Medicare Pays $220 Million a Year for Acthar Without Any Controlled Trials that Prove it Works - While We Have No Money to Develop Ebola Vaccines or Treatment?

Introduction - No Money for Ebola Vaccine Development

While a new Ebola epidemic continues in Africa, people in developed countries are getting worried. Even the 0.1%, who may have rarely worried about our dysfunctional health care system before, are getting nervous. For example, this week, the Donald seemed panic stricken that Ebola infected American health workers might be allowed to return to the US, no matter what the precautions.  As reported by Politico,

Donald Trump has a message for the Ebola patient coming to the United States for treatment: Stay out.

'Ebola patient will be brought to the U.S. in a few days — now I know for sure that our leaders are incompetent,' Trump tweeted Thursday night. “KEEP THEM OUT OF HERE!”

Yet, as we posted here, money was the major barrier to developing treatments of vaccines that could have helped contain the epidemic in Africa, but whose availability in the US could also have reassured the Donald.  Dr John Ashton, a top public health physician in the UK, wrote in the Independent,

 

We must also tackle the scandal of the unwillingness of the pharmaceutical industry to invest in research to produce treatments and vaccines, something they refuse to do because the numbers involved are, in their terms, so small and don't justify the investment. This is the moral bankruptcy of capitalism acting in the absence of an ethical and social framework.

 

It seems that in the US and UK, our market based health care system can only cannot develop treatments for dangerous diseases when the treatments will produce huge returns on investment.   The irony is that even people (like Mr Trump) who preached market triumphalism and limiting government, presumably from doing things like developing drugs, may now fear diseases for which the market alone provides no remedy.  

 

Meanwhile, while there was no money to develop vaccines and drugs for Ebola, a story about how much money we are spending on questionable remedies has reappeared.  

 

But a Huge Increase in Money for Acthar

This week, writing in ProPublica and the New York Times, Charles Ornstein noted the huge amounts being paid by the US government for a previously obscure drug,

An obscure injectable medication made from pigs' pituitary glands has surged up the list of drugs that cost Medicare the most money, taking a growing bite out of the program's resources.

Medicare's tab for the medication, H.P. Acthar Gel, jumped twentyfold from 2008 to 2012, reaching $141.5 million, according to Medicare prescribing data requested by ProPublica. The bill for 2013 is likely to be even higher, exceeding $220 million.

Over approximately the same time course, commercial US health care insurers and the Tricare program for military dependents noted a surge in the amounts they were paying for this drug too,

 At a recent conference hosted by Sanford C. Bernstein, Dr. Ed Pazella, Aetna's national medical director for pharmacy policy and strategy, explained the shift on Acthar.

Questcor's 'combination of aggressive marketing and aggressive price increases finally caused it to become a line item that a finance guy looked at and said: 'What the hell are we paying for this? Why? What is it?' And that's when we started looking at what's our policy around this stuff,' Pazella said.

You Heard it Here First - a Huge Price Increase for an Old Unproven Drug

This problem's development took quite some time.  As we first discussed in 2007, some clever  maneuvering by corporate executives around loopholes in government rules benefited the executives, but maybe no one else.

The clinical background is that Acthar is a form of a hormone (ACTH) that stimulates the adrenal gland to produce more cortisol and other related hormones.  The formulation is made from pig pituitaries, and was developed in the 1940s.  It was approved by the US Food and Drug Administration at a time when this action did nor require proof of efficacy, that is, proof that the drug worked.  For years, the drug was only used for a rare form of infantile seizures, and occasionally for symptoms of multiple sclerosis in adults.  As noted in several reviews by the Cochrane Collaboration, there is little good evidence that the drug works for either condition, and no evidence that it is better than simpler, cheaper alternatives, like synthetic alternatives to cortisol, for the latter. (See this blog post).

The drug languished for years, but Questcor purchased the rights to it in 2001, apparently for a mere $100,000 (look here).  In 2007, the company jacked its price up in 2007 from $1650 a vial to $23,000 a vial.

