Too Good to be True - Sovaldi Kerfuffle Focuses on Price, While Ignoring Limits of Evidence about Effectiveness and Safety

There seems to be rising skepticism about the prices we pay for the latest drugs, devices, and health care programs, especially in the US.  However, our faith in the near miraculous properties of the newest technology appears to go on unabated.  Skepticism, driven by the rigorous thinking that ought to be engendered by the dutiful application of the principles of evidence-based medicine, is rarely in evidence.

The latest example is of how concern about the sky high price of one new medication seems to have eclipsed any skepticism about how much good that medicine may do for patients.

The Sovaldi Pricing Kefuffle

Starting in early March, 2014, a media discussion began about the extremely high price set for a new drug for the treatment of hepatitis C.  As first reported by the Washington Post,

When the Food and Drug Administration approved a medication called Sovaldi [sofosbuvir, Gilead] in December, it was hailed as a breakthrough in the fight against hepatitis C, a blood-borne disease that affects 3.2 million Americans and kills more people in the U.S. annually than AIDS.

Then California-based Gilead Sciences, the manufacturer, announced the price: $84,000 for a 12-week course, more than what many cancer treatments cost in a year.

The coverage focused on whether the price could possible be justified, while it generally conceding that the drug was a huge advance that was genuinely valuable. For example, the Post article noted,

The drug has also prompted a new round of hand-wringing over a larger issue: the escalating cost of specialty drugs, which are designed to treat chronic illnesses such as rheumatoid arthritis and multiple sclerosis and sometimes require special handling.

While these therapies are delivering body blows to some of the world’s most pernicious diseases, they also are testing the limits of what society is willing to pay for sought-after treatments or cures.

The articles justified the drug's value with several assertions:

Sofosbuvir cures nearly everyone of hepatitis C

For example, the Post article stated,

Sovaldi promises to cure nearly all sufferers...

Similarly, a report by the authoritative Kaiser Health News stated that the drug has,

a success rate of better than 90 percent.

A Bloomberg article quoted Dr Leonard Berkowitz, chief of infectious disease as Brooklyn Hospital Center as saying the drug is

producing 'spectacular improvements' in cure rates....

Going even farther, a Denver Post article quoted Dr Greg Everson, a hepatologist at the University of Colorado,

The word is cure.  To me, the cure of hep C is one of the most significant medical developments of the last 50 years.

Sofosbuvir is extremely safe and has few side effects

For example, the Post article stated Sovaldi is

a once-daily pill that has far fewer side effects [than other treatments]

The Bloomberg article again quoted Dr Berkowitz as saying the drug has

minimal toxicity

The Denver Post quoted Dr Everson,

the side effects are almost nonexistent - mild headache and fatigue.

Without treatment, hepatitis C leads to very bad outcomes

For example, the Post article stated,

The disease can go undetected for years and can eventually lead to cancer or cirrhosis of the liver.

Kaiser Health News added,

If left untreated, hepatitis C can cause liver damage over the course of decades.

An article in the Los Angeles Times noted,

Left unchecked, some hepatitis C infections result in liver damage, liver cancer or death.

The Denver Post again quoted Dr Everson,

It's a devastating disease. [Also,] It can smolder for years without symptoms, then it destroys the liver - cirrhosis, cancer.

Sofosbuvir prevents nearly all these bad outcomes.

This was more implied by the media than directly stated, although the Los Angeles Times did quote an executive vice president of Gilead, the manufacturer of Sovaldi,

Sovaldi ... results in very high cure rates that can avoid future costs related to disease progression or treatment failure....

Only the New York Times provided just a hint of skunk odor at the garden party.  Its later article on some US congress members' attempt to investigate the pricing of Sovaldi contributed,

But most people with hepatitis C never experience serious liver problems.  So many people would be fine without treatment.

That little bit of odor notwithstanding, one could ask what is not to like about this drug.  But the coverage really focused on how many people felt the cost was still just too high.  Unstated, but again implied was the notion that these complaints were just sour grapes.  How could anyone begrudge a mere $84,000 for a safe, extremely effective curative drug that would prevent severe morbidity and premature death, yet cause almost no significant side effects?

