Phooled Again - More Settlements Suggesting Bad Behavior by Big Pharma/ Biotech

adulterated devices bribery Bristol-Myers-Squibb crime deception deferred prosecution agreement Genzyme intimidation legal settlements Pfizer Sanofi-Aventis

Phooled Again - More Settlements Suggesting Bad Behavior by Big Pharma/ Biotech

Unknown 10/16/2015 Komentar

Once again, here is a roundup of cases showing big multi-national pharmaceutical and biotechnology companies are up to their usual tricks.

Presented in alphabetical order...

Bristol-Myers Squibb Settles Charges of Bribery of Chinese Hospitals.

The best version of this I could find was in USA Today, in early October, 2015,

Pharmaceutical manufacturer Bristol-Myers Squibb has agreed to pay more than $14 million in fines to settle charges that its joint venture in China paid cash and other benefits to state-owned hospitals in exchange for prescription sales, the Securities and Exchange Commission announced Monday.

After its investigation, the SEC found that the New York-based company violated the Foreign Corrupt Practices Act in its dealings with Chinese hospitals and doctors and 'reaped more than $11 million in profits from its misconduct.'

Bristol-Myers Squibb neither admitted nor denied the findings, the SEC said.

The details, such as they were:

Chinese sales representatives at BMS China, the Chinese joint venture that is majority-owned by Bristol-Myers, paid bribes — including cash, jewelry, meals, travel, entertainment, sponsorships and other gifts — to health care providers between 2009 and 2014 to generate more sales. And Bristol-Myers Squibb 'failed to respond effectively to red flags' indicating such practices, the SEC said.

Apparently, some lower level Chinese employees were fired, although it is not clear whether they were involved in bribery, or in whistle-blowing about it, but top company management did not look too hard to see who might have authorized or directed the bad behavior,

Several BMS China employees who were fired by the company made claims that faked invoices, receipts and purchase orders were widely used to bribe health care providers. But Bristol-Myers Squibb did not investigate their claims, the SEC said.

Bristol-Myers Squibb was aware of improper payments as early as 2009, when an internal audit highlighted the problem. But the company was 'slow to remediate gaps in internal controls' over dealing with Chinese health care providers and monitor payments to them, the SEC said.

Needless to say, no one who might have authorized or directed the bad behavior, and who conceivably might have personally gotten bigger bonuses based on the revenue it brought it, suffered any negative consequences. Despite the settlement, of charges of bribery, no less, company public relations produced the usual,

We have resolved this matter with the United States Securities and Exchange Commission, and are committed to the highest standards of business integrity, vigilance and ethics across our organization.

Well then, that clears it up.

I cannot find any information about what BMS allegedly bribed the hospitals to do, and hence can draw no conclusions whether patients may have been harmed by receiving inappropriate medications.

UK Judge Found Pfizer Threatened Health Professionals

The most thorough coverage of this was, amazingly, in a medical journal, namely the British Medical Journal (Kmietowicz A. Pfizer loses UK patent for blockbuster pain drug after threats to doctors.  Brit Med J 2015; 351: h4918.  Link here.)  The background was,

The patent for the use of Lyrica for epilepsy and generalised anxiety disorder expired in July 2014, and manufacturers of generic versions already have licences for these two indications. But the manufacturer, Warner-Lambert (a subsidiary of Pfizer), holds a 'second medical use' patent for the use of pregabalin to treat peripheral and central neuropathic pain, which expires in July 2017. A second medical use patent is one that relates to a new medical use for a known compound.

Lyrica is one of Pfizer’s most successful products, with global sales in 2013 of some $4.6bn (£3bn; €4.1bn).

So apparently Pfizer set out to scare physicians away from prescribing generic pregabalin [generic Lyrica].

In his 174 page ruling Mr Justice Arnold said, 'Since late September 2014, Pfizer has taken extensive steps to try to ensure that generic pregabalin is neither prescribed nor dispensed for the treatment of pain.' This included sending a letter to the BMA and pharmacists stating that doctors and pharmacists risked infringing the patent if they supplied generic pregabalin for the pain indication and that this would be an unlawful act.

A letter sent to clinical commissioning groups in December 2014 was described by Arnold as 'calculated to have a chilling effect on the sales of Lecaent [the version of pregabalin made by Actavis].'

These letters would be seen by the recipients as a threat, said Mr Justice Arnold.

The Justice ultimately "overturned Pfizer's UK patent for pregabalin for pain control," in part because the "company made 'groundless claims' that its patent for Lyrica would be infringed if doctors did not specify Lyrica as opposed to a generic alternative when prescribing...."