A Further Price Increase, and a Big Marketing Push


As Mr Ornstein noted, its price is now $32,000 a vial.  One might expect that this huge price would quickly generate competition from generic drug manufacturers,  but, per Mr Ornstein,

Although it long ago lost patent protection, the drug is a complex biologic agent, and the manufacturing process is a trade secret. 

Furthermore, infantile spasms may be rare, but, 

Since Acthar came on the market in 1952, the rules about F.D.A. approval have changed. At the time, drug companies simply had to demonstrate that a drug was safe, rather than that it was effective. Acthar was initially authorized as a treatment for more than 50 diseases and conditions. (The list has since been cut to 19.)

Drug companies are barred by federal rules from marketing drugs for "off-label" indications, however, given the above, it was not obviously illegal when Questcor

 began marketing it for a broad menu of uses.

In addition, Medicare could not easily challenge the huge price Questcor was charging for this unproven remedy given to adults

Medicare cannot bar access to medications like Acthar, even in the face of rising expense and questions about efficacy, Aaron Albright, a spokesman for the Centers for Medicare and Medicaid Services, said in a written statement. The law mandates that Medicare's drug program, known as Part D, cover drugs for the uses authorized by the Food and Drug Administration, he said.

Questions about Questcor's Marketing

In fact, while it appears legal to promote Acthar for uses for which it has no proven efficacy, there are some questions about Questcor's marketing practices,

The company has disclosed in filings with the Securities and Exchange Commission that two United States attorney's offices and the S.E.C. are investigating its promotional practices.

A possible reason why was supplied by a companion ProPublica article, also by Charles Ornstein,

 Many of Medicare's top prescribers of the expensive specialty drug H.P. Acthar Gel have financial ties to the drug's maker.

Only 18 practitioners wrote 15 or more prescriptions for the drug in 2012. At least nine — and all of the top four — were promotional speakers, researchers or consultants for Questcor Pharmaceuticals, a ProPublica analysis shows.

Also, there are questions about whether Questcor has been concealing adverse events related to the increasing use of Acthar.  Until recently, as noted by Gretchen Morgenson in the NY Times in July, 2014,

For years, Questcor Pharmaceuticals has highlighted the potential benefits of Acthar, its immune-system drug, while saying little about its ill effects.

But as had been noted also by Gretchen Morgenson in the NY Times in June, 2014, more information about adverse events began coming out, not mainly for the benefit of patients, but apparently due to questions by investors about a pending takeover of Questcor by Mallinckrodt,

Since 2012, the events, as reported to the Food and Drug Administration’s Adverse Event Reporting System, or Faers (pronounced 'fares'), have included 20 deaths and six disabilities among patients reported to have been using Acthar and in which Acthar was recorded as 'suspect,' or the drug most likely to have been associated with the event. From January 2000 through 2011, by contrast, 13 deaths involving Acthar were reported to the F.D.A.’s system.

Although Questcor has reported some of these events to the F.D.A., as required, the company has not discussed the adverse outcomes in its financial filings. A Supreme Court ruling in 2011 concluded that reports of adverse events among patients using a drug, even if few in number, are of interest to investors weighing whether to buy or sell shares in the manufacturer.

The July, 2014 article by Gretchen Morgenson in the NY Times noted further,

according to a regulatory filing made by Questcor early Thursday, the number of patients reporting a so-called adverse event while using the drug last year represented almost 5 percent of prescriptions dispensed. The total number of events in 2013 reported by patients, who can experience multiple ill effects, was almost 14 percent of prescriptions, up from 9.1 percent in 2011.

 It was the first time Questcor, which has received a $5.6 billion takeover bid from Mallinckrodt Pharmaceuticals, had disclosed any problems experienced by Acthar patients, even though such information is of keen interest to investors.

That information might also be of interest to patients and doctors. 

