A Little Sunshine Peeking Through the Clouds? - the Sunshine Act is Finally Implemented, Sort of

"Conflicts of interest" is probably the most frequently used Health Care Renewal tag.  We believe conflicts of interest are a major causes of health care dysfunction.  Therefore, I felt that one of the truly reformative aspects of the US Accountable Care Act (ACA, "Obamacare") could be the "Sunshine Act," a provision championed by Iowa Senator Grassley (R) and his staff investigator, Paul Thacker, that would require public reporting of most financial interactions among health care corporations and health care professionals and hospitals.

The roll-out of Sunshine Act implementation occurred this week, and not unexpectedly, was very rocky.   As reported by the Wall Street Journal,

it hasn't been a smooth process. First, CMS delayed the public reporting of the data by a year to give companies more time to prepare. The Open Payments online system has experienced technical problems, including a data mix-up that resulted in some doctors being linked to payment records for other doctors with the same surname. The preview function for doctors had a cumbersome registration process, some doctors said, and was taken offline at times in recent weeks.

The first batch of data is incomplete. CMS in August said it removed about one-third of the payment records from the physician-preview database because it said some of the state medical-license numbers that companies reported for doctors didn't match a database that the agency was using for verification, among other problems. CMS now is releasing those records but without identifying the physicians tied to them. It will update the database to include the physicians' names for those records next year. Also, CMS isn't immediately releasing payments related to proprietary research-and-development; those will be reported at a later date.

 But why should we have expected anything else, given the parties involved?

Drug, Device and Biotechnology Companies

As reported by the NY Times,

all manufacturers of drugs, medical devices and medical supplies that have at least one product covered by Medicare or Medicaid must report payments or gifts they make to doctors and teaching hospitals. This can be as seemingly trivial as a bag of bagels — all payments above $10 are included — or as lofty as a research grant. It also includes meals, travel expenses and speakers’ fees. Group-purchasing organizations, which serve as middlemen between health care providers and manufacturers, also must disclose doctors’ ownership and investment interests in their companies.

Presumably such reporting actually was quite burdensome to the companies.

Furthermore,company executives might not be exactly thrilled about putting all this information out there.  As we have frequently discussed, to serve their own interests, such companies make all sorts of payments to physicians, other health care professional, and hospitals and other non-profit health care organizations.  In particular, payments to health care professionals may foster companies' marketing and public relations goals.

While some payments are made for technical and clinical consulting, many are to support "education" that may serve marketing or public relations.  In particular, many payments are for "drug talks," that is, talks sponsored by the drug companies, usually through speakers' bureaus, and given probably not as part of formal, accredited continuing medical education.  Since the publication of "Dr Drug Rep" in the New York Times in 2007, it became evident that such talks emphasize content provided by the pharmaceutical companies, and are intended to be corporate marketing exercises.  From that case we also learned that physicians who deviate from the marketing message do not last long on speakers' bureaus.  (See posts here and here.)

In addition, pharmaceutical companies often pay physicians deemed to be "key opinion leaders," whose opinions are promoted supposedly for their brilliance and erudition.  However, as noted here and here, the companies buying their services think of KOLs as sales people.    Evidence about key opinion leaders actually performing like marketers has come from documents revealed during litigation (e.g., see this recent example of a huge monetary settlement made of charges that GlaxoSmithKline, a major multinational drug company committed fraud among other things, and in the course of its unethical activities used key opinion leaders as marketers).   Also, see the Neurontin marketing plan (see post here), and the Lexapro marketing plan (see post here) for examples of how corporate managers view key opinion leaders as marketers.

Pharmaceutical, biotechnology, and device companies protest that much of the money they pay goes to support research.  But the clinical research they sponsor has been shown to be frequently subject to manipulation designed to increase the likelihood of results favorable to these companies' products.  When manipulation fails to provide sufficiently favorable results, corporations may simply  suppress it.  Academic institutions desperate for more external funding, and physicians whose continued gainful employment at such institutions requires external funding may not be too quick to protest manipulation and suppression by those paying the bills.

Vox just summarized some of the relevant evidence:

Research for decades has shown that relations with industry — from industry-sponsored education to encounters with pharmaceutical-company sales representatives, and even drug samples provided by those companies — can bias a doctor's judgment in all sorts of ways. It can color the medical education they give to future doctors, cause them to inappropriately prescribe drugs, to push for the FDA approval of medicine, or for drugs to be included on their hospital formularies. Industry-funded studies are also four times more likely to lead to favorable and positive results than independent research.

The side-effects of this 'Bad Pharma' behavior range from waste in the health system, to mistreatment of patients, and even avoidable patient death.

So is it any surprise that industry may not have been enthused or comfortable about complying with the Sunshine Act?  Instead of admitting that, of course, they have complained, as reported by the NY Times,

the website is being questioned by the industry, which says that technical problems and data inaccuracies limit its value.

But it seems that industry may have created the sorts of data problems about which they now complain.  Note that when ProPublica made this first assessment of the database,

Many drug and device companies attributed payments to multiple subsidiaries, rather than reporting them under the name of a single parent company. Johnson & Johnson, for instance, submitted payments under at least 15 subsidiaries. The device maker Medtronic reported payments by at least six subsidiaries. So did the drug maker Novartis. On first blush, that makes it tough to calculate how much each company spent overall.

