Attempts to Transform the CDC into a Propaganda Outlet and the Silence of the Health Care Leaders

First they came for the CDC staffers, but I was not a CDC staffer so I did nothing...

Then they came for me. And there was no one left to speak for me.

- with apologies to Martin Niemoller (look here) 

The US is continuing to suffer during the coronavirus pandemic.  Meanwhile, the lead US government public health agency, the Centers for Disease Control and Prevention (CDC) has suffered two attempts by the Trump administration to transform it into a propaganda outlet.

Mysterious Revisions of Pandemic Management Guidelines to Hinder Testing of Exposed Persons

This story broke in late August, 2020.  As reported by the New York Times on August 25, 2020:

The Centers for Disease Control and Prevention quietly modified its coronavirus testing guidelines this week to exclude people who do not have symptoms of Covid-19 — even if they have been recently exposed to the virus.

The new guidelines went against public health practice for managing epidemics.  People who have been exposed are at increased risk of infection.  Infected people may not have symptoms but may still transmit the virus to others.  Identifying infected people allows them to be quarantined, and any further contacts to be traced.  In particular, as the NYT article pointed out:

Although researchers remain unsure how often asymptomatic people unwittingly transmit the coronavirus, studies have shown that the silently infected can carry the virus in high amounts. The evidence is more clear-cut for pre-symptomatic people, in whom virus levels tend to peak just before illness sets in — a period when these individuals might be mingling with their peers, seeding superspreader events. Notably, experts can’t distinguish asymptomatic people from those who are pre-symptomatic until symptoms do or don’t appear.

No Obvious Justification and No One Accountable for the Change

The CDC did not initially provide a clear justification of the change:

The reasons behind the surprise shift in testing recommendations are unclear. In response to an inquiry from The New York Times, a representative for the C.D.C. directed the questions to the U.S. Department of Health and Human Services. 

A report from ABC News on August 26 quoted Admiral Brett Giroir of the White House coronavirus task force:

This is evidence-based decisions that are driven by the scientists and physicians, both within the CDC, within my office in the lab task force, and certainly amongst the task force members

However, he did not provide any of the evidence on which it was supposedly based, or any logic underlying the change based on this evidence.  Nor did he make clear who was accountable for the change

 I worked on them. Dr. Fauci worked on them. Dr. Birx worked on them. Dr. Hahn worked on them. Dr. Atlas provided input. So, it's kind of hard to know how much was written by one person at this time

On the other hand, a CNN report from the next day suggested that the change came due to political pressure:

A sudden change in federal guidelines on coronavirus testing came this week as a result of pressure from the upper ranks of the Trump administration, a federal health official close to the process tells CNN, and a key White House coronavirus task force member was not part of the meeting when the new guidelines were discussed.

'It's coming from the top down,' the official said of the new directive from the Centers for Disease Control and Prevention.

 

An AP article from August 26 included speculation about the real reasons for the change:

 

Dr. Carlos del Rio, an infectious diseases specialist at Emory University, suggested in a tweet that there are two possible explanations.

One is that it may be driven by testing supply issues that in many parts of the country have caused widely reported delays in results of a week or more, he suggested.

 Admitting problems providing testing might be a reason to consciously temporarily limit testing, of course, but not to pretend the testing would not be useful.  Then

Another possible explanation for the change is that President Donald Trump simply wants to see case counts drop, and discouraging more people from getting tested is one way to do it, del Rio said in his tweet.

A Washington Post article on August 27, 2020 explained this further:

The revised guidelines come as President Trump has feuded with the CDC and the Food and Drug Administration, both parts of the Department of Health and Human Services, and marginalized officials who would ordinarily play leading roles in a pandemic response. He has repeatedly said that he did not like that more testing had revealed more cases.

'I said to my people, ‘Slow the testing down, please!’ ' Trump said at a rally two months ago. Aides said he had been speaking tongue-in-cheek. But asked later whether he had been kidding, Trump replied, 'I don’t kid.'

Reducing testing, of course, would reduce the number of apparent, not real cases, allowing Trump to exaggerate his ability to manage the pandemic

On September 17, 2020, the source of the controversial change in the CDC guideline was somewhat clarified again according to the New York Times:

A heavily criticized recommendation from the Centers for Disease Control and Prevention last month about who should be tested for the coronavirus was not written by C.D.C. scientists and was posted to the agency’s website despite their serious objections

The source of the change was 

the Department of Health and Human Services [which] did the rewriting and then 'dropped' it into the C.D.C.’s public website, flouting the agency’s strict scientific review process.

'That was a doc that came from the top down, from the H.H.S. and the task force,' said a federal official with knowledge of the matter, referring to the White House task force on the coronavirus.

Yet neither that nor earlier reports explained who at "the top" directed the change.

And soon the change it self disappeared as mysteriously as it appeared.  On September 18, 2020 per the AP:

U.S. health officials on Friday dropped a controversial piece of coronavirus guidance and said anyone who has been in close contact with an infected person should get tested.The Centers for Disease Control and Prevention essentially returned to its previous testing guidance

Criticism of the Change

 Public health and health care professionals criticized the changes, e.g.,  per the AP article of August 26, 2020:

Dr. Tom Frieden, who was head of the CDC during the Obama administration, said the move follows another recent change: to no longer recommend quarantine for travelers coming from areas where infections are more common.