The problem is that the evidence that actually supports the "value proposition" for Sovaldi is actually not clear at all.  The bigger problem is that so far, discussion of this evidence in the media seems to be absent.

The Evidence about Treatment of Hepatitis C

Let us consider the assertions above, and what evidence there may be to support them,  in slightly different order.

Without treatment, hepatitis C leads to very bad outcomes

The earliest research on hepatitis C focused on patients who already had severe complications of the disease.  Thus, as Seeff et al wrote in 2000(1),

retrospective studies of person who have chronic, clinically obvious HCV infection may overemphasize more serious outcomes because they risk omitting persons with subclinical infection as well as those in whom infection spontaneously resolves.

Yet popular conceptions of hepatitis C, especially those reflected by the current Sovaldi pricing kerfuffle, seem to reflect only the experience of the most unfortunate hepatitis C patients.  In contrast, studies that have followed cohorts of patients who have evidence of early hepatitis C infection show very different results.

In 1999, Kenny-Walsh and colleagues reported a cohort of 390 women who had tested positive for hepatitis C after receiving infected immune globulin.(2)  They were able to follow them for 17 years.  In that time period, 43% of the women had no or minimal inflammation of the liver; 49% had no evidence of liver fibrosis; and only 2% had developed fibrosis.

In 2000, Seeff and colleagues reported 45 years of follow up of young military men who were found to have evidence of hepatitis C infection from analysis of long stored frozen serum.  Only one (less than 3%) of their admittedly small cohort of 34 positive men had been found to have any sort of liver problem in that time period.(1)

In 2001, Seeff and colleagues reported 20-year follow up of several cohorts including 222 patients who developed hepatitis characterized by abnormal liver enzymes after blood transfusion and for whom retrospective tests on stored blood revealed hepatitis C at that time.(3)  The total mortality over 20 years of the hepatitis C patients was not greater than a group of control patients who had been transfused but did not develop clinical hepatitis.  51% of the hepatitis C infected patients had no evidence of chronic hepatitis.  23% had no evidence of continuing hepatitis C infection.

These admittedly old studies show that a significant minority of patients with hepatitis C infection spontaneously resolve their infections, and that a majority of patients have no evidence of significant liver disease over decades of observation.  Cirrhosis is actually a relatively rare outcome of hepatitis C infection, and there is no clear evidence that hepatitis C infection increases total mortality.

Of course, once a patient with hepatitis C has been unfortunate enough to develop clear liver disease, that patient's prognosis is not so good.

Thus, there is no clear evidence that the majority of patients with hepatitis C infection could benefit from anti-viral treatment given prior to development of any significant complications of the infection, because the majority of such patients may never develop any adverse effects of the infection.  Thus it is not at all obvious that any current hepatitis C treatment could be widely life-saving.

Treatment Prevents Nearly All Bad Outcomes

There have been no long-term randomized controlled trials of any anti-viral treatment for hepatitis C that evaluated clinical outcomes like cirrhosis, liver failure, liver cancer, need for transplantation or death.  All trials of all agents have been relatively short term, and focused on reduction or elimination of detectable virus from the blood as an outcome.  As detailed in the latest evidence report from the US Preventive Services Task Force,(4) there have been observational studies that compared patients who were treated and had sustained virological responses (elimination of detectable virus from the blood) and those who did not in terms of long-term outcomes.  Such observational studies are liable, however, to confounding.  Patients who are willing to take treatment, fully comply with treatment, and respond better to therapy may be systematically different from those who refuse treatment, do not adhere to treatment, or whose treatment is not initially successful.  Most of these studies were considered to be of poor methodological quality, although the best, still only considered of fair quality, did show an association between virological responses and clinical outcomes.  There have been no studies of the comparative effectiveness of different anti-viral treatments.

Thus, the evidence that anti-viral treatment for hepatitis C prevents any bad clinical outcomes, like cirrhosis, liver failure, liver cancer, or premature death is unclear.