Questions about Questcor's Executive Compensation

While Questcor brought in huge amounts of money from an old unproven drug using aggressive marketing that did not dwell on the drug's adverse effects, its executives have been making lots of money, sometimes in questionable ways.  For example, in February, 2014, Jesse Eisinger also reported for ProPublica that the timing of Questcor CEO Don M Bailey's stock sales has seemed unusually fortuitous,

Questcor Pharmaceuticals is a biotechnology company with a $4 billion market capitalization. Good things keep happening to Questcor in the middle of the month. Here’s what’s notable: The middle of the month just happens to be the time that the company’s chief executive, Don M. Bailey, sells stock through his regular selling plan.

The question is whether the company timed its favorable press releases to coincide with the times its CEO was known to be selling his shares?

Also, in May, a blog on The Street noted that the CEO's daughter also appears to have been quite fortunate, for no obvious reason,

As reported this morning by my colleague Herb Greenberg in his "Reality Check" newsletter (subscription required), Kirsten Fereday, a Questcor employee who also happens to be Bailey's daughter, received a huge salary bump in  in 2013, according to the compensation portion of its yet-to-be-filed proxy two days ago in an amended 10-K.

According to the filing:

Kirsten Fereday, the daughter of Don M. Bailey, our Chief Executive Officer, was employed by us during 2013 as our Senior Director, Business Analytics and Evaluation, and received total cash and equity compensation for the year ended December 31, 2013 equal to approximately $1,035,246 in cash compensation and $200,000 in restricted stock grants (value based on intrinsic value method). Ms. Fereday's employment was approved in accordance with the Related Party Transaction Policy and our Chief Executive Officer is not involved in the determination of Ms. Fereday's compensation. [Emphasis added.]

Why did her pay go up so much compared to that received in the previous year?

Furthermore, while Questcor derives a tremendous amount of revenue from the US government, a deal is in the works for it to be acquired by Mallinckrodt, now based in Ireland, which, if successful, will make top Questcor executives even richer, as Gretchen Morgenson wrote in the NY Times in June, 2014,

If the acquisition by Mallinckrodt goes through, Questcor’s top six executives could receive severance packages totaling $63.5 million under the terms of their contracts, the merger proxy shows.

Also,

During the time that adverse events involving Acthar have risen, Questcor’s top executives have been actively selling shares. So far this year, securities filings show, sales by the top five executives at the company, four of them under prearranged selling plans set up last year, have generated gains of $39 million.

Summary

As Andrew Pollack wrote in the first NY Times coverage of how Questcor used an old unproven drug to generate huge returns,

How the price of this drug rose so far, so fast is a story for these troubled times in American health care — a tale of aggressive marketing, questionable medicine and, not least, out-of-control costs.

 The sorry case of Questcor and Acthar reveal how crazy the costs of health care in the US have become, driven now by a system that itself now seems crazy.  Through clever use of regulatory loopholes, the company acquired rights to an old drug whose efficacy was unproven, hugely increased its price, began aggressive marketing even though the drug's efficacy was completely unproven, while remaining largely silent about the drug's substantial risks.  Fueled by hundreds of millions of dollars in revenue thus generated, mainly from the US government, the company richly rewarded its top hired executives, who then have decided to sell it to a company outside of the US in a deal that will make these executives millions more.  So patients received a drug whose benefits are unknown, and whose risks may be much higher than they were told, at a cost of hundreds of millions of dollars, much of it borne by US taxpayers, while company executives got rich.


Just coupling for now the story of how we spent hundreds of millions on Acthar to enrich company executives with the story that we have no money to develop vaccines or treatments for Ebola virus (look here) demonstrates the massive failure of our experiment to turn our health care system over to market triumphalists and laissez faire mercantilists.  As long as we let the health care system be run by people who put their own enrichment ahead of patients' and the public's health, things will only get crazier.  And even the rich may not be immune from the results of that craziness

So to repeat, true health care reform would put in place leadership that understands the health care context, upholds health care professionals' values, and puts patients' and the public's health ahead of extraneous, particularly short-term financial concerns. We need health care governance that holds health care leaders accountable, and ensures their transparency, integrity and honesty.