Similarly, companies reported payments associated with particular drugs in different ways. The expensive drug Acthar, which is marketed for a variety of different conditions, is listed under at least eight different name variations. The diabetes drug Januvia is reported as both 'Januvia' and 'Januvia Diabetes.' There is one drug simply listed as 'KNEES' and another as 'Foot and Ankle.'

So it appears that the companies reported data in a confusing, perhaps deliberately confusing manner, obfuscating the relationships between companies and subsidiaries, and between essentially similar drugs with different names.  It is hard to believe that all, or even most of these problems were due to mishandling by the government.  So it is a little hard to take the companies' criticisms of the quality of the data seriously.

Physicians and Organized Medicine

"We have met the enemy and he is us." - Pogo

On the other hand, news articles suggested some physicians were also unhappy with the data release.  For example, per the WSJ article,

Some doctors disputed details of the payment data. The database shows John LeDonne, a surgeon from Baltimore, as having received about $78,200 in payments for food and beverage for the five-month period from medical-device maker Dr. LeDonne acknowledged he performs paid consulting work for health-care companies including Teleflex, but that he rarely received free meals. He said the total payment amount was in the right 'ballpark,' but should not have been classified in the food-and-beverage category. 

That seems to be a bit of quibble.  The amount he received, and its source, seem more important than whether it was labelled "consulting," or "food and beverage" payments.

More importantly, a few doctors were worried, as reported by the Minneapolis Star-Tribune, that the information may reflect negatively on them,

 'Overwhelmingly, the interaction between industry and physicians is positive,' said Dr. Robert Harbaugh, chairman of neurosurgery at Penn State and president of the American Association of Neurological Surgeons.

Maybe Dr Harbaugh should realize that there already are a lot of reasons to think about the negative aspects of physician - industry paid interactions, as summarized above. And Vox reported,

 Dr. Thomas Stossel, known as Harvard's 'pro-industry professor,' says 'doctors' work with industry is necessary and beneficial.' He worries that the Sunshine Act could make it embarrassing and difficult for doctors to do work like developing medical devices or designing clinical trials, and that industry may start avoiding working with American doctors because of the time and investment disclosure will require.  

Dr Stossel did not provide evidence to explain the necessity or benefits of the work for industry, nor why doctors could not design clinical trials outside of industry relationships. 
Doctors also complained about data quality, but I am not aware that the medical profession rushed to help with improving the data for the Sunshine Act.  Obviously, there are some physicians who have personally profited quite a lot from their relationships with drug, device, and biotechnology companies but who may not be comfortable having the figures booted around in public, e.g., per the WSJ,

Among individual physicians, Stephen Burkhart was one of the top recipients of non-research payments from industry. The San Antonio orthopedic surgeon received $7.4 million in non-research payments or transfers of value for the five-month period, mostly from device manufacturer Arthrex Inc. for payments identified as 'royalty or license.'

Dr. Burkhart couldn't be reached for comment. Arthrex said in a statement that it has 'financial relationships with a number of orthopedic surgeons and teaching hospitals,' like many manufacturers, for their advice and expertise.

Chitranjan Ranawat,a New York orthopedic surgeon, received about $4 million in nonresearch payments or transfers of value, mostly from DePuy Synthes unit for 'royalty or license,' according to the database. 

 Dr. Ranawat couldn't be reached for comment.

And those were payments made in a five month period.  Maybe the doctors have a reason to be uncomfortable.

Furthermore, ProPublica reported that 21% of the $3.5 billion in payments, approximately $735 million, reported by the system were for "promotional talks," a la "drug talks" as noted above.  Since "Dr Drug Rep," such talks have gotten something of a bad reputation, but are obviously lucrative, so those who got paid to give them may not be happy with their detailed disclosure.

The US Department of Health and Human Services

The Sunshine Act was but a small part of the huge ACA, most of which the US DHHS, and particularly the Center for Medicare and Medicaid Services (CMS) was charged with implementing, but probably with proportionately insufficient funding and time.  So no wonder that the Sunshine Act never seemed to find a vocal champion within DHHS.

Most likely money concerns, and the constant din of outside criticism of "government bureaucrats" by those demanding more "business-like" government lead CMS to outsource the work on the Sunshine Act database, as described by another ProPublica article,

While the payments database is a far cry from Healthcare.gov — and less complex – it's reasonable to expect some glitches. CGI Federal, the company that led what turned out to be the botched launch of Healthcare.gov, is also responsible for the release of the payment data.

Massachusetts also outsourced operation of its Health Connector to CGI Federal, with equally bad results.  The state had to terminate the contract (look here.)

So if lackadaisical bureaucrats outsourced the Sunshine Act to contractors of questionable competence, what result should have been expected?

Why the present administration, and the bureaucrats it supposedly commands, seemed so uninterested in this particular aspect of the ACA is not clear, but perhaps we should peer around some revolving doors for the answer.  (For example,  John Podesta, a current White House adviser, worked for non-profits funded by drug company Eli Lilly and device company Synthes [look here]; and Nancy-Ann DeParle, former White House "health czar," had previously served on the boards of of Boston Scientific, Cerner and Medco [look here], and now is involved in health care investments made by private equity, and is on the board of CVS [look here]).

