21 years and says that GSK is a repeat offender that tops the list.6

“Glaxo was the number one with $7.6bn in these penalties and the number one company in the world in terms of total criminal and civil penalties. The penalties are not large enough to deter these illegal activities. They keep doing it over and over again, and in one year Glaxo makes more money in terms of profits than all the penalties they’ve paid over the 21 years.”

GSK challenged Public Citizen’s calculations, however, telling Panorama that they included $3.4bn, which was “not a penalty or a fine and did not relate to sales and marketing practises.” GSK said the sum was “from a resolution we reached in 2006 with the US Internal Revenue Service (IRS) to pay tax related to transfer pricing.”

If the new allegations are shown to be true, then GSK might have violated both the UK’s Bribery Act and the US’s Foreign Corrupt Practices Act (FCPA). In both countries it is illegal for companies based there to bribe government employees abroad. In the US, some drug companies have already paid out settlements after allegations they contravened the FCPA.

The Bribery Act came into force in the UK only in 2010, and there have not yet been any drug company prosecutions.

The US has taken a tough stance in recent years on drug industry corruption at home and abroad, making extensive use of whistleblowing legislation, which rewards employees who come forward with information about law breaking.

It was evidence from some of GSK’s former employees in the US that resulted in the $3bn payout in 2012. Blair Hamrick, a GSK sales rep in Colorado for seven years until 2002, told Panorama he often made large payments to doctors for “educational” talks that were, in reality, purely promotional:

“We would have these Continuing Medical Education programmes that would get CME credit for the doctors, and they were nothing but a commercial,” he said.

“There was what’s called an ROI analysis [return on investment] about six months after a specific speaker programme. So if we spent $5000 on a speaker and we spent $20 000 on tickets and food, that’s $25 000 invested. They would take all those physicians and they would track their prescription volume, and they would want to see an increase in prescriptions greater than $25 000 worth of business.”

Hamrick adds, “The abhorrent behaviour that was going on, it was not only condoned, but we were compensated heavily for doing it.”

GSK announced in December that it is going to scrap the link between its reps’ pay and drug sales targets globally by 2016.

A Washington lawyer who represented two other GSK whistleblowers, however, points out that this was something the company had already agreed to do in the US, as part of a Corporate Integrity Agreement drawn up during negotiations for the $3bn settlement.

Erika Kelton of law firm Philips and Cohen told Panorama: “There were prospective requirements for ongoing compliance that were imposed on Glaxo. In the past, GlaxoSmithKline had compensated sales representatives by paying them bonuses based on the amount of revenue that they generated. That kind of incentive compensation that’s geared to how much revenue you’re bringing in encourages off-label marketing, encourages borderline or over the line practices to get more sales.”

The latest allegations against GSK are likely to prompt further debate over how little is known about industry payments made to doctors in the UK, even if they are not breaking the law.

In the US, GSK was forced to detail exactly how much it pays individual named doctors, and the company’s payments to US physicians have since plummeted by 75%, from $56.7m in 2010 to $14.6m in 2013. A similar effect has been seen with many other drug companies that have been forced to publish such details in the US.

Since 1 April 2014, when the Sunshine Act came into effect, all pharmaceutical companies must now detail their payments to named physicians in the US. By contrast, drug companies in the UK have been obliged only since last year to supply an aggregate total. There is no way of finding out which individual doctors are being paid or how much.

The latest UK figures published by the ABPI (Association of the British Pharmaceutical Industry) on 3 April show that payments from the pharmaceutical industry to healthcare professionals last year totalled around £38.5m, roughly level with the previous year.

Stephen Whitehead, ABPI’s chief executive, told Panorama: “You need to work with healthcare professionals to get understanding of the new science coming through, and that is a legitimate relationship. What you need to have to maintain confidence in these relationships is absolute crystal clear transparency about the money that changes hands. Then let people make their own judgment as to whether they think that’s appropriate.”

Whitehead says the ABPI is committed to full disclosure of payments in the UK by 2016 and is currently developing a searchable, centrally hosted register for payments in collaboration with the medical community.

Timeline

• July 2012—GSK pleads guilty to criminal charges over its business in the US in the early 2000s and pays $3bn (£1.8bn; €2.16) in fines, the largest settlement ever involving a pharmaceutical company
• January 2013—First reports emerge that GSK faces allegations of widespread corruption in its Chinese workforce in 2007-10
• December 2013—GSK becomes first major drug company to agree to full disclosure of all its trial data.
• 2014—Allegations of bribery by GSK in Iraq (as recently as 2012) and Poland (in 2010-12) reported
• 2016—GSK to end direct payments to doctors for promotional talks and attending conferences and stop setting individual targets for its sales reps

Notes

Cite this as: BMJ 2014;348:g2768

Footnotes

• The Panorama programme “Who’s Paying Your Doctor?” it to be broadcast at 8.30 pm on Monday 14 April on BBC 1.

