FDA Approval of Aducanumab

Almost twenty years ago, I was a volunteer nursing-home ombudsman. The doctor at the nursing home I visited was a huge proponent of preventive therapies, and prescribed as many preventive drugs as possible for residents (while frequently ignoring complaints about current medical problems that were bothering them). Among the drugs he very freely prescribed were cholinesterase inhibitors for Alzheimer's disease, then fairly new. I was stunned when I learned he prescribed one to a resident whom I knew well and who seemed fully oriented to me, but that was the case. From what I've learned since, these drugs don't have any really noticeable clinical benefits anyhow, so they are unimpressive.

But if prescribing those drugs so freely seemed like a dubious course of action to me then, they look almost good now by comparison to the latest drug approved by the FDA for Alzheimer's disease, aducanumab (Aduhelm). This drug doesn't have any convincing evidence that it benefits patients, AND it comes with potentially serious side effects that require a lot of monitoring.

The quality of life implications of this are troubling. As one doctor notes:

"This is a drug that medicalizes someone’s life,” said Mantyh. Besides the hourlong, once-monthly infusions, an Aduhelm prescription comes with frequent lab tests and brain scans to monitor for signs of swelling or bleeding. In two of Biogen’s clinical trials, more than one-third of participants who received Aduhelm developed painful brain swelling; about 17% to 19% had small bleeds in their brains. Headaches, dizziness, nausea — all might trigger more time spent in the hospital. Such constraints could make it difficult to travel internationally or spend time with family members in other states.

The article also notes that, except in the case of adverse side effects, it is hard to decide when to discontinue a drug when it's likely to be quite unclear whether it's benefitting the patient or not.

How did the FDA come to approve this drug without stronger evidence that it is actually beneficial? It used an "accelerated approval" pathway and based the approval on the fact that the drug diminishes the size of amyloid plaques. This was despite the fact that in multiple trials. reducing amyloid plaques has not been shown to improve things clinically for patients. As Derek Lowe wrote (and his whole post is well worth reading):

So the FDA has, for expediency’s sake, bought into the amyloid hypothesis although every single attempt to translate that into a beneficial clinical effect has failed. I really, really don’t like the precedent that this sets: what doesn’t get approved, now? I suppose only things that definitely cause harm, because otherwise why not just ask for the same deal that Biogen got, and go out and prove efficacy while you turn a profit?

A commenter on the Lowe blog ("Radioactive Man") wryly noted:

All the other companies that successfully developed anti-amyloid drugs then discontinued them for lack of efficacy must be kicking themselves to realise they were approvable all along. It makes me wonder, could they just simply dust off their old phase 3 results and go straight to applying for approval without even doing any more clinical studies? If those results are comparable to aducanumab, why not?

Elsehere too, there was speculation on whether other companies could go back and now seek approval of similar drugs that cleared plaque without showing clinical improvement.

[Could] a slew of amyloid-reducing agents from the past...now be re-evaluated under the accelerated approval pathway?...In a public defense of her agency’s decision on June 22, Woodcock said future approvals under this pathway would be possible if the magnitude of plaque reduction was great enough.

Not one of the FDA advisory committee members voted to recommend approving aducanumab. Ten voted against, and one voted "uncertain." Three have since resigned in protest. In his resignation letter, one stated this is "was probably the worst drug approval decision in recent FDA history."

A professor who has served on many FDA committees commented:

“This isn’t the first time when I was on a committee where the committee voted one way and the FDA decided another,” said biostatistician Scott Emerson....“This was the first time that nobody voted for approval of this drug — nobody — and they went against that.”

Despite the protests, proponents of the drug were breezy, lauding it as a great "breakthrough." The acting commissioner of the FDA, Janet Woodcock, said that she is “not that concerned” about criticisms of the approval. And meanwhile, the first patient got his first infused dose of aducanumab. Dr. Stephen Salloway, director of the memory and aging program at the Rhode Island hospital giving the infusion, stated at a press conference: "It's transforming how we treat Alzheimer's." He snottily added, "For those of you who don't know, it's a devastating disease."

Salloway's remarks make me really furious. A supposed medicine has to be judged by its results, not by the urgency or seriousness of the condition it is alleged to treat. And the "evidence" was totally cherry-picked post hoc after the failure of their Phase 3 trials, following the bad rule: "If you don't succeed, change the definition of success."

There's more to be said about the aducanumab approval, but this post is long enough. More in the next post.

Just Another Small Health Care Scam... the Trump Network and its Bogus Diagnostic Tests and Unproven Vitamin Treatments Resurfaces

Introduction

On Health Care Renewal, we frequently discuss deceptive marketing schemes designed to sell tests and treatments whose benefits for patients do not clearly outweigh their harms, and sometimes which are useless or dangerous.  In fact, we have to be selective about discussing such cases, because they are all too common.  Therefore, we tend to focus on cases involving the biggest and most powerful health care organizations, and/or the worst risks to patients.

We have generally not discussed the myriad promotions of dubious "nutritional" tests and therapies, because there are just so many of them, the players involved are generally small, and these products were effectively deregulated in the US by the 1994 Dietary Supplement Health and Education Act.

However,...

Just Another Multi-Level Marketing Scam?

In 2016, we posted about what appeared to be just another nutritional scam, but one that seemed at the time to have broader implications.  A colorful account of how it worked came from a 2011 New Yorker article, which focused on a marketer named Izzo:

He would order the vitamins from a company called Ideal Health. She would earn a commission on the sale and he, in turn, would become a part of her team and encourage other people to buy the vitamins. For those sales, Izzo would earn a commission, as would she (his 'upline'), and then the people he sold the vitamins to would become part of his sales team and would go on to create their own sales teams, who would go on to create their own sales teams, etc., ad infinitum, all of them funneling commissions from their sales up to Izzo and the woman on the phone. As he listened, 'something clicked,' Izzo says. 'I saw the beauty of the business model. And I said, ‘How can I do this, and do this big?’ '

Note that this was an interesting scam in that it involved a multi-level marketing (MLM) model, which sometimes are called pyramid schemes. What most interested the New Yorker back then, however. was that the scam got connected to a prominent, flashy New York businessman, one Donald J Trump, yes, that Donald J Trump:

'The name is hot!' Donald Trump booms over the speakerphone from his office at 725 Fifth Avenue, where, ever since The Apprentice breathed new life into his brand, he has presided over an ever-diversifying array of businesses. He is, of course, speaking of his own name. 'It’s on fire!'

In March 2009, Trump purchased Ideal Health, rebranding it the Trump Network. Though the packaging has now been imprinted with the Trump family crest, the product line is still much the same. There are the two multivitamins: Prime Essentials and the more expensive Custom Essentials, the ingredients of which are determined by the Trump Network–branded PrivaTest, a urine test that claims to determine which vitamins the user needs. There’s also a line of healthy snacks for kids called Snazzle Snaxxs, QuikStik energy drinks, and a Silhouette Solutions diet program. With the Trump investment, the company has added a skin-care line that goes by the seductively foreign name BioCé Cosmeceuticals.

How much of a scam was this?  The trick to this scheme was that it involved not only the sale of nutritional supplements, but the use of bogus urine testing to develop customized nutritional regimens.

 The Trump Network sold many health and wellness products, and its main one was a customized nutritional supplement whose composition was determined by a urine test, called the PrivaTest.

A former marketer provided STAT with a kit for Ideal Health’s PrivaTest. It contained a urine collection cup, five test tubes, a cold pack, a biohazard bag, a prepaid FedEx mailing label, and detailed instructions. Customers collected their urine and shipped it to a lab for analysis. That lab analyzed the urine with three tests and produced a report, which was sent to The Trump Network.

The Trump Network bundled the report with a package of pills and shipped it all back to the customer. The pills were marketed as 'Custom Essentials,' formulations based on the results of the test and manufactured by another lab. In all, there were 48 formulations.