'Both changes are highly problematic' and need to be better explained, said Frieden, who now is president of Resolve to Save Lives, a nonprofit program that works to prevent epidemics.

Also, Dr Leana Wen wrote an op-ed for the Washington Post on August 26, 2020:

you don’t have to be a public health expert to know the CDC’s guidance is nonsensical.  

In MedPage Today of August 28, 2020:

pulmonologist William Janssen, MD, section head of Critical Care Medicine at National Jewish Health, said the new guidance recommending testing for fewer people 'flies in the face of everything we have been told and understand about this disease.'

Also,

Another pulmonologist at National Jewish Health, Kenneth Lyn-Kew, MD, called the CDC move 'a step backwards.'

'The CDC was flat out wrong and the epidemiologists there know this,' he said, adding that testing and tracing are cornerstones of epidemiology.

Major health care organizations also criticized the change. The AMA issued a statement:

Suggesting that people without symptoms, who have known exposure to COVID-positive individuals, do not need testing is a recipe for community spread and more spikes in coronavirus. When the Centers for Disease Control and Prevention (CDC) updates a guidance the agency should provide a rationale for the change. We urge CDC and the Department of Health and Human Services to release the scientific justification for this change in testing guidelines

The American Association of Medical Colleges asserted:

These CDC guidelines go against the best interests of the American people and are a step backward in fighting the pandemic. The AAMC urges the CDC to return to its earlier testing recommendations

The Chair of the Board of Regents of the American College of Physicians wrote that the organization:

supports the use of science, based on the best available evidence, in the fight against COVID-19. Public health agencies should not be subjected to pressure or be influenced to issue policies that are not based on evidence and expert recommendations of their own scientists.

 Also

The recent revision of the CDC’s COVID-19 testing guidelines of asymptomatic individuals lacks transparency and clarity, sending a confusing message to both physicians and the public on appropriate and necessary testing that will ultimately help to mitigate the spread of COVID-19.

Summary

So far we only know that someone at "the top" of the government directed the change in the CDC guidelines.  No person or group has stepped forward as accountable. No one at any US government agency has explained the rationale for the change, much less provided clear evidence and logical reasoning underlying it.  The best explanation for the change seems to be that it fit President Trump's message. It would have made his administration's problems organizing adequate testing for coronavirus less apparent.  By reducing testing, it would make the rate of the spread of disease temporarily appear lower, allowing Trump to exaggerate his ability to manage the pandemic.

Yet I could find no health care or public health professional, or any leader of a health care organization willing to criticize "the top" of the US government for directing the change, to criticize the opaque, apparently evidence-free process that produced the change, or to question whether the change was meant to fit with Trump's propaganda, that is, his claims of brilliant management of the pandemic. 

Trump Political Appointees Attempt to Intimidate CDC Staff to Manipulate Publications in the Morbidity and Mortality Weekly

White House Installed Pro-Trump Propagandist with No Health Care or Public Health Background as Head of Public Relations for DHHS

 The second case began in April, 2020.  Then Politico reported:

 The White House is installing Trump campaign veteran Michael Caputo in the health department’s top communications position

Caputo was given the title of Assistant Secretary for Public Affairs. He has an unlikely background to have been named head of public relations for the Department of Health and Human Services (DHHS). He has no apparent background in health care or public health. Also, Politico noted:

Caputo is an intense Trump loyalist whose recent book 'The Ukraine Hoax,' alleged a conspiracy behind Trump’s impeachment.

Furthermore

 Caputo is a longtime friend of Trump ally Roger Stone and former Trump campaign chairman Paul Manafort, both of whom were convicted of crimes in the last two years. 

Then CNN reported:

The new spokesman for the Department of Health and Human Services in a series of now-deleted tweets made racist and derogatory comments about Chinese people, said Democrats wanted the coronavirus to kill millions of people and accused the media of intentionally creating panic around the pandemic to hurt President Donald Trump.

In particular,

In a series of tweets on March 12, Caputo responded to a baseless conspiracy theory that the United States brought the coronavirus to Wuhan, China, by tweeting that 'millions of Chinese suck the blood out of rabid bats as an appetizer and eat the ass out of anteaters.'

 

CNN had many more graphic examples.  

 

Also, Mother Jones reported more about Caputo's involvement in Russia and Ukraine:

 

A longtime Republican operative who was ousted from a job on Trump’s 2016 campaign, Caputo recently worked to boost discredited claims alleging that Ukraine, not Russia, meddled in the 2016 election.

 

In particular, Caputo was alleged to have been involved in political dirty tricks on behalf of Trump in 2016:

 

In June 2018, the Washington Post reported that ... [Caputo] and Stone had met in 2016 with Henry Oknyansky, a Russian expat living in Florida, who wanted to sell damaging information about Hillary Clinton. Caputo, in text messages with Stone the Post obtained, referred to Oknyansky as 'the Russian.' Though no deal was reached, news of the meeting seemed to contradict claims both Stone and Caputo had made in testimony to the House Intelligence Committee. Both men denied any contact with Russians during the 2016 campaign.