But this sort of reform would challenge the interests of managers who are getting very rich off the current system.  So I am afraid the US may end up going far down this final common pathway before enough people manifest enough strength to make real changes.

Oh, the Prices we Pay ... for Questionable Drug Marketing to Enrich Corporate Insiders - the Case of Questcor's H P Acthar Revisited

In 2007, we first discussed the case of the amazing pricing of H P Acthar, a very old drug of questionable usefulness, as an example of the irrationality of health care prices in the US, and of the failure of the organizations that ought to resist outrageous pricing in our mixed, pseudo-market based health care system to do so.  A recent New York Times article has updated this case.

Background

As we wrote in 2007, ACTH (adrenocorticotrophic hormone) is a naturally occurring hormone that stimulates the activity of the adrenal gland, which produces cortisol and other glucocorticoid and mineralocorticoid hormones.   ACTH produced from pigs' adrenals was first marketed as a biologic agent in the 1940s.  It was used for some conditions that appear to benefit from the effects of increasing cortisol production induced by ACTH.

It has been traditionally used to treat infantile spasms, a rare but distressing condition, and exacerbations of multiple sclerosis (MS).  However, since the drug was introduced so long ago, it was never subject to rigorous controlled trials to assess its efficacy and adverse effects for these indications.  Furthermore, since the 1940s, synthetic glucocorticoid hormones have become widely available as generic drugs.  Yet these slightly newer drugs have never been rigorously compared to ACTH for infantile spasms or MS.  The most recent review (edited in 2009) by the Cochrane Collaboration found that steroids and ACTH have some evidence in their favor for the treatment of acute MS, but found no evidence showing that ACTH was superior.  [Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, Candelise L. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001331. DOI: 10.1002/14651858.CD001331].  Also, the most recent review (edited in 2009) of treatment of infantile spasms concluded, "it is not clear which treatment [including ACTH] is optimal." [Hancock ED, Osborne JP, Edwards SW. Treatment of infantile spasms.  Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No. : CD001770. DOI: 10.1002/14541858.CD001700.pub2.]

The Pricing of H P Acthar

Possibly because some physicians thought ACTH might be useful for some patients with two conditions, infantile spasms and acute exacerbations of MS, ACTH has remained on the market.  It was manufactured by a single company, Aventis, (now part of Sanofi-Aventis), the successor to Rhone-Poulenc-Rorer.  In 2001, Aventis sold the rights to manufacture ACTH, with the trade name H P Acthar, to a new, small biotechnology company, Questcor.  In 2007, Questcor raised the price of ACTH from $1650 per vial to more $23,000 per vial.  That got the attention of the Philadelphia Inquirer, on whose article we based our commentary. We used the price increase as an example of how pricing in health care has become untethered from any sort of clinical reality, and wondered why insurance companies and the US government seemed willing to pay this outrageous price for an old drug with little evidence from clinical research to support its use.  But the issue then seemed, like many others we have discussed , to become anechoic, until the very end of 2012.


Now the  New York Times story has provided an example of how health care corporations can do very well without doing anyone, except corporate insiders, much good.  It included instances of many of the kinds of ethically questionable practices we have discussed over the years on Health Care Renewal.

Deceptive Marketing

Per the NY Times,

Questcor did almost no research or development to bring Acthar to market, merely buying the rights to the drug from its previous owner for $100,000 in 2001. And while the manufacturing of Acthar is complex, it accounts for only about 1 cent of every dollar that Questcor charges for the drug.

Moreover, the tiny 'orphan' market soon became much bigger. Before long, Questcor began marketing the drug fo multiple sclerosis, nephrotic syndrome and rheumatologic conditions, even though there is little evidence that Acthar is more effective for those other conditions than alternatives that are far cheaper. And the company did so without being required to prove that the drug actually works. That is because Acthar was approved for use in 1952, before the Food and Drug Administration required clinical trials to show a drug is effective for a particular disease. Acthar is essentially grandfathered in. 