According to an archived version of The Trump Network’s website that can still be found online, the PrivaTest, along with a month’s worth of the Custom Essentials, cost $139.95. Retesting was available for $99.95, plus shipping and handling. The company recommended retesting every nine to 12 months.

Other products purportedly tested for food allergies, stress, and digestive health. One claimed to measure 'the balance between your ‘good’ estrogen and your ‘bad’ estrogen.'

There was, however, no evidence that any of this testing meant anything, or that nutritional regimens constructed using it would do any good for patients.   First, there appeared to be no publicly available data on how the tests worked, what they actually tested, or how accurate they were.  Then there was no data about how the test results could rationally be used to suggest particular mixes of vitamin supplements.  Also, there was apparently no public data about what vitamins were in the potions sent to consumers, their purity, their strength, etc.

The New Yorker asked some experts about this:

 While the FDA may not have evaluated the tests or supplements, independent scientists have — and raised many questions.

Cohen, one of several scientists who reviewed materials from Ideal Health and The Trump Network, said that the tests were marketed too broadly and seemed to be 'pathologizing normal human life.'

The website, for example, recommended its “AllerTest” to anyone who had dark circles under their eyes, occasional digestive problems, fluctuating blood sugar, sinus and respiratory problems, or tiredness after eating.

'Does your blood sugar fluctuate?' Cohen said, laughing. 'If your blood sugar does not fluctuate, you are extremely ill. You will not be long on this planet.'

What’s more, the AllerTest did not measure food allergies, as the network’s website claimed it would, according to outside analysis of materials from the testing lab and Ideal Health publications.

The test measured information about an antibody known as immunoglobulin G, or IgG, according to company publications. The antibody is normally produced in the body and not indicative of a food allergy, said Dr. Robert Wood, director of pediatric allergy and immunology at Johns Hopkins School of Medicine.

'There’s no disease condition for which the IgG antibodies have any relevance at all,' Wood said.

Note that this did not discuss, but implied that administering bogus tests to people and patients could either make them think they have important medical problems when they do not, or make them think that they do not have problems which they actually have.  Thus systematically administering bogus tests to a population could harm that population.

 In any event, like many such scams, the whole thing eventually faded away, and Trump pulled out of the licensing deal in 2011.

There basically ended our post, noting that maybe it was significant that a then 2016 presidential candidate who was favored to win the Republican nomination once got involved in such an obvious, if relatively small-time health care scam (and one involving a possible pyramid scheme, and bogus diagnostic testing to boot).  And yet this story, like many involving unethical health care practices, seemed to fade away.  Of course, in this case, it was also rapidly drowned out by the increasing chaos being produced by Trump and his cronies.

But wait, there is more.

The Class Action Lawsuit Against Trump and Family for Allegedly Fraudulent Multi-Level Marketing Schemes

The Trump candidacy, of course, despite many predictions to the contrary, did not fade away.

And in 2018, a story appeared that again was nearly drowned out by the then ongoing Trump chaos.  As reported by the NY Times in October, a lawsuit surfaced:

The 160-page complaint alleges that Mr. Trump and his family received secret payments from three business entities in exchange for promoting them as legitimate opportunities, when in reality they were get-rich-quick schemes that harmed investors, many of whom were unsophisticated and struggling financially.

Those business entities were ACN, a telecommunications marketing company that paid Mr. Trump millions of dollars to endorse its products; the Trump Network, a vitamin marketing enterprise; and the Trump Institute, which the suit said offered 'extravagantly priced multiday training seminars' on Mr. Trump’s real estate 'secrets.'

Voila, the Trump Network scam reappears.

Of course, early in the NYT article was the caveat:

the lawsuit comes just days before the midterm elections, raising questions about whether its timing is politically motivated.

The Times always likes to report on both sides of the argument, regardless of the merits, but anyway...


Again, all was silent, while chaos raged about other matters, at least until early 2019, when Trump's legal filed their protest asking a judge to dismiss the lawsuit, as reported by Bloomberg,

In a filing Monday, the Trumps claimed they had nothing to do with any alleged fraud. Donald Trump provided celebrity endorsements to ACN from 2006 to 2015, but never owned or controlled the company. And the plaintiffs haven’t identified a single fraudulent statement made by any of the other defendants, the family said.

'No plaintiff is alleged to have paid or lost money to the defendants or to any Trump business, and no defendant is alleged to have solicited any plaintiff for anything,' the Trumps said in the court filing. 'It is undisputed that ACN -- and ACN alone -- through a network of ACN representatives, solicited and collected fees from plaintiffs, for the benefit of ACN'”

At least in the Bloomberg report, there was not a word about the small health care scam that was also alleged, and certainly not about the evidence from that New Yorker article from long ago about how involved Trump was in that, but never mind, and all was silent once again, until....

However, in July, 2019,this month, the judge ruled, again per Bloomberg,

President Donald Trump, his company and three of his children must face a class-action lawsuit in which people claim they were scammed into spending money on fraudulent, multilevel marketing ventures and a dubious live-seminar program.

U.S. District Judge Lorna Schofield in Manhattan ruled Wednesday that the case can go forward with claims of fraud, unfair competition, and deceptive trade practices. The decision likely opens the door for the plaintiffs to start gathering evidence from Trump and his company, including documents and testimony.

The implications are important.  The suit is not just against the Trump Organization, but against Donald J Trump personally, and three of his children.  Absent another challenge from the Trumps et al, there could soon be a discovery process, meaning lots of documents, emails, etc, the sorts of information Trump et al have struggled to keep secret in other contexts, might be disclosed.  Furthermore, additional coverage of this legal development underlined Trump's personal involvement with these schemes - as did, by the way, the old New Yorker coverage of the Trump Network nutritional testing scam, facts that long vanished from the public eye.

For example, Salon reported,

The complaint added, 'Central to Defendants' fraudulent scheme was a company called ACN, a multi-level marketing company ('MLM') that offers a business opportunity to individual participants. From 2005 to at least 2015, Defendants received millions of dollars in secret payments to promote and endorse ACN. In return, Donald J. Trump ('Trump') told prospective investors that '[y]ou have a great opportunity before you at ACN without any of the risks most entrepreneurs have to take,' and that ACN's flagship videophone was doing 'half-a-billion dollars' worth of sales a year.' Trump also told investors that he had 'experienced the opportunity' and 'done a lot of research,' and that his endorsement was 'not for any money.' Not a word of this was true.'"

It has since been revealed that Donald Trump earned $450,000 each for three speeches that he delivered for American Communications Network.

So it appears that Trump personally profited quite a bit from these little scams

Discussion

The nearly anechoic Trump Network story just adds to Trump's and cronies' long history of deception, unethical behavior, and to the questions about crime and corruption that have swirled around them for years, including times well before anyone ever could conceive of Trump as US President.  However, unlike many of the other cases (see this most recent summary here), this one involves health care, diagnostic testing, and patients, not just investors, as potential victims.

Thus this just adds to concerns that the Trump regime is enabling worsening of the ongoing problem of health care corruption in the US.  As we have said before, health care corruption has been nearly a taboo topic in the US, anechoic, presumably because its discussion would offend the people it makes rich and powerful. As suggested by the recent Transparency International report on corruption in the pharmaceutical industry,

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.

Presumably the leaders of other kinds of corrupt organizations can do the same. 

Yet,  Health Care Renewal has stressed "grand corruption," or the corruption of health care leaders.  We have noted the continuing impunity of top health care corporate managers.  Health care corporations have allegedly used kickbacks and fraud to enhance their revenue, but at best such corporations have been able to make legal settlements that result in fines that small relative to their  multi-billion revenues without admitting guilt.  Almost never are top corporate managers subject to any negative consequences.