 

Also, Caputo was alleged to have been involved in creating propaganda or disinformation about Ukraine's supposed intervention in the 2016 campaign, and Hunter Biden's actions there:

 

Last year, Caputo, along with other figures in Trump’s orbit, turned his focus to Ukraine. He says he travelled there last August to try to bolster the theory that Ukrainians interfered in 2016 election to help Clinton. He subsequently wrote a book, titled The Ukraine Hoax: How Decades of Corruption in the Former Soviet Republic Led to Trump’s Phony Impeachment, which pushes discredited allegations, including claims that former Vice President Joe Biden intervened in Ukrainian affairs to help his son, Hunter. Caputo produced a documentary offering similar allegations that aired in January on the rabidly pro-Trump One America News. Giuliani starred in a separate OAN series which pushed similar claims based his own trip to Ukraine.

 

Yet  despite Caputo's record as an unscrupulous political operator, and allegations that he was involved in peddling propaganda and disinformation, his appointment drew no outcry.

Assistant Secretary for Public Relations of DHHS Orchestrated Intimidation to Distort the Morbidity and Mortality Weekly Report

Somehow Caputo and the associates he brought to the DHHS managed to avoid much public notoriety for a few months.  Then on September 11, 2020 Politico reported that Caputo and his associates had been quietly busy.  Their apparent mission was to turn the respected CDC public health publication, the Morbidity and Mortality Weekly Report, into a vehicle for pro-Trump propaganda.  Politico noted that:

The CDC's Morbidity and Mortality Weekly Reports are authored by career scientists and serve as the main vehicle for the agency to inform doctors, researchers and the general public about how Covid-19 is spreading and who is at risk. Such reports have historically been published with little fanfare and no political interference, said several longtime health department officials, and have been viewed as a cornerstone of the nation's public health work for decades.

But since Michael Caputo, a former Trump campaign official with no medical or scientific background, was installed in April as the Health and Human Services department's new spokesperson, there have been substantial efforts to align the reports with Trump's statements, including the president's claims that fears about the outbreak are overstated, or stop the reports altogether.

In particular, Caputo et al tried to

retroactively change agency reports that they said wrongly inflated the risks of Covid-19 and should have made clear that Americans sickened by the virus may have been infected because of their own behavior

and

halt the release of some CDC reports, including delaying a report that addressed how doctors were prescribing hydroxychloroquine, the malaria drug favored by Trump as a coronavirus treatment despite scant evidence

To underscore that the effort was to promote Trump's political self-interest

an aide to Caputo berated CDC scientists for attempting to use the reports to 'hurt the President' in an Aug. 8 email sent to CDC Director Robert Redfield and other officials that was widely circulated inside the department and obtained by POLITICO. 'CDC to me appears to be writing hit pieces on the administration,' appointee Paul Alexander wrote, calling on Redfield to modify two already published reports

Alexander tried to gain control of the contents of the MMWR, calling

 on Redfield to halt all future MMWR reports until the agency modified its years-old publication process so he could personally review the entire report prior to publication, rather than a brief synopsis. Alexander, an assistant professor of health research at McMaster University near Toronto whom Caputo recruited this spring to be his scientific adviser, added that CDC needed to allow him to make line edits — and demanded an 'immediate stop' to the reports in the meantime.

Apparently CDC staffers resisted Caputo, Alexander et al, so that eventually contents untouched by their manipulations did become public.

One day after the Politico article, the New York Times  confirmed its essential findings

Current and former senior health officials with direct knowledge of phone calls, emails and other communication between the agencies said on Saturday that meddling from Washington was turning widely followed and otherwise apolitical guidance on infectious disease, the Morbidity and Mortality Weekly Reports, into a political loyalty test, with career scientists framed as adversaries of the administration.

The Times called Caputo's work a "bullying operation."  

The Washington Post also confirmed the Politico report after gaining access to emails sent by Alexander.

The Assistant Secretary's Actions Became Bizarre, and He Resigns Citing Mental Health Issues

As soon as the story of his attempts to "bully" the MMWR became public, Caputo's actions became more bizarre.  On September 14, 2020, the New York Times reported:

The top communications official at the powerful cabinet department in charge of combating the coronavirus made outlandish and false accusations on Sunday that career government scientists were engaging in 'sedition' in their handling of the pandemic and that left-wing hit squads were preparing for armed insurrection after the election.

Michael R. Caputo, the assistant secretary of public affairs at the Department of Health and Human Services, accused the Centers for Disease Control and Prevention of harboring a 'resistance unit' determined to undermine President Trump, even if that opposition bolsters the Covid-19 death toll.

Then he announced:

he personally could be in danger from opponents of the administration. 'If you carry guns, buy ammunition, ladies and gentlemen, because it’s going to be hard to get,' he urged his followers.

He went further, saying his physical health was in question, and his 'mental health has definitely failed.'

'I don’t like being alone in Washington,' Mr. Caputo said, describing 'shadows on the ceiling in my apartment, there alone, shadows are so long.'