Of course, the sort of conflicts of interest that were supposed to be revealed by the Sunshine Act are highly beneficial to the parties directly involved, whatever embarrassment they may cause.  Given the power of those parties, plus the lukewarm, outsourced effort by government perhaps influenced by government officials with their own "revolving door" conflicts of interest, is it any wonder that the Sunshine Act implementation was "rocky?"

Summary

Nonetheless, because of the Sunshine Act, we do now know a bit more about conflicts of interest involving drug, device, biotechnology and related companies on one hand, and physicians, other health care professionals and hospitals on the other.

Maybe throwing even veiled sunshine on some of these relationships will inspire some people to rethink whether they want to continue them.  There are other reasons they should do so.

We have called endlessly for full, detailed disclosures of all conflicts of interest, for honesty's sake if for no other reason.  We have also called for severe curtailment of all conflicts affecting clinical decision making, health care education, clinical and health care research, and health policy making.  But Health Care Renewal can easily be dismissed as a voice crying out in the wilderness.  However, we are really not alone.

The 2009 Institute of Medicine report set relatively tough standards for managing conflicts of interest affecting clinical research and teaching, which unfortunately since have largely been ignored.  It did call for senior institutional officials to disclose their conflicts of interest, and for institutional boards of trustees to form conflicts of interest committees that would exclude conflicted individuals, but otherwise did not address conflicts of interest affecting academic leaders or institutional trustees.  The 2013 Pew Charitable Trusts Conflicts-of-Interest Policies for Academic Medical Centers suggested restrictions on conflicts affecting faculty, trainees, and students, but again did not mention senior institutional leaders or boards of trustees.  Implementing even some of these recommendations would be true health care reform.

Maybe more publicity about the web of conflicts of interest that drapes of over health care will lead to some further steps in the needed direction. 

No Treatment or Vaccine for Ebola, but a $1000 Pill for Hepatitis C

The Ebola virus epidemic in West Africa continues to grow, and now appears to be the worst known epidemic of that disease to date.  In the US and Western Europe, press reports are now raising concerns that the disease could spread there.  For example, CNN, in an article entitled "Ebola Fears Hits Close to Home," was a section headed "Could Ebola spread to the US?" An ABC article was entitled, "How the US Government Could Evacuate Americans with Ebola."

Reasons for fear of spread are the increased mobility of people made possible by air travel, and the lack of specificity of early symptoms of Ebola, so infectious people may not realize the dangers their travel might pose.  A US citizen with Ebola was on his way back to the US via several connections, and made it as far as Lagos, Nigeria before becoming too ill to travel further (per CNN).  Making the fears worse are the high fatality rate of Ebola, the current epidemic included.  According to Vox, the current outbreak is the Zaire subtype of the virus, with an expected mortality rate of 68%.  Finally, there is no known effective treatment or vaccine for the Ebola virus.

Economics, not Science the Reason for Lack of Medical Options for Ebola

The reason there are no vaccines or treatments available for Ebola does not appear to be the scientific difficulty involved in developing them.  Vox also published a discussion for the economic genesis of the problem:

 Researchers have devoted lots of time to building a vaccine that could stop the disease altogether — and according to Daniel Bausch, a Tulane professor who researches Ebola and other infectious diseases, they're making really significant progress.

Bausch says that the obstacle to developing an Ebola vaccine isn't the science; researchers have actually made really great strides in figuring out how to fight back against Ebola and the Marburg virus, a similar disease.

'We now have a couple of different vaccine platforms that have shown to be protective with non-human primates,' says Bausch, who has received awards for his work containing disease outbreaks in Uganda. He is currently stationed in Lima, Peru, as the director of the emerging infections department of Naval Medical Research Unit 6.

The problem, instead, is the economics of drug development. Pharmaceutical companies have little incentive to pour research and development dollars into curing a disease that surfaces sporadically in low-income, African countries. They aren't likely to see a large pay-off at the end — and could stand to lose money.

Prof Bausch elaborated,

These outbreaks affect the poorest communities on the planet. Although they do create incredible upheaval, they are relatively rare events. So if you look at the interest of pharmaceutical companies, there is not huge enthusiasm to take an Ebola drug through phase one, two, and three of a trial and make an Ebola vaccine that maybe a few tens of thousands or hundreds of thousands of people will use.

Of course, that assumes that this outbreak, like previous ones, will remain relatively confined, at least to Africa.

The 10/90 Gap

So the implication is that had things been otherwise, those in developed countries now worried that Ebola could spread their way could have been reassured by the availability of a vaccine, or other treatment.

The irony, if that is the right word, is that we do not have an effective treatment or vaccine for a viral disease that is relatively easily spread, and could likely rapidly kill nearly 70% of those infected.  Yet in the last months, we have been arguing about how the use of an extremely expensive treatment for another viral disease that is difficult to spread, and may kill a few percent of its victims over up to 20 or 30 years after infection.

I am referring, of course, to Sovaldi, the recently announced $1000 pill for hepatitis C.  Hepatitis C does affect a lot of people, including relatively affluent people in developed countries.  As we noted previously, though, the majority of people infected with hepatitis C will never have serious medical repercussion from it.  Small proportions of patients will eventually develop severe liver disease, including cirrhosis, liver failure, and liver cancer, and may die from the disease.  (See the report by the Center for Evidence Based Policy). Yet the treatment is being promoted for all patients with hepatitis C, most of whom could not benefit from treatment.  Furthermore, the evidence that treatment will actually prevent bad clinical outcomes, cirrhosis, liver failure, liver cancer, and premature death, is weak (look here).   Yet considerable money was devoted to developing multiple hepatitis C treatments, with the expectation that huge amounts of money could be made from selling them.