This case was apparently only about the patent (and is subject to appeal), so it appears no one who apparently tried to authorize, direct or implement apparent intimidation of health care professionals with "groundless threats" will suffer any negative consequences.

This case does not seem to involve any obvious harms to patients.  However, "groundless threats" to health care professionals could have obviously demoralized them and clearly challenged their autonomy and professional values.

Sanofi Again Settles Charges of Misbranding Seprafilm

We discussed the first civil settlement the company made of this case in 2014 here.  A relatively clear summary of the new settlement was given by Reuters in September, 2015.

Genzyme Corp agreed to pay $32.59 million, admit wrongdoing and enter a deferred prosecution agreement to resolve U.S. criminal charges over its marketing of the surgical implant Seprafilm, the Department of Justice said on Thursday.

The biotechnology unit of French drug company Sanofi SA (SASY.PA) was accused of two misdemeanor counts of violating the federal Food, Drug and Cosmetic Act from 2005 to 2010 by allowing Seprafilm to be adulterated and misbranded while being sold. Sanofi bought Genzyme in 2011.

Seprafilm is a clear film used to reduce abnormal internal scarring that can cause organs and tissues to stick together following pelvic and abdominal surgeries known as laparotomies.

But the Justice Department said some sales representatives taught surgeons how to turn Seprafilm into a 'slurry' for use in increasingly popular laparoscopic surgery, even though U.S. regulators had never approved the film for that use.

According to papers filed with the federal court in Tampa, Florida, Genzyme admitted and accepted responsibility for the facts underlying the two criminal counts.

The two-year deferred prosecution agreement calls for improved oversight, and steps to halt Seprafilm sales for off-label uses. If Genzyme complies, the government will dismiss the charges.

Note that at least in this case, there was some admission by the company of the truth of the facts charged, and no protestation that "we adhere to the highest standards of integrity," or some such.

It seems possible that the use of the Seprafilm slurry in patients without clear evidence of its safety or effectiveness may have lead to patient harms, but I cannot find clear discussion of this.

Summary

So while big health care corporations, especially large drug and biotechnology companies, are always protesting how their main goal is to benefit patients, and how they support health care professionals, here are more cases in which it appears they at best set out to manipulate patients and health care professionals to maximize revenue.

Note that this is hardly the first time any of these companies have apparently misbehaved.  See our previous posts on BMS, on Genzyme (now a Sanofi subsidiary), and on Pfizer.  Note that our last discussion of the ever troubled Pfizer was only one month ago.

We have discussed endlessly how the march of legal settlements and other legal rulings affecting big health care corporations has raised questions about whether they are in it for patients and health care professionals, or just for the money.  That almost none of these legal actions has resulted in any real consequences for the individuals within the corporations who profited most from the misbehavior has allowed health care corporate managers' continued impunity, and has suggested how cozy health care corporate managers and goverment regulators and law enforcement officials have become, partially through the mechanism of the revolving door.

While these latest three cases have appeared, the mainstream media have begun to feature more discussion about how widespread managerial and corporate misbehavior is fueling the decline of the global economy, and perhaps of global society.  For example, as discussed in srticles in The Guardian, and more recently in the New York Times, Nobel Prize winners Robert Shiller and George Akerlof's new book, Phishing for Pfools: The Economics of Manipulation and Deception, suggests that widespread bad behavior in supposedly "free," and mainly unregulated markets can cause all sorts of evil.  In the Guardian, Shiller used the examples of how

 Most of us have suffered 'phishing': unwanted emails and phone calls designed to defraud us.  A 'phool' is anyone who does not fully comprehend the ubiquity of fishing.  A phool sees isolated examples of phishing, but does not appreciate the extent of professionalism devoted to it, nor how deeply this professionalism affects lives.  Sadly, a lot of us have been phools - including Akerlof and me, which is why we wrote this book

As Shiller wrote in the NYT, while he is a "free market advocate,"

we both believe that standard economic theory is typically overenthusiastic about unregulated free markets. It usually ignores the fact that, given normal human weaknesses, an unregulated competitive economy will inevitably spawn an immense amount of manipulation and deception.

Shiller and Akerlof believe that various kinds of manipulation and deception are enabled by technological advances, and that they are contagious,

When you realize that your competitor has used sophisticated and effective marketing tricks, then you will fall behind if you don’t follow suit.

This is really not a new idea,

In 1918, Irving Fisher, the Yale economist, argued that what people maximize in their actions is something that could better be described as 'wantability' rather than utility, for they are subject to temptation and mistakes in the vast array of purchases they make, leading profit-maximizing marketers to take advantage of them on a systematic basis.

In the first half of the 20th century, such critiques were of general interest. But they are little discussed today.