 One day later Politico reported an announcement:

Today, the Department of Health and Human Services is announcing that HHS Assistant Secretary for Public Affairs Michael Caputo has decided to take a leave of absence to focus on his health and the well-being of his family

Alexander also left the agency 

Since Caputo's departure, Politico published an article detailing how he placed "his own loyalists and Trump veterans" into public relations positions at the DHHS. 

Also, the New York Times published an article detailing some of his efforts to bully CDC staff,

Mr. Caputo moved to punish the C.D.C.’s communications team for granting interviews to NPR and trying to help a CNN reporter reach him about a public relations campaign. Current and former C.D.C. officials called it a five-month campaign of bullying and intimidation.

For instance, after Mr. Caputo forwarded the critique of Dr. Schuchat to Dr. Redfield, C.D.C. officials became concerned when a member of the health department’s White House liaison office — Catherine Granito — called the agency to ask questions about Dr. Schuchat’s biography, leaving the impression that some in Washington could have been searching for ways to fire her.

In another instance, Mr. Caputo wrote to C.D.C. communications officials on July 15 to demand they turn over the name of the press officer who approved a series of interviews between NPR and a longtime C.D.C. epidemiologist, after the department in Washington had moved to take ownership of the agency’s pandemic data collection.

'I need to know who did it,' Mr. Caputo wrote. A day later, still without a reply, Mr. Caputo wrote back. 'I have not received a response to my email for 20 hours. This is unacceptable,' he said.

Efforts to Turn the MMWR Into Propaganda Criticized byAcademics in Public Health and Health Care, and the CEO of the Robert Wood Johnson Foundation

Per the Politico article above, Jennifer Kates, leader of the Kaiser Family Foundation's global health work

defended the CDC's process as rigorous and said that there was no reason for politically appointed officials to review the work of scientists.

Per the New York Times article above, Dr. William Schaffner, an infectious disease specialist at Vanderbilt University who sits on the external editorial board of the Morbidity and Mortality Weekly Report, said Caputo's operation 

undermines the credibility of not only the M.M.W.R. but of the C.D.C. And the C.D.C.’s credibility has been tarnished throughout Covid already

Per USA Today on September 13, 2020:

The interference is not just anti-science but disinformation intended to deceive the American public, said Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Institute in La Jolla, California.

'This is outright egregious. It’s despicable,' Topol said, accusing Redfield and other leaders of allowing the agency to be hijacked by politics.

Also,

 On Twitter, Dr. Sherri Bucher, a global health researcher, wrote, 'There are no words to articulate how horrific this is. Trust & credibility, shattered, overnight. MMWR has been, for a long time, one of the most reliable, steadfast, scientific resources; unquestioned veracity, impeccable reputation for quality of data/analysis. No longer.

The Washington Post published an op-ed by Dr Erin Marcus, a professor of clinical medicine at the University of Miami Miller Medical School:

Caputo’s manipulation is appalling. If left unchecked, it could have disastrous consequences for the reputation and reliability of the CDC, which has already been battered by the U.S. response to covid-19. It could also prove devastating for medical practice in the United States more broadly.

In Scientific American, Dr Richard Besser, the CEO of the Robert Wood Johnson Foundation, wrote an op-ed entitled "We can't allow the CDC to be tainted by politics," noting:

 To meddle with, delay or politicize these [MMWR] reports would be a form of scientific blasphemy as well as a breach of public trust that could undermine the nation’s efforts to fight the coronavirus.

Summary

So to summarize, the White House put a pro-Trump political operative who had allegedly been involved in producing propaganda and disinformation in support of Trump to oversee all Department of Health and Human Services communications.  He and his hired cronies tried to bully and intimidate DHHS, particularly CDC staff, and to distort the contents of the renowned MMWR to support the Trump message.  Had these efforts succeeded they would have seriously impeded efforts to control the coronavirus pandemic by undermining the dissemination of scientific evidence needed for pandemic management and clinical care for affected patients.  

I found several academic public health and health care professionals willing to criticize Caputo and cronies' actions.  I found one leader of a prominent health care foundation willing to at least implicitly criticize them.  I found no one willing to hold accountable anyone at the "top" of the government who hired Caputo or encouraged his actions.  On this case, I could find no leader of a health care organization other than Dr Besser willing to say anything at all.   

Conclusions

Last month, we noted how disinformation about the coronavirus pandemic is being disseminated by the US president. 

Since then, two major efforts to use the CDC, the lead US public health organization, to support President Trump's political messaging, in effect, to function as a political propaganda outlet.  Individual US academic and practicing public health and health care professionals have been willing to decry these efforts, though not to directly hold Trump and his top lieutenants in the executive branch accountable.  In some cases, leaders of major medical organizations have been willing to state the principles that should have been upheld within the government.  

However, no chairpersons, deans, chancellors, vice-presidents for health affairs, university presidents; or journal editors, hospital executives, leaders of professional societies, executives of health care corporations, etc, etc were willing to publicly challenge Trump and his top collaborators.  Such leaders so far have also been unwilling to challenge Trump's efforts to spread disinformation.