This is an example of the 10/90 gap

A long time ago, in 1998, I was invited to Forum 2 of an organization called the Global Forum for Health Research  The GFHR was an organization dedicated to overcoming the "10/90 gap":

Less than 10% of the worldwide expenditure on health research and development is devoted to the major health problems of 90% of the population

Yet the 10/90 gap is probably getting worse.  In the US, our health care has now been heavily influenced by advocates of neoliberalism, or economism.  Health care is now largely run by generic managers trained in business schools, with no specific training or expertise in health care, and doubtful loyalty to its values.  Current business school dogma emphasizes the primacy of economic efficiency over all other goals (look here), to maximize "shareholder value," which usually practically means maximizing short term revenue, to the immediate advantage of shareholders sometimes, but nearly always to the great and immediate financial advantage of paid managers and executives.  The emphasis on short term revenue uber alles helps explain how we have multiple expensive hepatitis C drugs, and no Ebola drugs or vaccines.

The real irony is now that some very well paid managers may be worrying about the possibility of contracting Ebola whose transmission was facilitated by our increasingly global economy, globalized in part due to the advocacy of those advocating neoliberalism and economism.

Summary

Unfortunately, the fortunes of the Global Forum for Health Research seem to have faded.  It went into sudden decline in 2010, and was subsumed into COHRED, the Council on Health Research for Development.  The last Global Forum meeting was in 2012, although there seem to be plans for another next year.    Meanwhile, multiple international organizations. including Medicins Sans Frontieres, established a Drugs for Neglected Diseases initiative, although its progress seems to be slow (see Pedrique B, Strub-Wourgaft N, Some C et al.  The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.  Lancet Glob Health 2013; 1: e371.  Link here.).

In my humble opinion, as long as much of the health care system is run so as to put short-term revenue ahead of all else, a manifestation of financialization encouraged by the generic managers who run so much of health, partly in their own self-interest, and by business schools promoting the shareholder value theory, we will not make much progress on the 10/90 gap.  Ironically, the realization that even rich generic managers may no longer be protected from some of the deadliest diseases that used to only afflict the poorest people in the world may have an effect on this problem.   

As I have said before,  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.

ADDENDUM - This was re-posted on the Naked Capitalism blog. 

The Return of PharmaLot

After an unfortunate hiatus (see this post), PharmaLot is back.  PharmaLot was one of the premier sources of incisive information on the pharmaceutical industry, is back.  PharmaLot was and now is run by Ed Silverman, and is known for publishing important, but sometimes unpleasant truths.

Ed Silverman provided unbiased, insightful reporting.  Notably for the Health Care Renewal audience, he was not afraid to report on the good, the bad, and the ugly. He was no friend of marketing and public relations smarm.  Often he was first to break stories involving legal settlements, guilty pleas, and miscellaneous misconduct, and in some cases was one of the few to document such stories.

For example, when PharmaLot last disappeared, I noted that it provided one of the few accounts of a $21 million fine imposed on Merck by French antitrust regulators (here is the brief Reuters version.)  PharmaLot reported on a judgement against Actelion for anti-competitive practices in support of its drug for pulmonary artery hypertension.  The only other media report on this was in the San Francisco Chronicle, and it was less detailed. 

As we have noted endlessly, bad behavior by large health care organizations, including pharmaceutical and biotechnology companies and the various organizations with which they interact, like contract research organizations, medical education and communication companies (MECCs), etc has often been anechoic.  If one likes to get along by going along, it is not a good idea to make too much of a fuss about such issues and suppression and manipulation of clinical research, deception in  marketing, and perverse incentives including the creation of conflicts of interests, much less outright crime and corruption.  Ed Silverman was known to fuss about such issues.

So the return of his fearless reporting, and willingness to post controversial interviews and editorials, is a rare ray of light in the gloom. 

PharmaLot has just been added back to our blog roll.  Welcome back!

PS - It may be too much to hope that the back archives of older versions of PharmaLot can be restored to public view.  We wait with baited breath. 

Hat tips to 1BoringOldMan, Fear and Loathing in Bioethics

Some Authoritative Skepticism about the "Triumph" of Sovaldi to Add to Outrage about "Blood Money"

Three weeks ago we posted about the continuing controversy over the stratospheric price of the new antiviral drug for hepatitis C (HCV), sofosbuvir (Sovaldi, by Gilead).  While the amazing $1000 per pill price got deserved attention, at that time no one but your humble blogger seemed to be publicly skeptical about published assertions that the drug was some sort of modern miracle, and a triumph of medical science.  At that time, we noted that there is no "strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a 'triumph' that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price."


Since then, two other skeptical opinions have become public.

The German Institute for Quality and Efficiency in Health Care (IQWiG) Early Benefit Assessment

The German agency performed this assessment based on a dossier submitted by the drug manufacturer (presumably Gilead).  The assessment found some reason to think the drug beneficial, but that the evidence was sparse, left many questions unanswered, and was inadequate to assess the drug for some important patient populations.  At this point, only a summary is available in English.  It includes links to further information in German.

