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.
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 tacticsin this promotion.
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.
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.
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.