In the last few years, as discussed here, voluminous reports have surfaced about the corruption of the Trump regime (although none of which, of course, mentioned the small case of Trump's sleazy health care scams).  They included numerous, ongoing cases of Trump's violations of the emoluments clauses of the US Constitution, which forbids a President from receiving payments from foreign countries, of US or state and local governments.  They included numerous appointments of gross instances of the revolving door, in which people with leadership positions in industries, including health care corporations, were given control over agencies which regulate and enforce laws pertaining to the corporations they previously served. They included numerous instances in which US government decisions were made seemingly to benefit Trump, his associates, and his conflicted appointees.  They included instances in which the federal government was used to promote Trump's ongoing business interests.

And now they should include one small health care scam that might have harmed patients.

So anyone concerned about health care corruption needs to realize that when the fish is rotting from the head, it makes little sense to try to clean up minor problems halfway towards the tail. Why would a corrupt regime led by a president who is actively benefiting from corruption act to reduce corruption? The only way we can now address health care corruption is to excise the corruption at the heart of our government.  

It was just a small health care scam...

Johnson and Johnson's Latest Ethical Misadventures: Settled Kickback Allegations, Reportedly Concealed Knowledge of Adverse Effects of a "Sacred Cow" Product

Giant pharmaceutical/ biotechnology/ device company Johnson & Johnson has its famous "credo" which starts with

We believe our first responsibility is to the doctors, nurses and patients, to mothers and fathers and all others who use our products and services.  In meeting their needs everything we do must be of high quality..

Nonetheless, the company has a long history of ethical misadventures (look here, and see appendix below).  Now late in 2018,  we note two more Johnson & Johnson misadventures. In chronological order,


$360 Million Settlement of Allegations of Kickbacks to Medicare/ Medicaid Patients to Support Use of Extremely Expensive Drug

The story, per the New York Times, was that Actelion, a drug maker purchased by Johnson & Johnson in 2017, in 2014-2015 had

raised the price of its main drug, Tracleer, by nearly 30 times the rate of inflation. Tracleer, which is prescribed to treat pulmonary arterial hypertension, sells in pharmacies for an average cash price of about $14,500 for 60 tablets, according to the website GoodRx.

But to facilitate charging such high prices, pharmaceutical companies

often help patients pay their out-of-pocket costs through coupons or other financial assistance. These payments are not just about benevolence — they also help blunt the outrage over rising drug prices by limiting how much patients have to pay. Insurers then cover most of the cost.

But federal anti-kickback laws prohibit companies from giving such financial assistance to Medicare and Medicaid beneficiaries because doing so is considered an inducement to buy their drugs. For years, drug makers have skirted those laws by instead donating to nonprofit charities, which then give the money to Medicare patients. Such arrangements are legal as long as there is no direct coordination between the pharmaceutical company and the nonprofit organization.

However,

Federal prosecutors said Actelion violated the law by collecting detailed data in 2014 and 2015 about the patients receiving help from a nonprofit, the Caring Voice Coalition, and using the data to budget for future donations. As a result, Actelion ensured that the money it donated would be used only to assist patients who used its drugs, and not competing companies’ treatments for the pulmonary condition.

Prosecutors said Actelion kept up the practice even after the charity itself warned the company against it.

Actelion also steered Medicare patients to the Caring Voice Coalition who would have otherwise qualified financially for the company’s free drug program. By directing them to the nonprofit, the company avoided having to provide the drug to eligible patients and left Medicare to cover the cost instead, prosecutors said.

So,

Actelion Pharmaceuticals has agreed to a $360 million settlement stemming from an investigation into whether the company illegally funneled kickbacks through a patient-assistance charity, federal prosecutors said Thursday.

But keep in mind that Actelion is now a Johnson & Johnson subsidiary, and by buying it, Johnson & Johnson bought its financial, and ethical and legal liabilities.. So ultimately it will be Johnson & Johnson which pays the settlement.

Johnson & Johnson Alleged to Have Concealed Knowledge that its Baby Powder Contains Asbestos

The first reporting on this story was a lengthy investigative report from Reuters published December 14, 2018, based on newly released documents produced during a variety of lawsuits.  The report stated

that from at least 1971 to the early 2000s, the company’s raw talc and finished powders sometimes tested positive for small amounts of asbestos, and that company executives, mine managers, scientists, doctors and lawyers fretted over the problem and how to address it while failing to disclose it to regulators or the public.

The documents also depict successful efforts to influence U.S. regulators’ plans to limit asbestos in cosmetic talc products and scientific research on the health effects of talc.

Note that since the 1970s, exposure to asbestos has been recognized as an important health hazard.  In 1972, the US agency OSHA limited occupational exposure to asbestos.  Also,

The World Health Organization and other authorities recognize no safe level of exposure to asbestos.

Johnson & Johnson has been sued by

11,700 plaintiffs now claiming that the company’s talc caused their cancers — including thousands of women with ovarian cancer.

After three major jury verdicts that found Johnson & Johnson liable for cancers caused by asbestos in its baby power,

J&J has said it will appeal the recent verdicts against it. It has maintained in public statements that its talc is safe, as shown for years by the best tests available, and that the information it has been required to divulge in recent litigation shows the care the company takes to ensure its products are asbestos-free. It has blamed its losses on juror confusion, 'junk' science, unfair court rules and overzealous lawyers looking for a fresh pool of asbestos plaintiffs

However, there now seems to be substantial evidence that the company's public posturing is a smokescreen. While in the past Johnson & Johnson internal documents about its management decision making related to talc and asbestos were used in litigation,

Many were shielded from public view by court orders that allowed J&J to turn over thousands of documents it designated as confidential. [But] Much of their contents is reported here for the first time.

These showed,

The earliest mentions of tainted J&J talc that Reuters found come from 1957 and 1958 reports by a consulting lab. They describe contaminants in talc from J&J’s Italian supplier as fibrous and 'acicular,' or needle-like, tremolite. That’s one of the six minerals that in their naturally occurring fibrous form are classified as asbestos.

At various times from then into the early 2000s, reports by scientists at J&J, outside labs and J&J’s supplier yielded similar findings. The reports identify contaminants in talc and finished powder products as asbestos or describe them in terms typically applied to asbestos, such as 'fiberform' and 'rods.'

In 1976, as the U.S. Food and Drug Administration (FDA) was weighing limits on asbestos in cosmetic talc products, J&J assured the regulator that no asbestos was 'detected in any sample' of talc produced between December 1972 and October 1973. It didn’t tell the agency that at least three tests by three different labs from 1972 to 1975 had found asbestos in its talc – in one case at levels reported as 'rather high.'

The article shows that the company repeatedly found evidence that asbestos was present in the raw talc that went into its baby powder, first in 1957, and could be found at times in samples of the finished product since 1971.  Since the 1970s, Johnson & Johnson managers realized that the asbestos was a problem.  For example,

J&J research director DeWitt Petterson visited the company’s Vermont mining operation. 'Occasionally, sub-trace quantities of tremolite or actinolite are identifiable,' he wrote in an April 1973 report on the visit. 'And these might be classified as asbestos fiber.'

J&J should 'protect our powder franchise' by eliminating as many tiny fibers that can be inhaled in airborne talc dust as possible, Petterson wrote. He warned, however, that 'no final product will ever be made which will be totally free from respirable particles.' Introducing a cornstarch version of Baby Powder, he noted, 'is obviously another answer.'

Slightly later on December 14, 2018, the New York Times published its own story on asbestos in Johnson & Johnson talcum powder.  It corroborated the Reuters report while adding informative detail.  It started with:

An executive at Johnson & Johnson said the main ingredient in its best-selling baby powder could potentially be contaminated by asbestos, the dangerous mineral that can cause cancer. He recommended to senior staff in 1971 that the company 'upgrade' its quality control of talc.