In the Guardian, Shiller warned that failure to address this problem in the financial sector could lead to "a new Dark Age." I fear that we are already close to a dark age for health care.

Similarly, in the Wall Street Journal, of all places, Charles Moore, the authorized biographer of Margaret Thatcher, and former editor of the conservative UK Daily Telegraph, wrote:

The relationship between money and morality, on which the middle-class order depends, has been seriously compromised over the past decade.  Which means that the mass bourgeoisie (a phrase that Marx and Engles would have thought a contradiction in terms) start to feel like the new proletariat.

Furthermore,

To the extent that people cheat in markets, they are not real markets, any more than antifreeze labeled 'wine' is real wine.  Too many advocates of markets have allowed themselves to be suborned into becoming apologists for business.  And too many businesses now operate as if their responsibilities are only to themselves and not to consumers.

See the above examples, and all we have written about bribery, kick-backs, fraud, other crime, and corruption to show how prevalent cheating is in health care.

Shiller concluded,

Marx did have an insight about the disproportionate power of the ownership of capital. The owner of capital decides where money goes, whereas the people who sell only their labor lack that power. This makes it hard for society to be shaped in their interests. In recent years, that disproportion has reached destructive levels, so if we don’t want to be a Marxist society, we need to put it right.

I would add that if we do not put these things right in health care, ending up with a Marxist system will be the least of our worries.

So as a start, to quote Shiller, we need more

heroic effortsw of campaigners for better values, both among private organizations and advocates of government regulation

Who will step up?

Our musical diversion, "Won't Get Fooled Again," the Who, 1978 live version:

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With 10 Health Care Executives on it Board, US Chamber of Commerce Defends Big Tobacco Abroad

Abbott Celgene mission-hostile management Pfizer Sanofi-Aventis Steward Health Care tobacco US Chamber of Commerce WellPoint

With 10 Health Care Executives on it Board, US Chamber of Commerce Defends Big Tobacco Abroad

Unknown 8/17/2015 Komentar

Tobacco, especially smoked in cigarettes, is generally recognized by health care professionals as having health hazards that greatly outweigh its benefits to society.  Therefore, most health care organizations discourage tobacco use, and many have developed tobacco free policies.

However, the tobacco industry has its powerful supporters.  A recent NY Times investigative report, and a report entitled "Blowing Smoke for Big Tobacco," documented how the US Chamber of Commerce has defended the interests of tobacco companies overseas.  The apparent paradox here is that the leadership of the US Chamber of Commerce includes leaders of large health care organizations.  So far this paradox has not been explained by the parties involved.

How the US Chamber of Commerce Promotes Tobacco Interests Abroad

The NY Times Articles

On June 30, 2015, the NY Times published a wide ranging report on the pro-tobacco activities of the US Chamber of Commerce,

From Ukraine to Uruguay, Moldova to the Philippines, the U.S. Chamber of Commerce and its foreign affiliates have become the hammer for the tobacco industry, engaging in a worldwide effort to fight antismoking laws of all kinds, according to interviews with government ministers, lobbyists, lawmakers and public health groups in Asia, Europe, Latin America and the United States.

The U.S. Chamber’s work in support of the tobacco industry in recent years has emerged as a priority at the same time the industry has faced one of the most serious threats in its history. A global treaty, negotiated through the World Health Organization, mandates anti-smoking measures and also seeks to curb the influence of the tobacco industry in policy making. The treaty, which took effect in 2005, has been ratified by 179 countries; holdouts include Cuba, Haiti and the United States.

Facing a wave of new legislation around the world, the tobacco lobby has turned for help to the U.S. Chamber of Commerce, with the weight of American business behind it. While the chamber’s global tobacco lobbying has been largely hidden from public view, its influence has been widely felt.

Letters, emails and other documents from foreign governments, the chamber’s affiliates and antismoking groups, which were reviewed by The New York Times, show how the chamber has embraced the challenge, undertaking a three-pronged strategy in its global campaign to advance the interests of the tobacco industry.

In the capitals of far-flung nations, the chamber lobbies alongside its foreign affiliates to beat back antismoking laws.

In trade forums, the chamber pits countries against one another. The Ukrainian prime minister, Arseniy Yatsenyuk, recently revealed that his country’s case against Australia was prompted by a complaint from the U.S. Chamber.

And in Washington, Thomas J. Donohue, the chief executive of the chamber, has personally taken part in lobbying to defend the ability of the tobacco industry to sue under future international treaties, notably the Trans-Pacific Partnership, a trade agreement being negotiated between the United States and several Pacific Rim nations.