To be charitable, such leaders may be to used to a kinder, gentler era to be able to fully comprehend that parts of the US government meant to be apolitical advocates for public welfare, such as the CDC, are being pushed to become part of an incipient Ministry of Propaganda.  

Fighting a deadly pandemic is hard enough.  It is gut wrenching that the fight is being subverted by political leaders spreading propaganda and disinformation.  It is sad that front line public health and health care professionals are hardly supported in their work by those who claim to lead them.  Where is the courage?  Where is the outrage?

"If not now, when?"

 

As US Attorney, Labor Secretary Nominee Enabled Drug and Biotechnology Executives' Impunity

The new Trump administration nominee for US Secretary of Labor is a former US Attorney for the southern district of Florida.  In that role, he seemed to uphold the ideas that certain big corporations, particularly big pharmaceutical and biotechnology corporations, are too big to jail, and that top executives of big corporations should not be held accountable for their corporations' actions.

He had central involvement in three big settlements of charges of corporate misbehavior which held no individuals accountable for enabling, authorizing, directing or implementing the bad behavior.  The settlements imposed only monetary penalties on the corporations as a whole, accompanied at times by corporate integrity agreements.  In some cases, the failure to charge any individuals at the corporation occurred despite the corporations' history of previous bad behavior.  In each case, the penalties seemed unable to deter more bad behavior by the corporations going forward.  It was not obvious that any of the corporate integrity agreements were enforced. Thus, he enabled the continuing impunity enjoyed by the leadership of large health care organizations. 

The three cases, all discussed on Health Care Renewal, were, in approximate chronologic order:

2005 - GlaxoSmithKline Settled Charges of Overbilling Medicare and Medicaid for Zofran and Kytril

As we discussed in 2005, GlaxoSmithKline has settled for $150.8 million US Department of Justice charges that the company fraudulently overbilled Medicare and Medicaid. The alleged scheme involved inflating average wholesale prices for Zofran and Kytril used to set reimbursement rates.  According to the 2005 Department of Justice news release, "GlaxoSmithKline has agreed to enter into an addendum to its existing Corporate Integrity Agreement with the Office of Inspector General of the Department of Health and Human Services that, among other things, will require the company to report accurate average sales prices and average manufacturer's prices for its drugs covered by Medicare and other federal healthcare programs."

No individual who authorized, directed, enabled or implemented these alleged actions suffered any penalty.  The decision not to prosecute any individuals was made after the first (2004) famous Paxil case.  Paxil is the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General Elliott Spitzer.  That case included allegations of suppression and manipulation of clinical research, and was discussed in great detail in the book Side Effects by Alison Bass.  We posted about various aspects of this case, e.g., here, here, and here. 

Since 2005, we have discussed myriad examples of misbehavior by GSK.  Notably the company made a $3 billion settlement in 2012 for all sorts of allegations involving multiple drugs, (see this post).  Its most recent settlement was in 2016 for bribing Chinese doctors (see this post).  Other cases included the manipulation of Study 329 (see this post), the manipulation and suppression of evidence about Avandia (see this post).  So the 2005 settlement seemed to have little deterrent effect.

The 2005 DOJ press release included this quote

'As our nation struggles to contain healthcare costs, we must ensure that drug manufacturers do not take advantage of the poor, the elderly or the sick by illegally inflating the price of prescription drugs. That a manufacturer would fraudulently inflate the cost of a drug used primarily to reduce the side effects of cancer treatments is unconscionable,' said U.S. Attorney R. Alexander Acosta of the Southern District of Florida.      

2007 - Bristol Myers Squibb Settled Charges of Kickbacks to Physicians and Fraudulent Marketing of Abilify 

As we discussed in 2007, BMS was charged by the US government for promoting the atypical anti-psychotic drug Abilify for use by children and the elderly absent any good evidence that it provided benefits that outweighed harms for these group. So such patients who received these drugs due to the overpromotion might have been harmed, and probably did not benefit.   One means used to promote the drug was giving kickbacks to physicians.  The settlement included monetary penalties to the company totaling $515 million, and a five-year corporate integrity agreement to ensure its compliance with the law.

Note that the corporate integrity agreement did not appear to have improved subsequent BMS behavior.  Since 2007, we have noted that:
 - In 2014, BMS settled allegations its subsidiary Lantheus Medical Imaging Inc evaded state taxes (per the Corporate Crime Reporter)
 - In 2015, BMS settled allegations by the US Securities and Exchange Commission (SEC) that it bribed physicians in China to induce them to prescribe its drugs.  (Look at our post here).

No individual who authorized, directed, enabled or implemented the actions alleged in the 2007 settlement suffered any negative consequences. The decision not to charge any individuals seemed to be made despite the company's history of previous bad behavior, which included:
 - In 2003, for $617 million, BMS settled suits alleging it tried to prevent competition from low cost generic versions of its products Taxol and Buspar (per the NY Times).
- In 2004, for $150 million, BMS settled suits by the SEC alleging accounting fraud (per the NY Times here).
- In 2007, BMS paid a $1 million dollar penalty while pleading guilty to lying to federal agents about a deal with the Canadian drug company Apotex (per Law360).   In 2009, it paid additional financial penalties in response to a US Federal Trade Commission charge about this case (per the FTC).