Two years later, another executive raised a red flag, saying the company should no longer assume that its talc mines were asbestos-free. The powder, he said, sometimes contained materials that “might be classified as asbestos fiber.”

The carcinogen, which often appears underground near talc, has been a concern inside the company for decades. In hundreds of pages of memos, executives worried about a potential government ban of talc, the safety of the product and a public backlash over Johnson’s Baby Powder, a brand built on a reputation for trustworthiness and health.

Executives proposed new testing procedures or replacing talc outright, while trying to discredit research suggesting that the powder could be contaminated with asbestos, according to corporate documents unearthed by litigation, government records obtained by The New York Times through the Freedom of Information Act, and interviews with scientists and lawyers.

In one instance, Johnson & Johnson demanded that the government block unfavorable findings from being made public. An executive ultimately won assurances from an official at the Food and Drug Administration that the findings would be issued only 'over my dead body,' a memo summarizing the meeting said.

Thus, despite these warnings of asbestos in talcum powder, Johnson & Johnson continued to sell it.  There is certainly now strong reason to suspect that for decades Johnson & Johnson management has been denying its own fears about asbestos contamination of its baby powder, and doing its best to hide evidence of its hazards, thus benefiting the corporate bottom line, but allowing continued exposure of large number of people to a potentially hazardous, even fatal product.



The Business World Tries to Shrug It Off

Responding to the Reuters and New York Times story, many business pundits stated their confidence in Johnson & Johnson as an investment.  For example, Charley Grant wrote in the Wall Street Journal,

But while investors should be wary, they needn’t panic. J&J’s strong finances and diverse revenue base are good coping mechanisms.

Wells Fargo, per CNBC, opined

the selling based purely on the outcomes of any talc litigation is likely overstated.

But does Johnson & Johnson's management really act on its belief that its "first responsibility is to "doctors, nurses, and patients, to mothers and fathers?" On CNBC,  Bill George wrote,

It is not plausible that these leaders knew nearly five decades ago that their iconic baby powder caused cancer and continued to market the product. This is a company whose leaders consistently try to do the right thing, admit their mistakes, and continue to develop life-saving products that restore the health of millions of people around the world.

While the plaintiffs' attorneys may continue to pursue their cases, I feel confident that J&J will be shown to put the interests of its customers first, and maintain its reputation for the highest integrity.

I wonder if Mr George's confidence was boosted by his previous work as a paid speaker for Johnson & Johnson, and former chairman and CEO of Medtronic, a company which has had its own share of ethical misadventures (look here)?  In any case, some recent history calls into question Johnson & Johnson's "reputation for the highest integrity."

Johnson & Johnson's Long History of Ethical Misadventures

So, recent reports suggested that Johnson & Johnson willfully acquired a company that appears to have provided kickbacks to patients in apparent violation of US law in an effort to support high drug prices.  Furthermore, Johnson& Johnson appears to have concealed considerable evidence that one of its primary products might be dangerous in order to support the sales of a "'sacred cow,' as one internal email put it (per the Reuters report).

These are but  the latest in a long string of misadventures by the company, as we have been documenting over years.  (Our collected posts on Johnson & Johnson are here.  An updated version of their legal record since 2010 is at the end of this post.)

Perusing the list suggests that this giant company (with about $70 billion in yearly revenue) is a poster child for bad behavior by health care organizations.  It has faced a multitude of allegations leading to settlements, and sometimes findings of guilt.  The charges included many instances of deceptive and unethical marketing, some that promoted drugs or devices for use in situations in which they may have had harms outweighing their benefit, some that involved concealing knowledge of their risks, and some of selling adulterated drugs or defective products. 

So the new allegations of deceptive marketing meant to conceal a hazardous product are just the latest in the series.

What is striking is that the company and its management have not faced more consequences for this sorry track record.

Although the company has paid multiple fines and made numerous monetary settlements over the years, none have been big enough to affect its immense revenues.  Furthermore, ultimately the monies used to pay them came from all Johnson & Johnson employees in the form of smaller paychecks; customers, patients and the public at large in the form of higher prices; and only to some extent by investors in the form of slightly lower profits.  Meanwhile, it appears that the company's top managers made an awful lot of money, possibly in part as rewards for the revenues produced by the misadeventures.

Former Johnson & Johnson CEO William Weldon, upon his retirement in 2014, was to receive a retirement package estimated to be worth from $143 to $197 million (look here).  In 2010, his total compensation was $29 million (look here).   According to the 2012 Johnson and Johnson proxy statement, his 2011 total compensation was greater than $26 million. As far as I can tell, Mr Weldon never suffered any negative consequences for his company's sorry record, and retired a very rich man. (look here).

Current CEO Alex Gorsky received  $25 million total compensation in 2014 (look here).  More recently, the New York Times reported his 2017 total pay was $22.8 million, making him the seventh highest paid health care executive in that year, by their accounting. 

While management made so much money, very rarely has anyone at the company who was involved in authorizing, directing, or implementing any of the bad behavior had to suffer any negative consequences, therefore appearing to enjoy impunity.

So what was to deter management from embarking on further misadventures, as long as the results might be enlarging management's personal wealth?  

This is all in line with what we have been discussing for years.  In general, we have seen many legal settlements made by health care organizations of alllegations like fraud, bribery, and kickbacks.  Despite the unsavory nature of the behaviors revealed by most settlements, which often appeared to risk patient harms, the companies involved usually have had to pay fines that were tiny relative to their multi-billion dollar revenues.  They companies only seldom have had to admit responsibility, and almost never did a settlement cause company managers and leaders to  suffer any negative consequences for enabling, authorizing, directing or implementing the bad behavior.

This adds to the evidence suggesting that US health care is rigged to benefit top insiders and their cronies, and as such, is part of a larger rigged system.  We have previously discussed how market fundamentalism (or neoliberalism) led to deregulation, which enabled deception, fraud, bribery, and intimidation to become standard business practices, and allowed increasing concentration of power by large corporations. Managerialism allowed the top leaders of these corporations and their insider cronies to amass increasing power and money. Everyone else, other employees, stockholders of public corporations, customers, vendors and suppliers, and the public at large lost out.   In health care, these changes led to an increasingly costly system which produced increasingly bad results for patients and the public. 

We have called for true health care reform to derig the system. Unfortunately, despite our hopes, perceptions of a rigged system may not always inspire honest reform. Instead, they can enable the rise of demagogues and wouldbe dictators who promise only they can solve the problem.  Donald Trump cried out that only he could fix our problems and drain our swamps.  However, at least in terms of policing white-collar crime, particularly in health care, he seems to be letting the swamp waters rise.  And now he seems to have had his own record of impunity (look here).  

While we thus have bigger problems to solve than the impunity of health care leaders, let us remember the need for wholesale, real health care reform that would make health care leaders accountable for what their organizations do, particularly when these organizations misbehave.


Appendix - Johnson and Johnson Legal Record since 2010

 2010
- Convictions in two different states for misleading marketing of Risperdal
- A guilty plea for misbranding Topamax

2011
- Guilty pleas to bribery in Europe  by Johnson and Johnson's DePuy subsidiary
- A guilty plea for marketing Risperdal for unapproved uses  (see this link for all of the above)
- A guilty plea to misbranding Natrecor by J+J subsidiary Scios (see post here)

2012 
  - Testimony in a trial of allegations of unethical marketing of the drug Risperdal (risperidone) by the Janssen subsidiary revealed a systemic, deceptive stealth marketing campaign that fostered suppression of research whose results were unfavorable to the company, ghostwriting, the use of key opinion leaders as marketers in the guise of academics and professionals, and intimidation of whistleblowers. After these revelations, the company abruptly settled the case (see post here).
-  Johnson & Johnson was fined $1.1 billion by a judge in Arkansas for deceiving patients and physicians again about Risperdal (look here).
-  Johnson & Johnson announced it would pay $181 million to resolve claims of deceptive advertising again about Risperdal (see this post).