'They represent the interests of the tobacco industry,' said Dr. Vera Luiza da Costa e Silva, the head of the Secretariat that oversees the W.H.O treaty,...

The NYT asked the Chamber of Commerce for a response, and got only

The U.S. Chamber issued brief statements in response to inquiries. 'The Chamber regularly reaches out to governments around the world to urge them to avoid measures that discriminate against particular companies or industries, undermine their trademarks or brands, or destroy their intellectual property,' the statement said, adding, 'we’ve worked with a broad array of business organizations at home and abroad to defend these principles.'

The chamber declined to say if it supported any measures to curb smoking.

"Blowing Smoke for Big Tobacco"

Two weeks after the first NY Times article, a group of nine organizations including Campaign for Tobacco Free Kids, Corporate Accountability International, and Public Citizen released a report on the US Chamber of Commerce pro-tobacco actions. A summary article in the Huffington Post written by representatives of the latter two organizations included,

Our report and a two-part New York Times investigation shows that, while the Chamber throws its weight around in many Global South countries to protect its corporate members' interests, Big Tobacco has also pushed it to adopt particularly aggressive and radical positions in order to undermine the cascade of public health laws being passed as a result of the success of the global tobacco treaty.

In particular,

For tobacco control advocates familiar with this deadly industry's tactics, the Chamber's work in this space comes as no surprise. Internal documents tell us that as the tobacco industry lost its public credibility, it began to use third parties to advocate on its behalf.

Case studies in our report, from Africa to Latin America, make it clear that Big Tobacco is doggedly pursuing this strategy with the U.S. Chamber and its affiliates in Global South countries. In countries the tobacco industry has targeted around the world, the Chamber is delivering threatening letters that cast doubt on the science behind tobacco control, exaggerating exaggerate the economic impacts repercussions of proven measures like tobacco taxation and crying wolf about explosions in illicit trade. In pursuing these actions, the Chamber and its AmCham affiliates are exporting well-documented tobacco industry tactics to block health laws around the globe.

And as the New York Times points out in its investigation, (and then advocates that countries resist in their recent editorial: Tarred by Tobacco), these tactics are in some cases drafted by Big Tobacco executives themselves.

Who Runs the US Chamber of Commerce?

A 2010 MotherJones article noted that the US Chamber of Commerce as having a "name that evokes Main Street and Little League teams," and its history of "taking a moderate, nonpartisan approach."  So who is responsible for the US Chamber of Commerce becoming a tobacco advocate, at least outside of the US?

First, the Chamber has become more the creature of the biggest corporations than small businesses.  The MotherJones article noted that recently

The Chamber's politics became synonymous with its biggest corporate donors.  [Chamber President Tom] Donohue established special accounts for companies that feared taking controversial public stands, allowing them to anonymously funnel money to the Chamber, which advocated on their behalf.

Furthermore,

The Chamber claims that 96 percent of its members are small businesses, yet its self-seleted board includes just 6 representatives from small businesses, 1 from a local chamber, and 111 from large corporations.

Among these large corporations, tobacco corporations seem to be particularly influential.  The NY Times article noted,

The increasing global advocacy highlights the chamber’s enduring ties to the tobacco industry, which in years past centered on American regulation of cigarettes. A top executive at the tobacco giant Altria Group serves on the chamber’s board. Philip Morris International plays a leading role in the global campaign; one executive drafted a position paper used by a chamber affiliate in Brussels, while another accompanied a chamber executive to a meeting with the Philippine ambassador in Washington to lobby against a cigarette-tax increase. The cigarette makers’ payments to the chamber are not disclosed.

Yet the Chamber's governance also ostensibly includes health care viewpoints.  Its current board includes 10 member who are executives of large health care organizations:

- Richard Bagger Senior Vice President, Corporate Affairs & Strategic Market Access, Celgene Corporation, [biopharmaceutical company] Summit, NJ
- John Cannon Executive Vice President & Chief Administrative Officer, Health Care Service Corporation, [health insurance company] Chicago, IL
- Ken W. Cole Senior Vice President, Government Relations, Pfizer, Inc., [pharmaceutical company] Washington, DC
- Wayne S. DeVeydt Executive Vice President and Chief Financial Officer, Anthem, Inc., [health insurance company, formerly Wellpoint] Indianapolis, IN
- Ralph de la Torre, MD Chairman and CEO, Steward Health Care System LLC, [for-profit hospital system, owned by Cerberus Capital Management] Boston, MA
- Fuad El-Hibri Executive Chairman, Emergent BioSolutions Inc. [biopharmaceutical company] Gaithersburg, MD
- Daniel F. Evans, Jr. President & Chief Executive Officer, Indiana University Health, [non-profit hospital system] Indianapolis, IN
- Gregory Irace President and Chief Executive Officer, Sanofi US Services Inc., [US subsidiary of French pharmaceutical company] Bridgewater, NJ
- Paul J. Klaassen Founder, Sunrise Senior Living, Inc., [for-profit provider of nursing care, hospice care, etc] Arlington, VA
- Elaine R. Leavenworth Senior Vice President, Chief Marketing and External Affairs Officer, Abbott Laboratories, [pharmaceutical and device company] Abbott Park, IL