According to the 2007 Department of Justice news release,  one of the two US Attorneys involved in the 2007 BMS settlement was R Alexander Acosta of Florida.

2007 - Sanofi-Aventis Settled Charges of Overcharging Medicare for Anzemat

Per a 2007 post, Sanofi-Aventis settled allegations that it overcharged the US government for the drug Anzemet.  Of course, no individual who authorized, directed, enabled or implemented these alleged actions suffered any negative consequences.

As described by a Law360 post in 2007, he settlement also included yet another corporate integrity agreement.  This did not deter further misbehavior by Sanofi-Aventis.  It  settled charges of overcharging the US Medicaid system in 2009 for over $90 million  (see post here), and charges that it gave doctors kickbacks to induce them to prescribe the drug Hyalgan in 2012 (see post here).  In 2014, Sanofi's Genzyme subsidiary settled charges it promoted a surgical film product for unproven uses (see post here), and settled further charges from this case in 2015 (see post here).

Law360 also reported,

 U.S. Attorney for the Southern District of Florida R. Alexander Acosta said the lawsuit proved that corporations could not get away with misleading the government by exploiting a health care system based on honesty.

'Again, a corporation has been caught fraudulently inflating the cost of a drug used primarily to reduce the side effects of cancer treatments without regard to the increased costs borne by government health care programs or elderly and indigent patients,' Acosta said. 

Summary

President Trump promised time and again that he would stand up for the forgotten working people and families of the US, and would reduce the power of big corporate interests.  Now, his nominee to be Labor Secretary is an attorney who seemed unwilling to personally challenge top management of big drug and biotechnology companies when their companies misbehaved.  He did not hold management accountable even when their companies had previously and repeatedly misbehaved.  His failure to hold individuals accountable apparently failed to deter future bad behavior by the same companies.

There are many more examples on this blog of legal settlements, and even episodes involving bribery, fraud, kickbacks, and other crimes that demonstrate the continuing impunity of leaders of large health care organizations.  It is likely that such impunity has led to the general concerns that the system is "rigged" in favor of the wealthy, the well-connected, and the insiders.

And we have a President who has promised to act against the "rigged system," but seems to be bent on appointing wealthy, well-connected people to run his executive branch. Now he has just nominated someone who failed to hold wealthy, well-connected corporate executives accountable for their corporations bad behavior.  So, in any case, as we have said before...)

We once again see the perverse incentives at work that drive bad behavior by health care oragnizational leaders.  One can obviously become very rich by directing this bad behavior.  Up to now, the likelihood that one would eventually pay any penalty for doing so was tiny.  Now it is slightly higher.  Whether those up the ladder, who might have authorized the behavior, turned a blind eye to it, or avoided enquiring about anything that could be bad behavior, as long as the money came in, will suffer any negative consequences from these actions or inactions in the future is still unclear.

We will not make any progress reducing current health care dysfunction if we cannot have an honest conversation about what causes it and who profits from it.  True health care reform requires ending the anechoic effect, exposing the web of conflicts of interest that entangle health care, publicizing who benefits most from the current dysfunction, and how and why.  But it is painfully obvious that the people who have gotten so rich from the current status quo will use every tool at their disposal, paying for them with the money they have extracted from patients and taxpayers, to defend their position.  It will take grit, persistence, and courage to persevere in the cause of better health for patients and the public. 

Petitions for Research Integrity and Against Corruption Available for Signature

Recently, two petitions relevant to the goals of Health Care Renewal have become available. 

US Petition to "Stop False Reporting of Drug Benefits & Harms by Making FDA & NIH Work Together"

Health Care Renewal blogger Dr Bernard Carroll, along with Dr Mickey Nardo, who blogs on 1BoringOldMan, and Emeritus Professor John H Noble Jr have authored a petition to improve the reporting of clinical research in the US, and hence combat the manipulation of clinical research, a topic we often discuss.

Its essence is:

We now petition Congress to require the FDA and NIH to coordinate their monitoring and sharing of key information through ClinicalTrials.gov. Working together, the two agencies could enable stakeholders to verify whether purported scientific claims are faithful to the a priori protocols and plans of analysis originally registered with the FDA. Publication of analyses for which such fidelity cannot be verified shall be prohibited unless the deviations are positively identified (as in openly declared unplanned, secondary analyses). This prohibition shall include scientific claims for on-label or off-label uses made in medical journals, archival conference abstracts, continuing education materials, brochures distributed by sales representatives, direct-to-consumer advertising, and press releases issued by companies or their academic partners. It shall extend to FDA Phase 2, Phase 3, and Phase 4 clinical trials. By acting on this petition, Congress will create a mechanism for stakeholders independently to verify whether inferences about clinical use suggested by the unregulated corporate statistical analyses can be trusted.

The full petition is available online, and is sponsored by the Science and Evidence Council of the Right Care Alliance.