2013
-  Johnson & Johnson settled case by shareholders alleging that management made misleading statements and withheld material information about manufacturing problems (see this post)
-  Johnson & Johnson Janssen subsidiary pleaded guilty to a charge of misbranding Risperdal, and settled for a total of $2.2 billion allegations that it promoted the drug for elderly demented patients and adolescents without an indication, and despite evidence of its harms (see this post).
 -  Johnson & Johnson DePuy subsidiary agreed to settle with multiple plaintiffs for $2.5 billion allegations that it sold defective mental-on-metal artificial hip, and hid evidence of its harms .
- Johnson & Johnsonn Janssen subsidiary was found by two juries to have concealed harms of its drug Topamax (see this post for this and above case).
- Johnson & Johnson Ethicon subsidiary's Advanced Surgical Products and two of its executives agreed to settle charges by US FDA that is sold mislabeled products used to sterilize equipment such as endoscopes (see this post).
- Johnson & Johnson fined by European Commission for anticompetitive practices, that is, collusion with Novartis to delay marketing generic version of Fentanyl (see this post).

2014 
- Johnson & Johnson DePuy subsidiary settled Oregan state charges that it marketed the ASR XL metal-on-metal hip joint prosthesis without disclosing its high failure rate (see this post).

2015
-  Johnson & Johnson found by jury to have concealed harms of Risperdal.
-  Johnson & Johnson Ethicon subsidiary found by jury to have concealed harms of its vaginal mesh device.
-  Johnson & Johnson McNeil subsidiary pleaded guilty to marketing adulterated Tylenol. (see this post for three items above.)

2016
- Johnson & Johnson subsidiary Aclarent settled allegations that it sold its Stratus device for unapproved uses.  Two former executives of that subsidiary also were found guilty of distributing misbranded and adulterated devices (see this post) 

One Barely Noticed Settlement by Pfizer Suggests the Futility of Polite Protests about Health Policy

A few days ago we noticed just one more marcher in the parade of legal settlements.  But it was once again a huge health care corporation, and it had aspects that demanded attention.

Pfizer Makes $94 Million Settlement of Allegations of Fraud to Delay Generic Competition


A tiny item in Becker's Hospital News on November 28, 2017, stated:

Pfizer will pay $94 million to resolve allegations that it used fraudulent patents to delay generic competition for its anti-inflammatory drug Celebrex.

The lawsuit, brought by 32 direct purchasers of Celebrex in April and certified a class action lawsuit in August, claimed Pfizer attempted to revive its invalidated patent by making material misrepresentations to the U.S. Patent and Trademark Office. As a result, the U.S. PTO granted Pfizer a new patent based on this reportedly inaccurate information.

Further, the plaintiffs — including American Sales Co., Rochester Drug Co-Operative, Cesar Castillo and more — allege Pfizer filed a lawsuit against five generic manufacturers for infringing upon the fraudulently obtained patent to maintain monopoly over the drug.

That was about it.  I could find no more extensive coverage of this settlement in any source publicly available without a subscription.  So this settlement, like many previous ones which suggested less than perfection on the part of the leadership of our dysfunctional health care system, was anechoic.

Also, as is typical of settlements made by big health care corporations of unethical behavior, this settlement appeared small compared to the magnitude of the revenues likely generated by alleged bad behavior; and this settlement did not impose any negative consequences on any individual who might have authorized, enabled, directed, or implemented the bad behavior, and may have benefited from that behavior (for example, by getting a bigger bonus because of the revenue brought it).  Thus, it fit right in with the march of legal settlements that we have been documenting for years.  It was a slap on the corporate wrists that was unlikely to deter future bad behavior, and amounted to a grant of impunity to the corporate managers who were involved in and personally profited from the bad behavior.

Furthermore, the settlement seemingly was not informed by previous bad behavior by the corporation or its managers.  Pfizer, in fact, has a long and very sorry record of such behavior as documented by legal settlements, convictions and guilty pleas, and other governmental actions.  In the last few years we have noted....

Pfizer Fined $106M in UK for Using Monopoly on Production of Generic Phenytoin to Overcharge National Health Service

As reported by the Wall Street Journal on December 7, 2016,

The U.K.’s top antitrust regulator slapped Pfizer Inc. PFE 0.25% with a record $107 million fine, alleging it overcharged the national health-care system for an epilepsy treatment.

The Competition and Markets Authority said Pfizer and drug-distribution company Flynn Pharma Ltd. broke competition law by charging unfair prices in the U.K. for the drug, phenytoin sodium, used by about 48,000 patients in the country.

The CMA said the £84.2 million Pfizer fine was the highest it had ever imposed....

The article suggested that Pfizer took advantage of a loophole in UK law.  Drug companies must negotiate prices of branded drugs with the British NHS, but

Unbranded, or generic, drugs may be freely priced, but competition between suppliers typically drives the cost down.

The regulator said Pfizer and Flynn Pharma “deliberately debranded” the drug in 2012 to raise the price and were able to do so because there were no competing suppliers.

The CMA said the price of a 100-milligram pack of phenytoin sodium shot up—to £67.50 from £2.83—after Pfizer sold the rights to sell the drug to Flynn Pharma in September 2012. It said the price decreased to £54 in May 2014.

Before the agreement, Pfizer had sold phenytoin sodium capsules directly to U.K. wholesalers and pharmacies under the brand name Epanutin.

The price increase was partly because Pfizer, which continued to manufacture phenytoin sodium, sold the drug to Flynn Pharma at up to 17 times the price than it charged wholesalers and pharmacies previously, the regulator said. Flynn Pharma raised the price further still.

So this was the resolution of yet more anti-competitive behavior by Pfizer which allowed it to overcharge  taxpayers.  Like the settlement above, it allowed the Pfizer management involved impunity.

Pfizer Made $486 Million Settlement of  Allegations It Bilked Shareholders by Concealing Research Showing the Harms of Celebrex

As reported by Reuters in August, 2016,

Pfizer Inc (PFE.N) on Tuesday said it has reached a $486 million settlement of litigation accusing it of causing big losses for shareholders by concealing safety risks associated with its Celebrex and Bextra pain-relieving drugs.

As usual, there were no penalties for any individuals who may have been involved with the bilking.

Note that while this particular lawsuit was about financial losses to shareholders, concealing the harms of this drug obviously had the potential of allowing harms to patients.  Of course, this was just the most the second most recent settlement involving Celebrex.

Pfizer's Track Record Prior to mid-2016

Our over 100 posts on Pfizer can be found here.  Since 2000, Pfizer's troubles started, according to the Philadelphia Inquirer, with the following...

- In 2002, Pfizer and subsidiaries Warner-Lambert and Parke-Davis agreed to pay $49 million to settle allegations that the company fraudulently avoided paying fully rebates owed to the state and federal governments under the national Medicaid Rebate program for the cholesterol-lowering drug Lipitor.
- In 2004, Pfizer agreed to pay $430 million to settle DOJ claims involving the off-label promotion of the epilepsy drug Neurontin by subsidiary Warner-Lambert. The promotions included flying doctors to lavish resorts and paying them hefty speakers' fees to tout the drug. The company said the activity took place years before it bought Warner-Lambert in 2000.
- In 2007, Pfizer agreed to pay $34.7 million in fines to settle Department of Justice allegations that it improperly promoted the human growth hormone product Genotropin. The drugmaker's Pharmacia & Upjohn Co. subsidiary pleaded guilty to offering a kickback to a pharmacy-benefits manager to sell more of the drug.