These organizations ostensibly are all about promoting or sustaining individual or population health.  Executives of these organizations serving on the board of the US Chamber of Commerce are responsible for the governance and stewardship of the Chamber.  How could they square the missions of the organizations which the lead, and their responsibility for the Chamber's pro-tobacco stance?

The Health Care Organizations Dodge the Question

The answer to that question is elusive.

The NY Times article stated,

It is not clear how the chamber’s campaign reflects the interests of its broader membership, which includes technology companies like Google, pharmaceutical giants like Pfizer and health insurers like Anthem.

An accompanying NY Times editorial added,

Health insurance and hospital companies that are members of the U.S. Chamber of Commerce find themselves in an uncomfortable situation. Publicly, these companies support policies designed to reduce smoking, but the chamber, as Danny Hakim recently reported, has opposed anti-smoking measures around the world.

The controversy appears to have surprised health-related businesses like Anthem, one of the nation’s biggest health insurers, and Steward Health Care Systems of Boston, which have executives on the board of the chamber. 'If the chamber is in fact advocating for increased smoking, we do not agree with them on this public health issue,' a spokeswoman for Steward said in a statement to The Times.

In an article in the Indianapolis Business Journal, J K Wall recounted how he tried to get a substantive response to the NY Times article from Indiana University Health, whose President is on the Chamber board,

Indiana University Health CEO Dan Evans is one of the most anti-smoking health care executives I know.

Just a few months after I started covering health care for IBJ in 2007, Evans told me in an interview that Indiana employees 'should snatch the cigarettes out of their co-workers mouths and say, ‘Hey, you’re costing me money!’'

However, Evans was not available, and the only response was this statement from a spokesperson

We are proud of the many programs we have in place for smoking prevention and cessation, as well as health promotion and screenings for our team members, patients and members of the community. IU Health has been and will continue to be a leader in Indiana to prevent and curtail the use of tobacco products.

IU Health is a member of many diverse state and national organizations to support our public policy goals including the U.S. Chamber of Commerce and the Indiana State Chamber of Commerce. We are talking with U.S. Chamber leadership about the facts surrounding recent stories in the NY Times and will strongly encourage the U.S. Chamber to review its international programs to ensure they are consistent with its own stated policy to oppose smoking and promote wellness.

Similarly, a follow up story in the New York Times documented this response from Anthem, (formerly Wellpoint), whose Executive Vice President and CFO is on the Chamber board,

Anthem said it was 'dedicated to helping people quit smoking and has led the charge to end tobacco use.'

'Anthem has shared its strong, longstanding position with the chamber and will continue to address our concerns with the chamber directly,' the statement said.

Likewise, the Times noted this response from

Greg Thompson, a spokesman for the Health Care Service Corporation, said in a statement last week: 'We are convinced that ending smoking may help people live longer, enjoy a better quality of life and reduce costs in our health care system.'

'This is a point of view we have advocated for decades and made clear to organizations that we support.'

Those seem to be the only public responses from companies whose leadership is represented on the Chamber of Commerce board. They all ignored the main issue.  None of them seemed informed by the role their companies' executives on the Chamber of Commerce board play.  None of the executives or the companies for whom they worked acknowledged any accountability for the Board's vigorous foreign campaign of pro-tobacco activities.

The Times did note that Chamber of Commerce member CVS, which is not specifically represented on the Chamber board, and which recently stopped selling tobacco products, withdrew from Chamber membership. But as a simply a member of the Chamber, it had little direct responsibility for the Chamber's actions.

Discussion

US health care is increasingly dominated by large organizations.  Most of these organizations like to portray themselves as warm and fuzzy supporters of individual and population health.  For example, Pfizer has a statement of responsibility which begins

As a member of today’s rapidly changing global community, we are striving to adapt to the evolving needs of society and contribute to the overall health and wellness of our world.

Anthem's statement includes

Anthem is dedicated to delivering better care to our members, providing greater value to our customers and helping improve the health of our communities.

Yet on Health Care Renewal, we have documented actions by leaders of health care organizations that directly contradict their lofty mission statements, and may have threatened patients' or the public's health.