References

1. ↵
   Kmietowicz Z. GSK is to stop paying doctors to talk about its drugs and attend conferences. BMJ2014;347:f7579.

   FREE Full Text
2. ↵
   Glaxo investigates bribery accusations in the Mideast. http://online.wsj.com/news/articles/SB10001424052702303532704579476862300832806?mg=reno64-wsj&url=http%3A%2F%2Fonline.wsj.com%2Farticle%2FSB10001424052702303532704579476862300832806.html.
3. ↵
   Roehr B. GlaxoSmithkline is fined record $3bn in US. BMJ2012;345.e4568.
4. ↵
   Parry J. Head of GSK in China is replaced as details of fraud scandal emerge. BMJ2013;347.f4791.
5. ↵
   GlaxoSmithKline sacks some China staff for malpractice—source. Reuters, 2014. http://uk.reuters.com/article/2014/04/04/uk-gsk-china-idUKBREA330TA20140404.
6. ↵
   Almashat S, Wolfe S. Pharmacetical industy criminal and civil penalties: an update. Public Citizen, 2012. www.citizen.org/hrg2073,www.citizen.org/documents/20731.pdf.

http://www.bmj.com/content/348/bmj.g2768?sso=

Public Citizen Petitions FDA for a Black Box Warning on Testosterone Products

WASHINGTON - February 25 - Public Citizen today called on the U.S. Food and Drug Administration (FDA) to immediately add a black box warning about the increased risks of heart attacks and other cardiovascular dangers to the product labels of all testosterone-containing drugs available in the U.S.

The urgent petition is based on growing evidence of the risks of heart attacks and other cardiovascular dangers from many individual randomized studies going back as far as 2010 and a recently published overall analysis (meta-analysis) of 27 studies going back as far as 20 years. Although 13 of these studies, funded by the drug industry, collectively showed no increased risk, the 14 studies not funded by the industry collectively showed a highly significant increased cardiovascular risk.

More than five million U.S. prescriptions for testosterone products were filled in 2013. The most common of those, making up more than 90 percent of the testosterone prescriptions filled in 2013, include Androgel, Axiron, Testim and Fortesta.

The petition also was prompted by the most recent study, involving the experience of 55,000 men before and after starting testosterone. The risk of heart attacks among men 65 and older during the first three months of using the drug was twice the risk seen in the year before use. Further, the study found, for the first time, a 2.9-fold increase in heart attack risk among men under 65 with a history of heart disease who took testosterone.

The FDA-approved labeling for testosterone-containing products does not mention testosterone-induced cardiovascular risk.

Despite all of these studies, the FDA stated on Jan. 31 that it “has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death.”

“In the face of this accumulating evidence, this statement is reckless and is a betrayal of the FDA’s role as an agency in the U.S. Public Health Service,” said Dr. Sidney Wolfe, founder and senior adviser of Public Citizen’s Health Research Group. “It is quite clear that testosterone treatment increases the risks of cardiovascular diseases, including heart attacks.”

Although the FDA agrees that testosterone is “only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition,” the hyped-up nature of the low-T[estosterone] advertising campaigns, not adequately regulated by the FDA, assures that many men in the U.S. prescribed testosterone do not meet the FDA-specified criteria of both low testosterone levels and an associated medical condition due to hypogonadism. Evidence can be seen in the recent finding that almost 25 percent of men prescribed testosterone in this country had not previously had a blood test to even determine if their testosterone level was low.

“Unless the FDA immediately begins to provide strong, adequate black-boxed warnings about the risks of heart attacks and other cardiovascular diseases, the continuing toll of heart attacks, many in people who are not even candidates for testosterone, will continue,” Wolfe said. “At the present rate of prescribing, almost 13,000 prescriptions a day are filled for testosterone products in this country. Each day of delay of the black box warning ensures much more exposure, too often for men who cannot benefit from the drug but will only be exposed to its risks.”

In addition, the petition urges the FDA to delay its decision date on approving a new long-acting injectable testosterone product Aveed (testosterone undecanoate, Endo), now set for Feb. 28, because its approval, absent the new black box warning, would cause further cardiovascular damage to new users.

The petition is available at http://www.citizen.org/hrg2184.