Now to consider the best evidence available about sofosbuvir.

Sofosbuvir cures nearly everyone of hepatitis C

So far, the best study reported about sofosbuvir seems to be one in the New England Journal of Medicine in 2013.(5)  This report included an open-label (not blinded) controlled trial called FISSION of sofosbuvir plus ribivirin versus peginterferon alfa-21 plus ribivirin.  Its primary outcome measure was viral response 12 weeks after therapy (which lasted 12 weeks in the first group, 24 in the second).  The proportion of patients with responses 12 weeks after therapy were 67% in both groups.  Patients who received sofosbivir had lower rates of the common, uncomfortable complications attributed to interferon therapy than those who received peginterferon (e.g., fatigue, 36% versus 55%; nausea, 18% versus 29%).  However, while small, the proportion of patients with serious adverse events, not further defined in the article, were higher in the sofosbivir group, 3% versus 1%.

Note that the above report also included what was euphemistically called a "single-group, open-label study."  This seems to be a fancy name for what is usually called a case series, that is, a series of patients given a particular treatment, without a control group.  The consensus in the evidence-based medicine community has long been that barring miraculous results, case series are nearly useless as evidence about treatments, primarily because it is not possible to separate the effects of the patient selection process from the treatment on the apparent outcomes.  Why this case series was included in the report is a secret known only to New England Journal editors.

So setting aside that distraction, it is not obvious that sofosbivir increases even short-term virological response (at 12 weeks after treatment) compared to the best previously available treatment.  There is no evidence that sofosbivir can cure nearly everyone.  (Much of the enthusiasm seems to come from blood tests on treatment, disregarding the results shortly after treatment.)  These are not "spectacular" results."

Sofosbuvir is extremely safe and has few side effects

From the above trial results, it is not obvious that the drug is extremely safe.  In fact, there is a suggestion that it may lead to an increase in serious adverse effects.

While the drug does seem to produce fewer bothersome adverse effects, even the rates of these symptoms in those treated are not negligible.

Summary

While there is concern about the gargantuan price asked for Sovaldi, the new treatment for hepatitis C, there seems to be little skepticism about the near miraculous claims made for the value of the new drug.  In fact, it almost appears that the debate about the price is reinforcing current dogma which promises nearly universal cures without major risks.  Yet the evidence is that many, perhaps most patients with hepatitis C will not benefit from treatment, and that the new drug is not much more, or any more likely to cure patients than older drugs.  Meanwhile, the evidence that the new drug is safer and causes fewer adverse effects is weak at best.

The US health care system, and to some extent the health care systems in most developed countries are experiencing ever higher prices.  Much of these prices' effects seem to drive up remuneration of health care executives and managers, but whether they buy better care or outcomes for most people is not so clear.  The ever rising prices seem to be buoyed by endless enthusiasm for new tests, treatments, programs, and unbridled faith in the benefits of all new technology.  It is not clear how much of that is due to evidence, how much is based on ideology and unquestioning faith in technological progress, and how much is driven by marketing and public relations, which not always may be entirely honest and free from deception.

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 lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.

References
1.  Seeff LB, Miller RN, Rabkin CS et al.  45-year follow-up of hepatitis C virus infection in healthy young adults.  Ann Intern Med 2000; 132: 105-111.  Link here.
2.  Kenny-Walsh E, for the Irish Hepatology Research Group.  Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.  N Engl J Med 1999; 340: 1228- 1233.  Link here.
3. Seeff LB, Hollilnger B, Alter HJ et al.  Long-term mortality and morbidity of transfusion- associated non-A, non-B, and type C hepatitis: a National Heart Lung and Blood Institute Collaborative Study.  Hepatology 2001; 33: 455-463.  Link here.
4. Chou R, Hartung D, Rahman B et al.  Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review.  Ann Intern Med 2013; 158: 114.-123.  Link here.
5.  Lawitz E, Mangia A, Wyles D et al.  Sofosbuvir for previously untreated chronic hepatitis C infection.  N Engl J Med 2013; 368: 1878-1887.  Link here.