The overall assessment was,

The dossier submitted by the drug manufacturer provides indications of added benefit for non-pretreated patients infected with the virus of genotype 2. However, the extent cannot be quantified. There were no suitable data in the dossier for patients who are infected with other virus types (genotype 1 and 3 to 6) or who are coinfected with HIV.

Limited Generalizability


Particular problems with data about genotypes other than 2 were:

The manufacturer presented no adequate analyses for infection with type 1 and type 3 to 6 viruses and for HIV coinfection. It analysed results from studies in which the respective comparator therapy was tested in at least one study arm and compared these in a 'historical' comparison.

It included both randomized controlled trials (RCTs) and one-arm studies on the sofosbuvir side, but only RCTs on the comparator side. It justified this by claiming that it wanted to reduce the number of hits of its literature search. However, the database for the comparison was different because of this and the comparison itself was therefore unsuitable. A first literature search by IQWiG showed that a number of studies were not considered in the dossier.

Thus the assessment concluded that the drug company dossier included at best irrelevant data that it tried to pass off  as important, and inexplicably left out other data that might have been relevant.

Problem with Random Allocation

The German assessment focused on the single randomized controlled trial which compared sofosbuvir and ribavirin to peg-interferon and ribavirin whose results were published in the New England Journal and discussed in our previous posts (here and here).   However, the German assessment analyzed what was submitted in the company's dossier about this trial, rather than the published results in the NEJM.  It found problems in addition to those we found, starting with problems with the randomization,

Overall, IQWiG assessed the risk of bias of the FISSION study as high. The main reason was that the manufacturer only included those participants in the analysis who had received at least one dose of the medication they were randomized to. However, particularly in the control arm, where not the new drug, but conventional drugs were administered, some patients refused to have their planned treatment.

This is a general problem of open-label studies, where it is known who receives which treatment. This poses the risk that patients discontinue the study prematurely depending on which treatment they were randomized to. This compromises the aim of randomization: the comparability of the treatment groups.  This is exactly what happened in the FISSION study, which may lead to (highly) biased results.

Thus, the assessment concluded that the study had a major problem with randomized allocation.  This should be added to the other problems we found: unblinded ascertainment of adverse effects potentially leading to bias, apparently deliberate obfuscation of adverse effects, especially deaths occurring during the trial, and lack of long term followup.  This suggests that the study was manipulated to increase the likelihood of favorable results

Failure to Consider Important Outcomes

The German assessment also concluded that the trial provided no information about mortality or quality of life benefits,

 As no deaths occurred in the FISSION study in the therapeutic indication genotype 2, there could be no differences between the treatment groups, and therefore no proof of added benefit, in the outcome 'mortality'. This also applies to health-related quality of life, but in this case because the dossier contained no evaluable data for this outcome.

Note, however, that this suggests that the data submitted in the dossier was different than that reported in the New England Journal of Medicine.  We noted that in the supplemental data from the trial available on the web appeared data on mortality.  However, it showed higher (albeit still very minimal) mortality in the sofosbuvir group than in the peg-interferon group. The fact that the dossier submitted in Germany omitted all mortality results should be added to the fact that the NEJM report buried the mortality data in the on-line supplement, increasing the likelihood that the dissemination of this part of the results was manipulated to forestall the questions that it ought to provoke.

The German assessment further noted that the dossier included no good data about possible harms or adverse effects of the new drug,

The data on side effects contained in the dossier could only be assessed to a limited extent. The manufacturer presented these data on the basis of the proportions of patients with at least one event. However, this type of analysis is only suitable to a limited extent because the observation period of the patients was different in the two study arms.

Note that is suggests another type of study manipulation, unequal assessment of harms in the study arms perhaps meant to minimize the apparent harms of the new drug.  

Furthermore, again the data in the dossier appeared discrepant from that in the NEJM article (which we discussed here),

 Severe adverse events only occurred once in each of the two study arms. A statistically significant difference in the outcome 'treatment discontinuation due to adverse events' in favour of sofosbuvir was not robust in the sensitivity analyses performed by IQWiG. With regard to side effects, IQWiG therefore considers the added benefit as not proven.

The severe adverse event rates reported in the New England Journal article were higher, and the reason for this discrepancy is unclear.  

A Non-Quantifiable Benefit?

So ultimately only a qualitative assessment of the drug's benefits for genotype 2 patients was possible,

 For treatment-naive patients with genotype 2 chronic hepatitis C, an overall positive effect of sofosbuvir in comparison with the appropriate comparator therapy remains with regard to serious secondary diseases. The extent of this added benefit – which was determined with the surrogate 'SVR' – is non-quantifiable, however, because it is unclear how often the development of liver cancer can in fact be prevented. 

Note that mention of the IQWiG assessment has been made so far in only one major US media outlet, Bloomberg.  

 The Institute for Clinical and Economic Review Evidence Report

This report just appeared online in JAMA Internal Medicine [Ollendorf DA, Tice JA et al.  The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection.  JAMA Inte Med 2014.  Link here.] 

The review found again that there were major limitations in the available data, and so much of it was based on a network meta-analysis and simulation studies,

The review was limited to patients with genotype 1, 2, and 3 infections, which account for most HCV cases in the United States. At the time of the review, no head-to-head trials of the direct-acting antiviral drugs had been performed, and most of the data on sofosbuvir came from uncontrolled studies We therefore used network meta-analytic techniques to perform indirect comparisons of sustained virologic response outcomes across treatment options and used these results as the input to a simulation model that compared the estimated clinical and economic outcomes of treatment after 1 and 20 years.