Public Citizen is a national, nonprofit consumer advocacy organization founded in 1971 to represent consumer interests in Congress, the executive branch and the courts.

http://www.commondreams.org/newswire/2014/02/25-4?

Merry Christmas Big Pharma, from PharmaGossip and Sid Wolfe

Escalating criminal and civil violations: pharma has corporate integrity? Not really

Sidney M Wolfe looks at the system that should, but does not, deter drug companies from breaking the law

Are criminal and civil penalties of hundreds of millions of dollars an important deterrent to law breaking by international drug companies?

Further, would external monitoring in the form of US government mandated corporate integrity agreements (CIA)1 to prevent recurrences of such illegal activities, lasting five years after being signed, be an additional deterrent? Yes in both cases, but only if the size of the penalties outweighed the companies’ gains while violating the laws and only if enforcement of the CIAs were effective. Unfortunately, neither is the case. This evaluation is based on the recent, sharp escalation in the frequency with which many giant multinational drug companies repeatedly engage in illegal criminal and civil activity after previously paying enormous fines and despite monitoring under CIAs. It seems that for some companies, commission of such criminal and civil violations has become part of their business models.

In 2012, we updated previous data to include all civil and criminal penalties paid to the US federal and state governments by pharmaceutical companies from January 1991 through 18 July 2012. The overall findings included: $30.2bn (£18.5bn; €22bn) in criminal and civil penalties was paid by drug companies to federal and state governments during this time period.

More than half of the total amounts of penalties were either for illegal promotion or illegally overcharging government programs for drugs. In the past three and a half years alone (2009 to mid-2012), criminal and civil penalties have totaled $18bn, well over half the total for the past 21 years. The largest growth has been for criminal penalties, leaping more than fivefold from $920m in 2005-8, to $5.1bn from 2009 to mid-2012, the latter comprising 76% of all criminal penalties paid since 1991. GlaxoSmithKline (GSK) topped the list of repeat offenders with total criminal and civil penalties of $7.56bn since 1991, comprised six different federal settlements and an additional number with states. Pfizer was the second highest with $2.96bn.2Overall, since 1991, 11 other companies also had criminal or civil settlements or both exceeding $50m on at least two occasions.3

An analysis of several of the repeat civil payments and criminal penalties by GSK and Pfizer based on publicly available government documents illustrates the failure of such large penalties and the parallel failure of the accompanying CIAs to curb such behavior.

In 2003, GSK paid $87m to the US federal government and states to settle allegations that the company violated the False Claims Act (submitting false claims to the government)—for underpaying rebates, effectively overcharging a government program (Medicaid), and signed a CIA, lasting until 2008, to “ensure that GSK will accurately reports its ‘best price’ information to the government in the future.”4

In 2005, slightly more than two years later, GSK paid an additional $150m, again to resolve allegations that it violated the False Claims Act “through fraudulent drug pricing and marketing of two antiemetic drugs, Zofran [ondansetron] and Kytril [granisetron],” and signed an amended CIA, extending until 2010.5

Then in 2010, a GSK subsidiary paid $150m in criminal penalties, and GSK agreed to pay $600m to resolve civil allegations, again involving alleged violations of the False Claims Act related to selling drugs that were adulterated. The government stated such “adulterated drugs undermine the integrity of the US Food and Drug Administration’s approval process, can introduce substandard or ineffective drugs on to the market and, in the worst cases, can potentially put patients’ health at risk.”6 It is not clear why, despite continuation of illegal activity while under a previous CIA, there was no new or amended CIA from 2010 until 2015.

However in 2012, GSK paid the government $3bn, in criminal penalties and to resolve allegations of civil violations, described by the government as the “Largest health care fraud settlement in US history.”7 Again, for at least the fourth time including 2003, there were also allegations of False Claims Act violations, amounting to $2bn to resolve civil liability for illegal off label promotion of several drugs, including allegations that “GSK paid kickbacks to health care professionals to induce them to promote and prescribe these [and other] drugs.”

But there was also a $1bn criminal penalty for withholding information from the US Food and Drug Administration about the risks of rosiglitazone (marketed as Avandia) and for introducing misbranded drugs into interstate commerce. Unlike in 2010, there was a CIA accompanying the $3bn 2012 criminal and civil payments. GSK will therefore have been under a series of CIAs from 2003 through 2018, with the exception of the 2010 to 2012 interval.