Thereafter,
- In 2009, Pfizer paid a $2.3 billion settlement of civil and criminal allegations and a Pfizer subsidiary entered a guilty plea to charges it violated federal law regarding its marketing of Bextra (see post here).
- Pfizer was involved in two other major cases from then to early 2010, including one in which a jury found the company guilty of violating the RICO (racketeer-influenced corrupt organization) statute (see post here).  In that year the company was listed as one of the pharmaceutical "big four" companies in terms of defrauding the government (see post here).
- In early 2011, Pfizer's Pharmacia subsidiary settled allegations that it inflated drugs costs paid by New York (see post here).
- In March, 2011, a settlement was announced in a long-running class action case which involved allegations that another Pfizer subsidiary had exposed many people to asbestos (see this story in Bloomberg).
- In October, 2011, Pfizer settled allegations that it illegally marketed bladder control drug Detrol (see this post).
- In August, 2012, Pfizer settled allegations that its subsidiaries bribed foreign (that is, with respect to the US) government officials, including government-employed doctors (see this post).
- In December, 2012, Pfizer settled federal charges that its Wyeth subsidiary deceptively marketed the proton pump inhibitor drug Protonix, using systematic efforts to deceive approved by top management, and settled charges by multiple states' Attorneys' General that it deceptively marketed Zyvox and Lyrica (see this post).
- In January, 2013, Pfizer settled Texas charges that it had misreported information to and over-billed Medicaid (see this post).
- In July, 2013, Pfizer settled charges of illegal marketing of Rapamune (see this post.)
- In April, 2014, Pfizer settled allegations of anti-trust law violations for delaying generic versions of Neurontin( see this post).
- In June, 2014, Pfizer settled another lawsuit alleging illegal marketing of Neurontin (see this post).
- In 2015, a settlement by Pfizer of a shareholders' lawsuit stemming from charges of illegal marketing was announced (see this post).
- In October, 2015, a  UK judge found that the company had threatened health care professionals for using a generic competitor (see this post).
- In February, 2016, Pfizer settled a lawsuit for $785 million for overcharging the US government for Protonix (look here).

That is a stupifyingly bad ethical record stretching over about 17 years.  Yet each new settlement seems to disregard all the others before.  And since 2000, no top Pfizer executive has ever suffered any negative consequences for any of this  behavior.  All CEOs who have retired did so as rich men.


Summary

Pfizer provides an amazing example of a huge health care corporation that just marches along, settling or otherwise resolving case after case of over-charging, anti-competitive behavior, deception, sometimes fraud, bribery, and various other unethical and potentially illegal behaviors, without ever too greatly inconveniencing the managers and top executives who have been profiting from this behavior.   We have again and again railed against how the US government (and actually governments of other developed countries) have use light-touch regulation on big health care corporations that allows impunity for their top leaders.  For example, we wrote in 2015,

As long as top managers of big health care organizations can act with impunity, can avoid all responsibility for their organizations' bad behaviors, and can personally profit wildly from their companies actions, the health care death spiral will continue.  Will we continue to cry out in the wilderness, or will anyone else see the writing on the wall?

But it gets worse.  Note that two of the recent Pfizer settlements were of private litigation in which the US government was not involved.  One was of alleged anti-competitive behavior, and the other of alleged deceptions that could have resulted in patient harm.  Both of these could have been causes of government action, but were not.  So it appears that the US government is getting less inclined to do anything to challenge the impunity of top corporate leaders.

Instead, the current Trump regime and its allies in Congress seem hell-bent on further rewarding top corporate leaders.  For example, while the supposed tax reform legislation that just passed Congress was pushed by Trump as a way to improve the economy, it looks like it will most benefit corporate leaders.  A story in Bloomberg on November 29, 2017, stated,

Major companies including Cisco Systems Inc., Pfizer Inc. and Coca-Cola Co. say they’ll turn over most gains from proposed corporate tax cuts to their shareholders, undercutting President Donald Trump’s promise that his plan will create jobs and boost wages for the middle class.

The president has held fast to his pledge even as top executives’ comments have run counter to it for months. Instead of hiring more workers or raising their pay, many companies say they’ll first increase dividends or buy back their own shares.

In particular,

Robert Bradway, chief executive of Amgen Inc., said in an Oct. 25 earnings call that the company has been “actively returning capital in the form of growing dividend and buyback and I’d expect us to continue that.” Executives including Coca-Cola CEO James Quincey, Pfizer Chief Financial Officer Frank D’Amelio and Cisco CFO Kelly Kramer have recently made similar statements.

Share buybacks, like dividend increases, tend to benefit stockholders, but not workers (much less customers, or in Pfizer's case, patients), 

in testimony before the bicameral Joint Economic Committee on Wednesday, Federal Reserve Chair Janet Yellen said that the plans outlined by corporate executives to reward investors were unlikely to raise wages for workers.

'I don’t think share buybacks would increase wages,' Yellen said when asked by Michigan Democratic Senator Gary Peters about the impact of CEOs’ plans. Investment in capital and equipment, not buybacks, would raise productivity and pay, she said.

Left unstated is that top corporate executives are now paid mainly in stock shares and stock options.  So they would be major beneficiaries of increased dividends and increased stock prices.

For example, the Pfizer 2017 proxy statement lists the following share holdings of its top-paid executives:

                                      common stock shares     stock units

Group President, Pfizer Innovation Health
Albert Bourla DVM, PhD         112,489                           30,653

Executive Vice President, Business Operations
and CFO
Frank A D'Amelio                     342,176                             76,009

President, Worldwide Research and Development
Mikael Dolsten MD, PhD           50,820                            191,189

Former Group President,
Global Innovative Pharma Business
Geno J Germano                        115,712                           35,546

Chairman of the Board, CEO
Ian C Read                                645,370                       317,117

Group President, Pfizer Essential Health
John D Young                            92,434                            78,559

Note that Mr D'Amelio was quoted in the article above.  As an owner of more than 400,000 Pfizer shares or share equivalents, he would be expected to substantially personally profit from increases in dividends and stock buybacks.

And how likely is it that the Trump regime will respond to any entreaties about tougher law enforcement and more rigorous regulation of pharmaceutical and other large health care corporations?  After all, huge numbers of executive branch appointments to positions that deal with health care have been coming through the revolving door from health care corporations and  their lobbying firms, etc.  At the time of his appointment, the current head of the US Food and Drug Administration had huge conflicts of interest generated by his former positions in and allied with the pharmaceutical industry (look here and here).  The gentleman currently nominated to be Secretary of the Department of Health and Human Services was a former top executive at pharmaceutical giant Eli Lilly (look here).

And do we really expect rigorous law enforcement from a regime whose former national security adviser just pleaded guilty to lying to the Federal Bureau of Investigation (look here);  and whose former national security adviser and current nominee to be Ambassador to Singapore K T McFarland was just shown to have admitted that Russia had "thrown" the election to Mr Trump, but seemed to think that Mr Trump should then reward Russia by reducing sanctions imposed by the Obama administration (look here)?

The Sunlight Foundation has found that President Trump has over 600 conflicts of interest, and that his family has over 1100 (look here).  Do we really expect his regime to improve the integrity of  health care leadership? 

It is now past time to expect that our polite protests about health policy and measured calls for true health care reform will have any impact on health policy, as long as the inmates are in control of the asylum.  We need wholesale changes in  top health care leadership in government, and wholesale changes in the top leadership of the government, if we want anything even slightly resembling true health care reform. Achieving true health care reform will require much more than polite protests.

Efficacy, We Don't Need No Stinking Proof of Efficacy - Says Apparent Trump Candidate to Lead FDA

Multiple media reports suggest that US president-elect Donald Trump is considering a most unusual candidate for commissioner of the Food and Drug Administration (FDA).  The basics, as reported by Bloomberg:

President-elect Donald Trump’s transition team is considering a Silicon Valley investor close to billionaire Peter Thiel to head the Food and Drug Administration, according to people familiar with the matter.