Transparency International Declaration Against Corruption

Transparency International is sponsoring a declaration, valid globally, against corruption.  We often discuss health care corruption, despite the apparent taboo against doing so.  As we just noted, this comes as Transparency International is launching a major initiative against health care corruption.

Its essence is:

I will not pay bribes
I will not seek bribes
I will work with others to campaign against corruption
I will speak out against corruption and report on abuse
I will only support candidates for public office who say no to corruption and demonstrate transparency, integrity and accountability.

It is available for signature here.  

Transparency International Reports on Massive Corruption in the Pharmaceutical Sector - Media Hardly Notices

Health Care Corruption as a Taboo Topic

Transparency International (TI) defines corruption as

Abuse of entrusted power for private gain

In 2006, TI published a report on health care corruption, which asserted that corruption is widespread throughout the world, serious, and causes severe harm to patients and society.

the scale of corruption is vast in both rich and poor countries.

Also,

Corruption might mean the difference between life and death for those in need of urgent care. It is invariably the poor in society who are affected most by corruption because they often cannot afford bribes or private health care. But corruption in the richest parts of the world also has its costs.

The report did not get much attention.  Since then, health care corruption has been nearly a taboo topic in the US.  When health care corruption is discussed in English speaking developed countries, it is almost always in terms of a problem that affects benighted less developed countries.  On Health Care Renewal, we have repeatedly asserted that health care corruption is a big problem in all countries, including the US, but the topic remains anechoic.

Yet somehow, a substantial minority of US citizens, 43%, seemed to believe that corruption is an important problem in US health care, according to a TI survey published in 2013 (look here).  But that survey was largely ignored in the media and health care and medical scholarly literature in the developed world, and when it was discussed, it was again in terms of results in less developed countries.  Health Care Renewal was practically the only source of coverage in the US of the survey's results.

Transparency International's New Report on Corruption in the Pharmaceutical Sector

Now Transparency International (TI) has tried, and Health Care Reenewal will try again.  In June, 2016 Transparency International published a new report entittled

Corruption in the Pharmaceutical Sector

The report's executive summary states:

Within the health sector, pharmaceuticals stands out as sub-sector that is particularly prone to corruption. There are abundant examples globally that display how corruption in the pharmaceutical sector endangers positive health outcomes.

In my humble opinion, the report is particularly significant in that it classifies as corrupt various kinds of activities that occur within the pharmaceutical sector (and also in other parts of health care) which are often discussed publicly as anything from standard operating procedure through unfortunate errors to unethical behavior. These include many activities which we have frequently discussed on Health Care Renewal. For example,

Manipulation of Clinical Research

We have frequently discussed how pharmaceutical companies, and biotechnology, medical device, and other health care companies and organizations, may manipulate clinical research to enhance the likelihood that is results will favor their products and marketing goals, even if the results are biased, inaccurate, could mislead physicians and patients, and ultimately harm patients.  The TI report included: 

As pharmaceutical companies rely on gaining market entry in order to recoup R&D costs, when there is a lack of oversight in clinical trial data publication a conflict of interest exists in which a pharmaceutical company may have an incentive to manipulate clinical trial data. When clinical trial data is manipulated medical literature can become biased with positive findings fabricated, positive findings exaggerated or negative results hidden. This can result in inadequate prescribing patterns because HCPs rely on clinical trial data to make decisions on which medicines to use to treat patients.

Suppression of Clinical Research

We have frequently discussed how health care organizations (as above) may outright suppress clinical research when the results fail to support their interests.  The TI report included:

Transparency and access to information through mandatory clinical trial registration, sanctions for not registering results or providing clinical trial information, and the publication of both positive and negative results are commonly discussed as helpful tools to curb corruption. With the European Medicines Agency (EMA) as a notable positive exception, public agencies and authorities do not require R&D-based pharmaceutical companies to make their raw data publicly available, making it impossible to verify whether the reported results are accurate. Based on laws and regulations clinical trial data is considered to be proprietary information, which allows pharmaceutical companies to conceal important data from the public domain.

Manipulation of the Dissemination of Clinical Research

We have frequently discussed how health care organizations may manipulate the dissemination of clinical research, through various forms of publications, presentations, courses, media summaries, etc, to favor their products and marketing goals, even if the results are misleading and could harm patients.  For example, a while back we discussed the problem of "ghost-written" articles appearing in scholarly journals. The TI report included:

The practice of ghostwriting is also a risk with clinical trials. Ghostwriting involves the writing of clinical trial publications by industry and then having a highly esteemed researcher pass these findings off as their own without disclosing their actual involvement with the authorship of the article. It is a common practice, particularly in industry led trials. Ghostwriting is done to increase the prestige and reputation of the findings, while simultaneously researchers are able to improve their reputation, which can lead to promotions. Clearly this practice can result in inaccurate results being published.

Deceptive Marketing

We have frequently discussed how marketing of pharmaceuticals (and nearly everything else in health care) may be deceptive, favoring companies' products and services, but again misleading health care professionals and patients, and ultimately risking patient harm.  In the extreme, pharmaceutical companies (and other health care organizations) may resort to bribes or kickbacks.  The TI report included:

There are several methods for a corrupt pharmaceutical company to unethically market its medicines. At its most simple a pharmaceutical company can bribe a HCP directly with payments so its medicines are more likely to be prescribed. More abstrusely individuals may include a pharmaceutical company’s medicine on the national list that is reimbursed by public funds, in return for an indirect bribe by being sent to inappropriate holiday destinations for lavish conferences.