Then there is Pfizer. In 2002, the company paid $49m to settle allegations that it violated the False Claims Act. The government charged that Pfizer “fraudulently avoided paying fully the rebates owed to the state and federal governments under the national drug Medicaid Rebate program for the cholesterol lowering drug Lipitor [avorvastatin].” Pfizer signed a CIA which was to last until 2007.8 But in 2004, a Pfizer subsidiary paid $430m in criminal fines and other payments to settle allegations of civil violations, including False Claims Act violations, involving illegal off label marketing of gabapentin (Neurontin) and kickbacks. The government stated that “This illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision making, thereby putting patients at risk.”9

In 2009, Pfizer and a subsidiary paid $2.3bn in criminal fines and payments to resolve allegations of civil violations for, among other offenses, illegal off label promotion of the painkiller valdecoxib (marketed as Bextra) and other drugs. The $1.3bn criminal penalty at the time was the largest ever against a drug company, and the $1bn civil settlement again involved alleged violations of the False Claims Act. Another CIA was signed that year, extending into 2014. The government stated that “Illegal conduct and fraud by pharmaceutical companies puts the public health at risk, corrupts medical decisions by health care providers, and costs the government billions of dollars.”10

Because of the repeat nature of Pfizer’s 2004 and 2009 criminal fines and civil settlement payments, we sought reports from the government documenting the degree of “compliance” with the 2004 CIA. After we filed a Freedom of Information Act request in 2009, the US government, in agreement with Pfizer, denied us access to many of the most important portions of these reports, claiming they were trade secret/confidential commercial information. In September, 2011, we filed suit in federal court against the government to obtain these documents. The litigation is continuing in Federal District Court in Washington, DC.11

Profits in 2012 alone for GSK amounted to $7.7bn12 and, for Pfizer, $10bn,13 both greater than the entire amount the companies paid to the government during the 21 plus year interval from January 1991 to mid-2012.

These escalating patterns of repeated criminal violations and civil settlements to resolve serious allegations of civil lawlessness hardly bespeak corporate integrity for GSK, Pfizer, or the many other companies who are also repeat offenders. We are forced to conclude that neither the current level of penalties nor corporate integrity agreements are effective and that there is a pathological lack of corporate integrity in many drug companies.

Notes

Cite this as: BMJ 2014;348:f7507

Footnotes

• Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare that I have no relevant conflict of interest to declare.

  http://www.bmj.com/content/347/bmj.f7507

Public Citizen - Unacceptable Behavior: FDA Advisory Committee Chair to Give Drug Industry Tips on Getting Drugs Approved

FDA Should Tell Dr. Lynn Drake Not to Speak at Conference or Remove Her From the Committee

October 24, 2013

Contact: Angela Bradbery (202) 588-7741; Sam Jewler (202) 588-7779

WASHINGTON, D.C. – The chair of a Food and Drug Administration (FDA) advisory committee should not advise drug company representatives at an upcoming conference how to get drugs approved by FDA committees, Public Citizen told the agency today.

According to a conference brochure, Dr. Lynn Drake, chair of the FDA Dermatologic and Ophthalmic Drugs Advisory Committee and a lecturer at Harvard Medical School, will speak in February at a conference in Washington, D.C., titled “FDA Advisory Committee Prep: Real World Best Practices to Achieve Favorable Recommendations.”

Drake plans to give a talk titled, “Pitfalls to Avoid as You Prepare for, and Present to, an Advisory Committee.” The brochure says that attendees will “hear directly from an FDA advisory committee chairperson about what mistakes she has seen first-hand that she wishes the sponsoring companies had avoided.” The conference urges potential attendees to “learn from current and former [FDA] advisory board members.” Drake’s presentation will likely be a major attraction for the pharmaceutical industry.

“The decision of a current FDA advisory committee chair to speak at this conference reflects poor judgment and seriously undermines and demeans the important FDA advisory committee process, particularly when the chair seeks to help drug companies get drugs approved,” said Dr. Sidney Wolfe, founder and senior adviser to Public Citizen’s Health Research Group. Wolfe served on the FDA’s Drug Safety and Risk Management Advisory Committee from 2008-2012. “Dr. Drake’s participation in this conference raises concerns that she is approaching the work of the committee from a pro-industry perspective, rather than as an impartial expert.”

Public Citizen is calling on the FDA to tell Drake to pull out of the conference or remove her from the advisory committee. In addition, the FDA should develop a written policy for advisory committee members to curb such behavior.

Public Citizen also is questioning the FDA’s redaction of 32 items on Drake’s curriculum vitae from the webpage on which the agency has posted her CV.

The letter and brochure are available at http://www.citizen.org/hrg2166.