Jim O’Neill, the Thiel associate, hasn’t been officially selected, according to the people, who asked to remain anonymous because the decision process is private, and the Trump team could still go in another direction.

O’Neill is a managing director at Thiel’s Mithril Capital Management, and last served in government during the George W. Bush administration as principal associate deputy secretary at the Department of Health and Human Services. He’s also a board member of the Seasteading Institute, a Thiel-backed venture to create new societies at sea, away from existing governments.

Thiel’s spokesman Jeremiah Hall said O’Neill is a good candidate. 'Jim O’Neill has extensive experience in government and in Silicon Valley. He is a strong candidate for any of several key positions,' Hall said in an e-mail. Separately, Politico and CNBC reported that O’Neill could be under consideration for various positions.

Mr O'Neill would be a very unusual candidate to lead the FDA

Ill-Informed

Mr O'Neill has no medical, health care, or biomedical research background.  As Bloomberg noted, "the head of the FDA for the last five decades has either been a trained physician or a prominent scientific researcher."   However, Mr O'Neill's relevant track record is that he

did his undergraduate studies at Yale University, where he was a member of the concert band and played the horn, and has a masters degree from the University of Chicago, both in the humanities. He joined the Health and Human Services Department under Bush in 2002, first as a speechwriter, rising in the final years of the administration to head some policy functions,...

We have frequently discussed how current leaders of health-care organizations are often ill-informed about biomedical science, health care, medicine, public health and related issues.  Mr O'Neill would fit right in with them were he to run the FDA.  

About to Transit the Revolving Door

Mr O'Neill seemed to be on Mr Trump's radar since he was "a close associate of [Trump confidant Peter] Theil for nearly a decade." More recently, Mr O'Neill

served as a managing director at Clarium Capital -- Thiel’s hedge fund that made a mint by correctly predicting the housing bubble and then crumbled -- and since 2012 has worked at Mithril Capital, Thiel’s late-stage venture firm, where he is a managing director.

His recent work would imply that to become FDA commissioner would transit the revolving door.  As reported by the International Business Times,

'He brings strong ties to industry and would reflect a tremendous bias in their favor at the FDA,' Dr. Michael Carome, director of the public health research group at the consumer watchdog Public Citizen, told International Business Times. 'He’s senior executive in a hedge fund investing in medical healthcare products. That alone should be disqualifying.'

In particular,

In the private sector, O'Neill has a clear financial stake in the outcome the regulatory process — a process he could oversee as head of the FDA.

For example, in 2014, Mithril invested $15 million in the German medical device company MagForce — which manufactures cancer treatment technologies — in exchange for 23 percent ownership in its U.S. subsidiary. In June, the company announced it filed for an 'Investigational Device Exemption' with the FDA — basically a permit to use its unapproved product to gather evidence for clinical trials. MagForce’s profitability could very well hinge on how the FDA regulates its products: According to 2015 financial filings, MagForce is 'working with the FDA to update preclinical studies, which were conducted approximately ten years ago, to current US regulatory standards.'

Challenging Evidence-Based Medicine, with Dangerous Implications

Perhaps because of his lack of understanding of health care and medicine, and his financial interests, Mr O'Neill has advocated for radical changes at the FDA, particularly for allowing drugs and devices to be marketed without any good evidence of their efficacy, that is, that they provide any benefits to patients.

 In a 2014 speech, he said he supported reforming FDA approval rules so that drugs could hit the market after they’ve been proven safe, but without any proof that they worked, something he called 'progressive approval.'

'We should reform FDA so there is approving drugs after their sponsors have demonstrated safety -- and let people start using them, at their own risk, but not much risk of safety,' O’Neill said in a speech at an August 2014 conference called Rejuvenation Biotechnology. 'Let’s prove efficacy after they’ve been legalized.'

It might sound plausible, at least if you know nothing about medicine.

The big problem with it is, as I was taught in medical school, that all medical interventions, including drugs and devices, have their risks.  No intervention is free of all potential to cause harm.  So we advocates of evidence-based medicine suggest that no intervention should be given to patients without clear evidence that its benefits outweigh its harms.  You cannot show benefits outweigh harms without having some good evidence about benefits.

Even big pharma has become reconciled to this notion.  An article in the Hill quoted one Mr Peter Pitts thus,

'People need to understand that safety doesn’t exist without the balance of risk,' said Peter Pitts, president of the Center for Medicine in the Public Interest and a former FDA associate commissioner under President George W. Bush.

He said that 'every drug has risks,' so the important consideration is balancing the risks against how effective the drug will be. Side effects that would never be approved for Aspirin might be approved for a lung cancer drug, he noted.

And this from someone who did public relations for big pharma for a long time (look here).  Mr Pitts still works for CMPI, which historically obtained much of its money from the pharmaceutical industry (look here). 

Furthermore, the studies of treatments usually done prior to efficiacy trials are not designed to assure their safety, just that they do not have catastrophic adverse effects for a lot of patients.  Phase I and II trials do not enroll enough patients or follow them long enough to rule out rare but dangerous adverse effects occurring early, or any adverse effects occurring late.

So the International Business Times noted that

Dr. Aaron S. Kesselheim, associate professor of medicine at Harvard Medical School and the director of Brigham and Women’s Hospital program on regulation, therapeutics, and law, says O’Neill’s proposals could transform the drug market into an unregulated space that resembles the vitamin and supplement market. 'You’d have all these expensive products out there without being shown to work while presenting substantial safety risks — and being pushed on physicians and patients by overzealous marketing,' Kesselheim told IBT.

'He’s coming at things from an agenda-driven and non-evidence -based point of view,' Kesselheim said. 'That should be very scary for patients and physicians.'

By the way, this just underlines just how Mr O'Neill would be a prototypical ill-informed leader were he to be appointed to run the FDA.

Also, per the Hill article,

Dr. Michael Carome, director of Public Citizen’s health research group, said he was 'just stunned' when he heard O’Neill’s name reported to be in consideration for FDA.

He said O’Neill’s proposals would bring the country back to 19th century 'snake oil salesmen' being able to fool people into using ineffective products.

Just to ice the cake, O'Neill's bright idea would apparently violate the law.  As Matthew Herper wrote in Forbes,

the 1962 Kefauver amendment ... said drugs must be proved safe and effective before they can be sold. This law was put in place after an FDA reviewer kept a drug for morning sickness, thalidomide, from being sold in the U.S. The medicine caused birth defects in the rest of the world.

So not only would Mr O'Neill be an tremendously ill-informed leader of the FDA, he has the potential of being a prototypically mission-hostile leader were he to try to carry out his idea of eliminated prospective efficacy testing.  We have also frequently written about the havoc that can be wrecked on health care by such leaders.

So Mr O'Neill's bright idea would effectively make all patients into guinea pigs.  What would happen if a large number of patients received treatments that might be useless, and whose harms doubtless exist, but are unknown?  Some, whether they were Democrats or Republicans, whether they supported Mr Trump, Secretary Clinton or someone else in the last election,  might end up here:

So add anyone who might be or ever become a patient to the long list of people who should be worried about a future Trump administration.

Discussion

We could do our usual rant about the revolving door here.   Obviously, the revolving door pheonomenon is a serious conflict of interest, if not form of corruption, that should have no place in our government, particularly in its agencies that are concerned with health care. Similarly, we could rant about how ill-informed and mission-hostile leaders have to take much responsibility for our currently dysfunctional health care system.

It should be no surprise that Mr Trump, a businessman who has no experience in government, and who often seems at ignorant , if not contemptuous of the US Constitution he may be sworn to uphold, would appoint similarly ill-informed and mission-hostile cabinet secretaries and agency leaders.  Ill-informed, mission-hostile leadership of the FDA could harm a lot of patients.  Such an FDA commissioner, acting in concert with other members of an equally ill-informed and mission-hostile Trump administration could do catastrophic damage to patients, citizens the country and the world. 