It is very hard for me to independently evaluate the credibility of these indirect methods of analysis of what amounts to sketchy data.  However, I should note that Ollendorf et al did not some other specific problems with the available data on sofosbuvir:

Yet at the time of this review there were several reasons for caution. First, the evidence base on the comparative clinical effectiveness of these 2 new drugs remained thin in most areas and notably incomplete in others. For example, in some subgroups, such as patients who have failed earlier treatments, there were little or no data available. There were no long-term data demonstrating the durability of short-term sustained virologic response rates for either drug; nor had either drug been compared head-to-head in a randomized clinical trial with each other or with a first-generation direct-acting antiviral drug. Finally, the evidence necessary for sofosbuvir to gain marketing approval through the FDA’s breakthrough designation was particularly sparse and did not include requirements for controlled trials.

Furthermore, it suggested reduced enthusiasm for treatment since most patients with hepatitis C will not develop severe complications, limiting the potential benefits of treatment,

 HCV is an indolent infection, and most adults with this infection will never develop negative health effects during their lifetime. Many people with HCV infection have no evident liver dysfunction. For such patients, the decision about whether and when to initiate treatment should involve careful consideration of the balance of risks and benefits and shared decision-making with experienced clinicians.

Note that at least to date, I have seen no discussion of the Ollendorf report in the media.

Pricing Unrelated to Production or Research and Development Costs

Meanwhile, there has been continued outrage in the media over the pricing of this probably not so miraculous drug.  Some has focused on the likelihood that most of the price represents pure profit, excess marketing (and perhaps huge payments to corporate insiders), rather than production or research and development costs.  For example, Bernard Munos wrote in Forbes

To compound the outrage, there is hardly a relationship between drug prices and their actual costs, which makes many patients feel as if they were held to ransom. Gilead, to its credit, has negotiated a deal that makes Sovaldi available to Egyptian patients at a 99% discount, but it may have also bolstered suspicions of profiteering.

Similarly, Julian Urrutia wrote in the Bill of Health blog from the Harvard Law School Petrie-Flom Center,

Gilead is working to offer lower prices in dozens of developing countries (of the 150 million patients with HCV, only about 1% are in the USA).

To me, this implies one of two things. Either Gilead will be selling the drug in developing countries at a price that allows it to make normal profits (in which case Gilead is capturing enormous rents in the USA market from $84K price tag), or whoever pays for the treatment of patients with HCV in developed countries will be subsidizing the treatment of patients in the developing world.

 The Editor of Modern Healthcare, Merrill Goozner wrote, an analysis of how Gilead's immense revenue was built on US government funded research, and academics who could privatize the research they did with such funding on university time,

 The National Institutes of Health invested heavily in university-based scientists to understand the genetic weak points of hepatitis C, just as it did for HIV. It gave grants to build virology labs, come up with potential drugs and conduct clinical trials.

One of those scientists was Raymond Schinazi, director of the Laboratory of Biochemical Pharmacology at the Emory School of Medicine in Atlanta. During the past 20 years, Schinazi's laboratory received at least $7.7 million from the National Institute of Allergy and Infectious Diseases. He wasn't alone. Some, like Kevin Raney, chair of the biochemistry and molecular biology department at the University of Arkansas for Medical Sciences, even developed drugs on their government grants, although his never made it into clinical trials.

Schinazi, a serial entrepreneur, took a different path. In the late 1990s, he formed the pharmaceutical company Pharmasset, to develop an antiviral drug invented at Emory. The company also worked on cures for HIV and hepatitis B. The original drug candidate went nowhere, he told me in a telephone interview. But chemists working inside Pharmasset—at the time of its sale to Gilead in 2011 it had only 82 employees—developed several novel therapeutics for the diseases, including one that eventually became Sovaldi.

Securities and Exchange Commission filings for Pharmasset during its years as a stand-alone research and development company revealed it spent under $7 million on R&D in 2003. In its early years, it received $1 million in government grants. Its total losses through 2011 came to $314.8 million. It was also investigating drugs for HIV and hepatitis B throughout that period.

The company hit the jackpot with hepatitis C and Sovaldi though, which led Gilead, whose initial success came from HIV drugs, to pay $11 billion for the company. Schinazi, who had retained a sizable stake in the firm after cutting his ties in 2006, walked away with over $400 million, according to a published report.

Gilead spent tens of millions of dollars to complete Sovaldi's clinical trials. Yet last August, the NIAID issued a news release touting its role in running one of those trials when positive results were reported in JAMA. The government, it turns out, had kept its hand in the development of Sovaldi.

So it appears that the pricing of Sovaldi has almost nothing to do with production or research and development costs.  Much of the initial research needed to develop Sovaldi was underwritten by the government.  Gilead paid royally for the results of the research, but most of the money went to investors and executives, including the former academic who did some early development work on government money and became tremendously rich from Gilead's largesse.