Today, only about 10 percent of the drug’s sales are for infantile spasms. The new uses, Mr. Bailey has told analysts, represent multibillion-dollar opportunities for Acthar and Questcor, its sole maker. 

The results have been beyond even the company’s wildest dreams. Sales of Acthar, which accounts for essentially all of Questcor’s sales, totaled nearly $350 million in the first nine months this year, up 145 percent from the period a year earlier. In the same period, Questcor’s earnings per share nearly tripled, to $2.12. In the five years after the big Acthar price increase in August 2007, Questcor shares rose from around 60 cents to about $50, in one of the best performances of any stock in any industry. 

So Questcor leadership was clever enough to use loopholes in the law to promote ACTH for particular kinds of patients without any good evidence that it did those patients any good.  Furthermore, Questcor used several questionable tactics 

in this promotion.

Manipulated Research

Apparently Questcor leaders decided they needed some sort of minimal research results to promote their products, so as the Times reported,

Because Acthar was approved for these conditions decades ago, Questcor has not had to do large clinical trials to show that the drug works. It has paid for some small studies, mainly by individual doctors, who then publish a paper that the sales force can present to doctors. 

The study that justified calling on rheumatologists involved five patients with rare conditions, all of them treated by a single doctor. All the patients had much improvement on Acthar after failing to benefit from more standard therapies, the doctor, Todd Levine, said in a Questcor conference call.

Too call the research Questcor sponsored minimalist would be too polite.  A case series of five patients, lacking any control group proves almost nothing.  It proves less when the research is done in an unblinded  fashion by a single doctor who presumably was invested in the outcome being favorable for his sponsor's product.  (I suppose some might quibble with calling this research manipulated, but I contend but doing such crude research when it would be possible to do something much more credible amounts to manipulation.)

Suppression of Research

Moreover, it seems that even such rudimentary studies sometimes failed to produce the wanted results.  In these cases, the Times reported that Questcor simply suppressed them.

Still, it appears that at least a couple of small studies that may have raised questions about the drug have been suspended. 

'From my standpoint it just didn’t work,' said Dr. Sungchun Lee, a Phoenix nephrologist who stopped a small study testing Acthar as a treatment for nephrotic syndrome. 'I think they were O.K. with me stopping because we weren’t getting the results,' he said. 

Another study that was terminated sought to determine whether multiple sclerosis patients who did not have a good response to steroids should be treated with either another round of steroids or with Acthar. The study was halted midway through 'to analyze data,' according to the summary of the trial on the federal clinical trial database. 

Use of Paid Key Opinion Leaders

Despite the lack of good clinical evidence in support ACTH, there are some physicians who defend its use.  One example in the Times article was a physician who is paid by Questcor

But some doctors say Acthar can be effective in cases that are not well treated by steroids. They say that there is emerging evidence that Acthar does more than just stimulate the body to produce its own steroids. 

'It really looks like the ACTH does bring something different to the table that standard steroids don’t,' said Dr Ben W Thrower, director of the multiple sclerosis institute at the Shepherd Center, a hospital in Atlanta. Dr. Thrower, who is a paid speaker for Questcor, said his institute had tried Acthar for about 60 of its 3,000 patients, ones who did not respond to steroid treatment. Acthar made the symptoms subside in about half of them.

Where to begin?  Just because ACTH is different does not mean it is better.  Since MS is a disease whose symptoms wax and wane, patients who fail standard treatment may get better on their own, and without a control group, it is impossible to say whether the ACTH given to such patients was the reason they got better. 

Creation of Institutional Conflicts of Interest for Disease Specific Foundations

Questcor's ACTH also has support from a disease specific foundation, but one that Questcor has also supported financially.

Dr Lawrence Brown, a neurologist at the Children's Hospital of Philadelphia, and the president of the Child Neurology Foundation, says of Questcor: 'They have gone out of their way to help every kid who needs the medicine to get it quickly and efficiently.'

This year, the foundation awarded its first corporate citizenship award to Questcor. Dr. Brown says Questcor’s donations — the amount has not been disclosed — to the foundation didn’t influence the award.