In its aggressive international promotion of tobacco interests, the US Chamber of Commerce appears to be promoting the use of products that directly threaten individual's and the public's health.  Even though the Chamber protested that it was merely reaching out

to governments around the world to urge them to avoid measures that discriminate against particular companies or industries, undermine their trademarks or brands...

their protestation ignored how tobacco is a different product than that of nearly all industries.  It seems inherently dangerous to patient's the and public's health even when used as intended, and has no known health or societal benefits that even partially compensate for its risks.  Therefore, what is the argument not to discriminate those who make and promote such an inherently dangerous product from those who make products that do not threaten health, or provide obvious benefits that may compensate for their risks?

It is obvious why tobacco companies might want the Chamber's support.  What, however, could be the rationale for executives of corporations pledge to promote health to preside over the international promotion of tobacco?

The executives on the Chamber board, and their companies have not as yet even tried to provide an answer.

Thus, in the absence of better responses, in my humble opinion the presence of health care executives on the US Chamber of Commerce board is another example - an important one - of mission-hostile actions by top leaders of US health care organizations.

As we have said far too many times - without much impact so far, unfortunately - true health care reform would put in place leadership that understands the health care context, upholds health care professionals' values, and puts patients' and the public's health ahead of extraneous, particularly short-term financial concerns. We need health care governance that holds health care leaders accountable, and ensures their transparency, integrity and honesty.

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Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients

aliromucab evidence-based medicine health care prices manipulating clinical research PCSK9 inhibitor Praluent Regeneron Sanofi-Aventis

Praluent, the Next Expensive "Game Changer," Blockbuster," "New Hope," - But Not Yet Shown to Benefit Patients

Unknown 8/06/2015 Komentar

Here we go again.  The same month that it approved Entresto (look here), the US Food and Drug Administration approved a new PCSK9 inhibitor cholesterol lowering agent, alirocumab, immediately marketed as the pricy Praluent by Sanofi and Regeneron, and heralded by a blast of media hype.  Yet the evidence that this drug benefits patients is lacking, and critical review of the one big published randomized controlled trial of it raises many concerns.

Media Hype

Let us first consider the media hype.  The TIME coverage started with this headline,

This New FDA-Approved Cholesterol Drug is a Game Changer

The New York Times article by Andrew Pollack quoted Katherine Wilemon, founder and president of the FH foundation, an advocacy group for patients with familial hypercholesterolemia, who have very high cholesterol values and increased risk of heart and vascular disease,

It represents a new era of hope for us.

The Washington Post article started with,

The Food and Drug Administration on Friday approved the first in a new class of cholesterol-busting drugs that many doctors believe will trigger a breakthrough in reducing the incidence of strokes and heart attacks, which kill hundreds of thousands of Americans each year.

USA Today reported,

The drugs are predicted to be blockbusters many times over, adding billions of dollars to prescription drug costs, said Steve Miller, senior vice president and chief medical officer at Express Scripts, a leading pharmacy benefit manager.

Another NY Times article by Gina Kolata directly described the drug as

powerful almost beyond belief.

Ms Colata also quoted a cardiologist who characterized the drug again as a "game changer."

To be fair, note that while the WaPo article, NYT article by Pollack and the USA Today article provided hype attributed to "doctors," or identified individuals, they also quoted some people who were very skeptical about the drug.  However, in most of the media coverage, the positivity seemed to be more prominent and extreme than the skepticism. 

The High Price

In general, the media coverage noted that the "breakthrough," "blockbuster," "powerful" new drug would not come cheap.  Praluent would cost about $14,600 a year.  Naturally, those selling it saw this as a bargain.  For example, Andrew Pollack wrote in the NYT,

Sanofi and Regeneron Pharmaceuticals, which developed the product, said the price was justified by the potential benefits to patients and savings to the health care system that the drug would provide by preventing heart attacks and strokes — though the ability of the drug to do that has not been proved.

'We came to a price that is reflective of value, not what the market will bear,' said Elias Zerhouni, head of research and development at Sanofi, who said his own brother had suffered three heart attacks and needed new options to control cholesterol.

Gina Kolata went farther,

The $14,600 yearly price of the drug, which is injected under the skin once every two weeks, is a stunner. Yet for some patients, that might actually be a bargain.

She justified this by comparing the cost to apheresis, a radical procedure to treat high cholesterol. She did not discuss whether it had any evidence of clinical benefit. Yet,

'Cost is in the eye of the beholder,' said Dr. Daniel Soffer, [Mr. DeRuchie’s cardiologist at the University of Pennsylvania.

Presumably, Dr Soffer was the one who had recommended the apheresis treatment.