Growing Outrage over Extortionate Behavior


Some has focused on how the price represents unethical, if not extortionate behavior by corporate executives.  For example, Munos also wrote,

What has changed is perhaps the fact that the industry no longer realizes – or accepts – that it has a covenant with society. This is no ordinary business as it can only operate by the will of the people. Drug makers get intellectual property rights, which are essentially a license to print money, but in exchange society expects affordable innovation. For most of the past century, that bargain has worked remarkably well. But, if drug companies fail to live up to it, society can also revisit its part, and scale back patent rights, or deny reimbursement. And this is happening in a rapidly-growing list of countries – not just India and China, but Germany, the UK, France, Canada, and soon… coming to a drugstore near you.

The legendary leaders who built the pharmaceutical industry as one of the most respected understood that bargain. One remembers George Merck's admonition ('Medicine is for the people. It is not for the profits'), Jonas Salk’s quaint remark about the polio vaccine patent, Robert Wood Johnson’s Credo, and Roy Vagelos’ more recent warning about the industry’s ill-conceived pricing policies.  They understood that self-policy is always better than regulation, and such moderation served them well. But their successors’ failure to uphold their advice has led to an onslaught of regulations and policy changes that threatens to permanently remake the industry.

Elisabeth Rosenthal wrote in the NY Times, quoting Steve Francesco, a pharmaceutical consultant,

'To understand drug pricing you have to shed your sense of value as a consumer and as a noble human being,' Mr. Francesco said. 'You have to put on the lens of the health care industry, where what you’re doing is looking for opportunities to maximize return.'

Also in Forbes, Dr Robert Pearl wrote this about Sovaldi pricing,

 But at $1000 a pill, its pricing is exorbitant, monopolistic, and disrespectful to the purchasers and patients who will bear the brunt of the massive cost.

Dr Frank Huyler wrote in the New York Daily News about blood money,

This sort of blood money is nothing new. But it is among the worst of recent examples; yet another evil act, yet another predation on mostly poor, mostly desperate people, who inevitably will ask taxpayers to save them.

Summary

It is even bloodier money if the assumption that the drug is a "well-tolerated and effective cure," which  Dr Huyler held, proves not to be true.  It is clear that most of the money that Gilead is now scooping up in the US is not to pay retrospectively for research and development or drug production. Instead, it seems likely to be supporting marketing, public relations, some investors' profits, and huge executive compensation.  When the public realizes that the money may not be buying miracles, the outrage should increase.  

The Sovaldi case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will not buy us the promised miracles and triumphs.  

True health care reform would revisit the pact society once made with drug, biotechnology and device companies meant to promote reasonably priced innovation, but now promoting oligarchy; support transparency and honesty in clinical research; and challenge how health care managers can make millions or billions from unproven, and sometimes worthless or dangerous products.

Knee Deep in the Hoopla - "A Triumph of Medical Technology" Sans Evidence of Superiority from Published Randomized Double Blind Controlled Trials

With the publication of several new articles in the prestigious New England Journal of Medicine, the buzz about Sovaldi (sofosbuvir - Gilead), a new oral treatment of hepatitis C, has become feverish.  The drug had been hailed as near miraculous, and the only debate has been about its near stratospheric cost (look here). 

This week, of all weeks, however we should be extremely skeptical about expensive drugs promoted as the cures of our most feared ills.  This week a series of articles appeared in the British Medical Journal showing that there was no evidence to support the clinical value of the  antiviral drugs stockpiled for governments as proof against dreaded influenza epidemics (look here to start).  

The Latest Buzz

As we posted earlier, the discussions contrast the ostensibly near miraculous aspects of the drug's performance with its extremely high price.  For example, a few days ago the Los Angeles Times reported,

In a series of clinical trial results, a new generation of antiviral medications was able to clear the liver-ravaging virus from virtually all patients' bloodstreams in as little as eight weeks. Even in patients with the most stubborn infections, the new drugs were capable of suppressing the virus completely at rates well over 90%. The treatments, however, come with a steep price tag.

So,

The new medications are 'a triumph of modern medical technology,' said Dr. Jeffrey Tice, a UC San Francisco physician who was not involved in any of the clinical trials.

Accompanying the research reports in the New England Journal was a commentary by Dr Raymond T Chung and Dr Thomas F Baumert.  Its title proclaimed Sovaldi and similar drugs also to be part of "The Arc of Medical Triumph."(1)  Buried in the commentary's supplementary material was a link to disclosure forms that showed that:

Dr Chung reports grant support from Gilead Sciences [the manufacturer of Sovaldi], Mass Biologics, Vertex and Merck, and personal fees from Abbvie, Enanta and Idenix.

Note that Abbvie and Merck are also at work on antiviral treatments for hepatitis C.

and

Dr Baumert reports several patents ... and pending patents [apparently that could be conflicts of interest]

It is clear that there have been major scientific advances in the characterization of the hepatitis C virus, and development of multiple new antiviral agents which promise to treat that infection.  Furthermore, clearly there is reason for hope for treatment of hepatitis C that prevents its long-term complications and averts premature death. (Of course, that hope could be a bit stronger in the hearts of those who have financial relationships with the corporations that stand to profit from sales of these drugs.)

But it is not obvious that there is sufficient clear evidence from clinical research, particularly from double-blind randomized controlled trials (RCTs), that shows the newest treatments will provide triumphal benefits to patients that outweigh their possible harms.

One Published Unblinded RCT Compared Sovaldi to Peg-Interferon


In our previous post, written after the immense price of the new drug in the US became apparent, we questioned whether the evidence from controlled trials then available would justify the hype, and the high price.