Who could be so naive to think that giving an organization funding might influence its actions?  After all, human response to financial incentives is the basis for most current economic thinking.

Insiders Get Rich

Admittedly, these questionable tactics did lead to an increase in "shareholder value,"  As the company's proxy statement boasted in 2011,

While we generated strong financial returns in 2011, we are most proud of our patient focus and investments in Questcor which we believe will generate sustainable value to our shareholders, employees, patients and all of the communities that we serve. We believe that our patient focus and commitment to generating sustainable value to all of our constituencies results in strong value creation for our shareholders.

However, as of today, Qustcor's share price has dropped to $26.74 from a peak of 53.42 in June, 2012, with most of the drop in December, 2012, around the time the Times article came out, according to Google Finance.  So whether share holder value will turn out to have increased in the long run is not clear. 

Meanwhile, some Questcor employees did very well.  The largess started with some drug representatives,

Questcor sales representatives who are lucky enough or skillful enough to have a big prescriber in their territory can reap bonuses of $50,000 a quarter, according to former employees of the company.

More highly placed corporate insiders did even better.

Executives are paid well, too. In 2009, Mr. Bailey, [the CEO]  hired his daughter Kirsten Fereday as director of business analytics and evaluation, a job that paid $275,000 in cash and stock last year. 

 Left out of the Times article, somewhat surprisingly, was what the top executives make.  Information from up to 2011 is publicly available, however, in proxy fillings.

In the company's 2012 proxy statement, we find the following figures for total compensation:
Don M Bailey, President and CEO - $4,546,230, up 192% of his compensation in $1,554,503 in 2009
Michael H Mulroy, Senior Vice President, Chief Financial Officer and General Counsel -  $1,749,891 (his first year)
Stephen L Cartt, Chief Operating Officer -  $2,298,308, up 168% from $855,460 in 2009
David J Medeiros, Executive Vice President and Chief Technical Officer - $1,232,556, up 78% from $692,188 in 2009
David Young Pharm D, Chief Scientific Officer - $1,948,804 up 182% from $1,066,159 in 2009

In addition, by 2011, Mr Bailey, the CEO, had acquired 1.92% of the company's total stock, 3,834,910 shares, today worth $102,545,490.

Finally, per the Times,

one group of shareholders has done pretty well for itself. Over the last two years, as the company’s share price mainly soared, Questcor insiders have sold more than $100 million of stock. 

Summary

 So, in summary, a small biotechnology company drastically increased the price of its only product, a drug which has never been subject to modern clinical trials, and whose efficacy has never been proven.  Its marketing tactics have included manipulation and suppression of research, and payments to physicians and non-profit organizations.  Although its most breathtaking price increases were made in 2007, they attracted little public attention until five years later.   Meanwhile, corporate insiders, from drug representatives to top executives and their relatives, have done very well for themselves.

In the US, there a lot of people who advocate free market based health care for its efficiency and innovation.  For example, see "Yes, Mr President, a Free Market Can Fix Health Care," published by the Cato Institute, in which its Director of Health Policy Studies proclaimed, "The great advantage of a free market is that innovation and more prudent decisionmaking means that fewer patients will fall through the cracks," and then "a free market can and would control costs, expand choice, improve health care quality, and make health coverage more secure." [italics added for emphasis]

Unfortunately, the case of Questcor's ACTH makes it seem that in the current US system, which is supposedly more market based than systems in many other countries, the efficiency and innovation is characteristic of the marketing of corporate health care, not of the health care itself.  Here is a stellar example of how clever, and not always very scrupulous marketing can be used to sell a very old drug with little demonstrated clinical value for a stratospheric price, enriching corporate insiders, perhaps enriching stockholders (although, not so much lately, and we will see how they do in 2013), at the expense of the public who pays taxes and insurance premium.  This case suggests a need for more attention to market failures and less insistence on market fundamentalism.  Of course, it also suggests the continuing need for health care professionals, policy makers, patients and the public to be extremely skeptical about heavily promoted commercial health products.