Note that at best, the company that sells this drug can justify the price only in terms of potential, not actual value or results.  

No Evidence for Clinical Benefit

Praluent, generic name alirocumb, is certainly a breakthrough in that it seeks to lower cholesterol through a novel mechanism.  The drug is a biologic, a monoclonal antibody that inhibits the enzyme PCSK9.

Yet a close reading of the one large published randomized controlled trial of alirocumab(1) belays the hype beyond that.  The study by Robinson et al was a double blind randomized controlled trial of alirocumab injections every 2 weeks versus placebo.  The protocol called for patients to be treated for 78 weeks, and followed for 8 more weeks, a bit more than one and one-half years.

Loss to Follow Up and Missing Data

The study enrolled 1553 patients in the alirocumab group, and 788 in the placebo group.  However, many patients did not complete the study: a total of 437 (28.1%) in the alirocumab group, and 193 (24.5% in the placebo group).  Reasons for noncompletion were adverse events (113, 7.2% alirocumab vs 47, 6.0% placebo); "nonadherent" to treatment (60, 3.9% vs 38, 4.7%), and "other reason," (264, 17.0% vs 108, 13.7%).

So the drop out rate was fairly high.  It was particularly troubling that the reasons for most of the drop outs were vague "other reaons."  I could not find a clarification of this term in the main article or  supplemental materials.

Furthermore, it was not clear how the investigators intended to collect data from patients after they dropped out, and how complete data collection about clinical events was for patients who dropped out.  (Note that for patients that dropped out, the investigators simply imputed, that is estimated cholesterol values, but did not necessarily measure them.  So even this measure was "potential.")

Drop outs and missing data are classically problematic because patients may drop out after suffering  events that could be counted as study outcomes.  The rate of these events could differ according to treatment group.  If patients who dropped out of the alirocumab group had more adverse events than those who dropped out of the placebo group, and these events were not recorded, the high drop out rate could have concealed important harms of the drug.

Thus it is quite possible that the study by Robinson et al undercounted adverse events due to aliromucab.

Multiple Study Sites

The study enrolled patients at a remarkable number of sites, 320 in 27 countries, so that the average number of patients enrolled per site was only seven.    It seems improbable that a study involving so many investigators and centers, most of whom must have devoted little of their time and effort to this particular study, would have adequate quality control.  I could not find a discussion of implementation quality control in the published article.

Thus it is possible that poor quality of study implementation, which could have affected enrollment and data collection, may have challenged the validity of the Robinson et al study.

 Lack of Generalizability in the Patient Population

The complete list of exclusion criteria, only appearing in the supplementary material, was extensive.  Patients with many common problems were supposed to be excluded, and the definition of the some exclusion criteria were vague and subjective.

Common conditions leading to exclusion were:
- Recent heart and cardiovascular problems, i.e., "(within 3 months prior to the screening visit [Week -3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, CABG, PCI, carotid surgery or stenting, cerebrovascular accident, transient ischemic attack, endovascular procedure or surgical intervention for peripheral vascular disease."
- "Planned to undergo scheduled PCI, CABG, carotid or peripheral revascularization during the study"
-  Severe congestive heart failure, i.e., "New York Heart Association Class III or IV heart failure within the past 12 months"
- Poorly controlled hypertension, i.e., "Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at screening visit or randomization visit."
- "History of hemorrhagic stroke."
- "History of active optic nerve disease."
- Use of systemic corticosteroids, other than for replacement 
- "History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer."
- "History of HIV positivity."
-   "Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody (confirmed by reflexive testing)."
- Kidney dysfunction, specifically, "eGFR <30 nbsp="" p="">- Poorly controlled diabetes, specifically, HbA1c >10%.
- Abnormal liver enzymes, specifically, ALT or AST > x ULN

Vaguely described exclusions were:

E 25. Conditions/situations such as:
A) Any clinically significant abnormality identified at the time of screening that in the
judgment of the Investigator or any sub-Investigator would preclude safe completion
of the study or constrain endpoints assessment such as major systemic diseases,
patients with short life expectancy.
B) Patients considered by the Investigator or any sub-Investigator as inappropriate
for this study for any reason, e.g.:
i) Those deemed unable to meet specific protocol requirements, such as scheduled
visits.
ii) Those deemed unable to administer or tolerate long-term injections as per the
patient or the investigator.

Also,

iv) Presence of any other conditions (eg, geographic, social….) actual or anticipated,
that the Investigator feels would restrict or limit the patient’s participation for the
duration of the study.