Maybe we would all be better off if Mr Tump finds something else to do for the next four years.  Maybe he should stick to being executive producer of the Apprentice. 

Not So Wondrous Drugs? - New Warnings about Severe Adverse Effects of New, Heavily Marketed Drugs for Hepatits C,

Background - Wonder Drugs for Hepatitis C

In our April, 2014, post we noted how Sovaldi (sofosbuvir), the new antiviral drug made by Gilead for hepatitis C was touted as a "triumph of of medical technology."  In that, and subsequent posts we discussed how such claims were not buttressed by much good data from clinical research.

We could find only one published randomized clinical trial of sofosbuvir (and ribavirin), which compared it to the older drug used to treat hepatitis C, peg-interferon (and ribavirin).  At best, the new drug showed about the same ability to eliminate detectable virus from the patients' blood in the short-term as did the older drug.  The new drug also produced fewer unpleasant side effects, but possibly more severe adverse effects.  Just like all previous known published trials of hepatitis C treatments, this trial of sofosbuvir did not follow patients long enough to determine if the drug had any effect on the serious, but not inevitable long-term complications of hepatitis C infection, severe hepatitis, cirrhosis, liver failure, liver cancer, and premature death.

I could find no other published trials of sofosbuvir versus either older drugs or placebo.  Most of the subsequently published, and loudly hyped studies of the drug were of highly selected patients, and did not include control groups which did not receive sofosbuvir.  So the very high short term "cure" rates - which were really rates of elimination of detectable virus from the blood, could have been mainly a function of these studies' highly selected patient populations.

Yet the lack of strong evidence that sofosbuvir, and subsequent competing drugs actually made patients better, i.e., feel better, function better, avoid serious subsequent medical problems, or live longer, did not stop tremendous enthusiasm in the media for the new drug.  Much of it doubtless stemmed from huge marketing and public relations expenditures.  Nor did did the lack of evidence stop Gilead and other drug makers from pricing the new drugs in the stratosphere.  Initially a 12 week course of of Sovaldi cost $84,000.

Since then, there has been tremendous buzz about the price of these new antiviral drugs for hepatitis C, and tremendous anxiety about the consequent difficult access to these presumptively "life saving" therapies.  However, my and others' questions about whether these drugs actually benefit patients, and whether any benefits might be worth their harms, remained anechoic (See appendix below.)

The Harms of the "Wonder Drugs" Begin to Appear

Nowadays new drugs, devices, and other health care technologies are often touted based on little evidence.  What evidence is produced mainly comes from commercially sponsored clinical trials.  Commercial sponsors may manipulate the design, implementation, analysis and dissemination of these studies to increase the likelihood that they will make their products look good.

In particular, such trials may fail to detect adverse effects of the new products to be hyped.  The trials  often enroll only small numbers of patients, decreasing the likelihood of finding rare but serious problems.  Often patients who have any health problems other than the disease of interest are excluded from trials, decreasing the likelihood of detecting adverse events that might affect patients with multiple morbidities or on other treatments.  Trials may fail to follow patients long-term, so they may fail to detect adverse effects that appear only after prolonged therapy.  These sorts of problems certainly afflicted the very few real clinical trials of sofosbuvir, and other new antiviral drugs for hepatitis C.   

So it should not have been surprising that sofosbuvir has now been found to produce two kinds of severe adverse events that were undetected, or at least undisclosed when it was launched.  The second kind of adverse event was just announced, and also seems to occur after administration of other new anti-hepatitis C drugs.

Severe Heart Rhythm Abnormalities

In March, 2015, as discussed by Dr John Mandrola in Medscape,

As reported by heartwire , the US FDA recently announced a change in labeling for the hepatitis-C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after their manufacturers reported bradycardia, pacemaker intervention, and even death in patients who took the medications along with amiodarone. Notably, six of these nine cases occurred within 24 hours of sofosbuvir dosing.

While Dr Mandrola was concerned about this adverse effect, the news media put more emphasis on the Wall Street analysts who thought the problem would have "zero impact" on sales of the fabulously expensive antiviral drugs. (See this post by Ed Silverman on PharmaLot.)

So all remained serene, until this week.

Reactivation of Hepatitis B Infection

On October 4, 2016, Medscape reported

Patients with a past or current hepatitis B virus (HBV) infection can experience sometimes fatal HBV reactivation if they take any of nine direct-acting antivirals for hepatitis virus C (HCV) infection, the US Food and Drug Administration (FDA) announced today.

The agency will require a boxed warning for the drugs advising clinicians to screen patients for evidence of a past or current HBV infection before ordering antiviral treatment for HCV.

Also,

The FDA said in a news release that it had identified 24 cases of HBV reactivation in coinfected patients treated with these antivirals from November 22, 2013, to July 18, 2016, in reports to the agency and published literature. Two patients died, and one needed a liver transplant.

Why were we not made aware of this before?  Failure to detect this adverse effect was apparently due to the exclusion of patients with a history of hepatitis B from previous studies of the new drugs.  As we mentioned above, commercially sponsored trials often exclude patients with nearly any medical conditions other than the one of interest.  Yet hepatitis C patients often have comorbidities.  I

clinical trials for the HCV drugs in question did not report HBV reactivation because they excluded patients infected with HBV.

Will this prompt a reexamination of our enthusiasm for new antiviral hepatitis C treatments? I suspect not. Even FDA officials suggested we should not be too alarmed. In particular, Dr. John Farley, deputy director of FDA's Office of Antimicrobial Products, said according to NBC News,

I think it is important to recognize that these hepatitis C drugs are lifesaving medications. What we don't want to do is discourage patients with hepatitis C from getting treatment,...

But remember, there has never been a controlled trial that showed that treatment of hepatitis C with anything actually reduced the risk of later severe hepatitis, cirrhosis, liver failure, liver cancer, or premature death. And there may be other adverse effects of this new treatment that remain unknown.

Even government regulators, who are supposed to put the public health ahead of the profits of the pharmaceutical industry, seem to have fallen for the life saving miracle drug meme in this case.

Summary

The ongoing story of hepatitis C treatment demonstrates how hype and buzz, largely generated by marketing and public relations, and likely fueled by financial relationships among commercial health care firms and health care professionals and academics, has triumphed over rigorous skeptical evaluation of the best available evidence from clinical research.

There has never been good evidence that hepatits C treatments prolong life, or prevent severe liver disease in the long run.  There has never been good evidence that these drugs' clinical benefits outweigh their harms.  Yet they have been relentlessly promoted as game changers, miraculous, triumphant lifesaving medicines.

One obvious lesson is that health care professionals, policy makers, and the public at large have to be much more skeptical about commercial claims for drugs, devices, tests, etc.  We need to figure out when claims are coming from marketing departments and public relations hacks.  We need to figure out when researchers and professionals who are supporting these claims could be influenced by financial relationships with the firms benefiting from the claims.

Furthermore, it is high time to revisit all the regulatory and policy changes over the last 30 years that have put manufacturers in charge of the research meant to test their own health care products.

In conclusion, 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. If only such skepticism were easier to find.


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APPENDIX - Clinical Research about Hepatitis C Treatments

Starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous.  The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.

However, as we pointed out (e.g., here and here)
-  The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment.
-  There is no evidence from randomized controlled trials that treatment prevents most of these severe complications
-  There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. 
-  While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.

Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns.  These included
- a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here)
- an article in JAMA Internal Medicine from the Institute for Clinical and Economic Review (1)
- a report from the Center for Evidence-Based Policy (link here)
- an article in Prescrire International (2)

These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally.  (See posts here,  here, and here.)

References

 1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014;174(7):1170-1171. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.

ADDENDUM (11 October, 2016) - This post was republished on the Naked Capitalism blog.