Corrupt marketing practices also include pharmaceutical companies providing misleading information regarding the safety and efficacy of a medicine to influence doctors’ prescribing habits and encouraging off-label, unlicensed use to increase sales.

Other Topics

Finally, the report mentions such issues as the revolving door, regulatory capture, etc, etc, etc

A Striking, and Strikingly Anechoic Report

Again, while the report summarizes information that is likely familiar to most Health Care Renewal readers, what is striking is that it describes manipulation of clinical research, suppression of clinical research, manipulation of dissemination of clinical research, and deceptive marketing as corruption.  That is a sentiment rarely heard in the US, and one that appears nearly taboo.  

Demonstrating the strength of the taboo, this striking report has gotten almost no attention in the media or scholarly medical and health care literature in the developed English-speaking countries.  Let me note the important exceptions, however.

I learned of the report from a brief news item from the BMJ, the prestigious UK journal that seems most at the forefront of championing the integrity of medical and health care research.(1)  The only substantial news article I could find on the report was also from the UK, in the Independent.  Its sub-title is worth repeating:

Transparency International says corruption is making a few rich and wrecking the health of some of the world's poorest people

Also, there were brief articles in Reuters, and in (web-only) FiercePharma.  That is about it so far.

The report itself suggests why it has been so anechoic, just like nearly every other attempt to expose health care corruption to public discussion.  Essentially, there is so much money to be made through pharmaceutical (and by implication, other health care corruption) that the corrupt have the money, power, and resources to protect their wealth accumulation by keeping it obscure.  In the TI Report itself,

However, strong control over key processes combined with huge resources and big profits to be made make the pharmaceutical industry particularly vulnerable to corruption. Pharmaceutical companies have the opportunity to use their influence and resources to exploit weak governance structures and divert policy and institutions away from public health objectives and towards their own profit maximising interests.

Keep in mind that the money made from corruption does not just go to innocent peoples' retirement funds that are invested in pharmaceutical stocks.  It predominantly goes to top corporate executives and managers, and their cronies who preside over the corrupt practices.


I might as well repeat myself once again.  As I wrote in 2015,

If we are not willing to even talk about health care corruption, how will we ever challenge it? 

So to repeat an ending to one of my previous posts on health care corruption....  if we really want to reform health care, in the little time we may have before our health care bubble bursts, we will need to take strong action against health care corruption.  Such action will really disturb the insiders within large health care organizations who have gotten rich from their organizations' misbehavior, and thus taking such action will require some courage.  Yet such action cannot begin until we acknowledge and freely discuss the problem.  The first step against health care corruption is to be able to say or write the words, health care corruption.

Reference

1.  Torjesen I.  Group calls for more to be done to tackle corruption in the pharmaceutical industry. BMJ 2016;353:i3099. Link here.

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

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.  

Entresto: Blockbuster, or Just Over Hyped? - Whatever, It Will Cost $4500 a Year

The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price.  Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.  


Questions Raised by the One Big Published Controlled Trial

Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.

Does Sacubitril Actually Work?

 The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril.  Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF.  However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day.  Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done.  So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril.  Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.

What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?

The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan.  Furthermore, the trial had an active run-in period which resulted in the exclusion of  patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period.  This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial.  Finally, the trial, while big, was not big enough to discover rare but severe adverse effects.  Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.

How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?

The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease.  CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.

Other Doubts and Questions

In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity.  These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.

As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions.  As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.

So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.

More Enthusiasm and Hype about Entresto

These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it.  As soon as it was approved, the hype machine started up in a big way.

Per the NY Times,

'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis’s pharmaceutical division, said in an interview.

Per the Wall Street Journal,

Clyde Yancy, chief of cardiology at Chicago’s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It’s clearly superior to what we have.'

Per a Medscape news post, Dr Clyde Yancy also said,

A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.

And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,

I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.

The Medscape article did document some doubts.  Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem.  Finally, Dr Yancy allowed that the early termination might be a problem.   Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem.  Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,

Can we change the narrative?  I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.

Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis.  Is is possible these commercial relationships tempered any concerns that might have had about the study design. 

I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death.  So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer.  But is it crystal clear the latest innovation is that good?

Billions of Dollars in Play

But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap.  Per the NY Times,

Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....

Novartis wants to convince you that it's not really that expensive

Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.

He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice.  Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either. 

In the financial news, you could almost imagine the salivation.  Per the WSJ,

Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.

In Reuters,

Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.

Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.

'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'

Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year.  But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?

Summary

We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections.  Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.

Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.

 Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor.  It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better.  As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,

When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.

To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits.  The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here).   Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous.  This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.


The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism.  We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them.  The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.

True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care. 



References

1.   McMurray JJV, Packer M, Desai AS et al.  Angiotensin - neprilysin inhibition versus enalapril in heart failure.  N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077  Link here.

2.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.