Thus the study would have excluded patients with a variety of common conditions, and may have excluded many other patients based on rather poorly defined decisions by individual investigators.  Since patients in clinical practice commonly have common conditions, the generalizability of the results of this study to many practices and patients was not clear.

No Evidence of Clinical Benefit

Patients should not be subject to treatments whose benefits do not clearly outweigh their harms.  The Robinson et al article focused on reductions in measured cholesterol, particularly LDL cholesterol.  The new drug certainly did seem to clearl reduce cholesterol, particularly LDL cholesterol.  However, these are only the results of laboratory tests.

Although high cholesterol and high LDL cholesterol indicate increased risk of future cardiac events, many patients with abnormal values do not have such events.  Having a high cholesterol or LDL cholesterol does not directly cause symptoms, or dysfunction.  Thus simply lowering cholesterol does not immediately or directly benefit patients.  Furthermore, other drug have been shown to lower cholesterol, but ultimately they accomplished this without ever being shown to benefit patients, e.g., by preventing heart attacks, strokes, or premature death.

However, cholesterol values are considered intermediate or surrogate variables.  They are not directly related to what happens to patients, who they feel or function, whether they get new diseases, or when they die.  So only showing that the new drug lowers cholesterol does not prove clinical patient benefit.

Although the published trial did attempt to record cardiovascular events, it did not find that the drug prevented them.  The small difference in total cardiovascular events affecting patients given alirocumab (4.6%) versus placebo (5.1%) did not reach statistical significance, that is, could well have been due to chance alone.

Furthermore, while elevated cholesterol is a chronic problem, and the problems with which it is correlated occur over the long run, the study ran for less than 2 years.  It could not measure the effects of the new drug beyond that.

So the clinical benefit of the drug was not evident in this trial.

On the other hand, the drug was not without its own risks.  More patients who received aliromucab left the study due to adverse events (7.2%) thand did those who got placebo (5.8%),  as noted above.  Also, as noted above, it was possible that adverse events affecting dropouts were not fully recorded.  Given that there were higher rates of dropouts due to non adherence and "other" reasons among patients who received alirocumab, the study might still have missed important adverse effects of the new drug.

So the study did not prove that the new drug has any clinical benefits, showed it does have clinical harms, and could still have easily underestimated its harms.  So it certainly did not show it had benefits that outweighed its harms.

Summary and Conclusions

The NEJM study was accompanied by an editorial by Stone and Lloyd-Jones(2) which documented that drugs previously shown to lower cholesterol were never proved to do any good for patients, and concluded,

it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. 

After an FDA advisory committee recommended approval of aliromucab in June, 2015, John Mandrola entitled a Medscape article,

Dear FDA: Resist the Urge on PCSK9 Drugs

His reasons included lack of proof of clinical benefits, and concerns that harms may have been missed but mainly because of its inability to detect long-term outcomes.


Again, the current media articles also noted the concerns raised by Dr Mandrola and the NEJM editorial These concerns, however, did not dissuade the FDA from approving aliromucab.  These concerns did not apparently affect the pricing of Praluent.  These concerns will likely not deter the drug manufacturers from continuing an aggressive marketing campaign.  Whether these concerns will deter physicians from prescribing, or patients from asking for these drugs is unknown, but unlikely.

And I have not seen anything published so far that addressed how the problem with dropouts and missing data may have lead to further underestimation of aliromucab's harms, the multiplicity of study sites may have lead to quality control problems further challenging the study's validity, and the extensive exclusion criteria may have reduced the study's generalizability.

So here we go again.  Another new drug is put on the market accompanied by a mighty hoopla, yet in the absence of clear data that it does more good for patients than harm.

As we said last year about valsartan-sacubitril, also just (July, 2015) put on the market as Entresto, at a high price and with lots of hype,...

All the enthusiasm about this drug may be premature, and does not appear to be evidence-based.  That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors' products look better than they really are is now an old story.  We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised.  Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.  Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. 

Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.


How high must our health care costs go, and how many unproven treatments must eventually be exposed as such before we learn that lesson?

ADDENDUM (6 August, 2015) - Fixed minor errors: misspelling of Ms Kolata's name fixed, misstatement re apharesis fixed, erroneous reference to second approved PCSK9 inhibitor removed.  

ADDENDUM (9 August, 2015) - Note that his post was republished on the Naked Capitalism blog.  


References
1. Robinson JG, Farnier M, Krempf M et al.  Efficacy and safety of alirocumab in reduincg lipids and cardiovascular events.  N Engl J Med 2015; 372: 1489-1499.  Link here.
2.  Stone NJ, Lloyd-Jones DM.  Lowering LDL cholestero is good, but how in whom?  N Engl J Med 2015; 372: 1564-5.  Link here.  

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