We looked at what appeared to be the then single best available study. The most prominent randomized controlled trial of Sovaldi for patients who had not had previous therapy for hepatitis C that had been published by March, 2014, appeared in the New England Journal of Medicine in May, 2013.(2)   While it provided some reason for hope, it did not provide clear evidence that Sovaldi was a miracle drug.

The study showed that Sovaldi plus ribavirin produced the same rate of sustained virologic response (SVR), 67%, as did the previously accepted standard treatment, peg-interferon plus ribavirin, again 67%.  (SVR means that the hepatitis C virus has become undetectable in the patient's blood, and is believed, but not proven to represent a cure.)

While Sovaldi had lower rates of unpleasant side effects than did peg-interferon, these rates were not negligible. For example, the rate of nausea after peg-interferon was reported to be 29%, but after Sovaldi it was still 18%.  Given that the trial was unblinded, and that some of these side effects have a subjective element, these figures could have been biased due to patient expectations that the new drug would have fewer side effects.

Furthermore, Sovaldi appeared to produce higher rates of severe adverse effects (3%) than peg-interferon (1%).  However, the article did not mention any deaths in either treatment group.  When I later reviewed the  supplemental data available on the web from the May, 2013 article, I found that buried within this information were the facts that two people died during treatment with Sovaldi, and one after treatment with peg-interferon.  So, the rate of  severe adverse effects or death after Sovaldi treatment was more than double (9/256 ) than that after peg-interferon (4/243).  It is very curious and concerning that the authors chose not to mention deaths of study subjects in the paper that reported their trial results.   

Finally, the trial, like just about all previous trials of treatment of hepatitis C, did not follow patients long-term, and hence could not show whether treatment actually resulted in better clinical outcomes, for example, longer survival, decreased rates of severe liver disease, etc.  We thus concluded that there really was no clear evidence that Sovaldi was really a miracle drug, which could cure more people, in fact, nearly everyone, compared to standard therapy, yet with fewer side effects and more safety.

Any Evidence from Other Controlled Trials?

We looked through the newly published articles, the articles they cited, and the official US label for sofosbuvir to see if there is any other evidence from controlled trials to support the triumphant claims about sofosbuvir.  To simplify this casual, not systematic review, we only looked at articles about patients who had not been previously treated for hepatitis C.

The drug label mentioned a controlled trial that compared sofosbuvir to placebo.  The POSITRON study (study 107) was a trail that compared Sovaldi and ribavirin to placebo in patients who are "interferon intolerant, ineligible or unwilling."  The overall SVR in the treated group was 78%.  The label did not mention adverse effects rates in this trial, and as far as I can tell, it was not published.  Again, while the SVR was good, it was NOT over 90%.  As far as I could tell, the results of this study have not otherwise been published. 

The new studies in the New England Journal, and the studies cited by one of them were NOT double-blind randomized controlled trials of sofosbuvir versus some other treatment, or versus placebo for that matter.

For example, the study by Afdhal et al in the New England Journal considered sofosbuvir in combination with another new drug from Gilead, ledipasvir.  However, this was an open label (unblinded) study that compared patients given different durations of treatment with both sofosbuvir and ledipasvir with or without ribavirin.  It did NOT directly compare sofosbuvir (or ledipasvir) to any other treatment, or to placebo.(3) Another study by Sulkowski et al in the NEJM focused on previously treated patients.

Cited by Afdhal et al were studies by Osinusi et al (an unblinded study that compared different doses of ribavirin given to patients also who all received sofosbuvir)(4); Lawitz et al (an unblinded study that compared different durations of treatment for both sofosbuvir and ledipavir with or without ribavirin)(5); and Gane et al (a study that compared various drugs again all added to sofosbuvir)(6).  Again, NO study compared sofosbuvir to any other treatment, or to placebo.

Thus so far I have been unable to find any additional studies that compared Sovaldi (sofosbuvir) to any other potential treatments for hepatitis C.  Without a comparison to another treatment, it is not possible to tell whether the high rates of patients whose blood tests show no detectable hepatitis C virus in the short-term after treatment were due to the excellence of the treatment, or due to selection of patients with particularly good prognoses.   Recall that there is evidence that some patients with hepatitis C spontaneously clear their blood of hepatitis C, and become spontaneously cured (see our previous discussion, and particularly the study by Seeff et al[7]). 

There is evidence that the studies above may have been designed to only include patients with the best prognoses.  They generally were designed with very complicated, restrictive and subjective inclusion and exclusion criteria that could have eliminated all but the healthiest patients.  For example, according to the study protocol found in the supplementary material for the study by Afdhal et al, patients with "clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol" would have been excluded, as would have "subjects currently under evaluation for a potentially clinically-significant illness (other than HCV)...."

So, while many articles about sofosbuvir (Sovaldi) have appeared recently, in my humble opinion they do not provide strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a "triumph" that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price.

Summary

While the buzz about Sovaldi intensifies, there still seems to be little clear evidence to justify extravagant claims made for it, or the extravagant price demanded for it.  Yet there seems to be a bandwagon building to somehow pay whatever it takes to provide the "triumph" of medical science to every patient who needs it.  At the current price, that should make the CEO of Gilead even richer (increases in the stock price after the $84,000/ course drug price was announced already turned him into a billionaire on paper, look here.)  As noted above, it is not clear what benefits such a costly policy would bring to patients, and at what risks.

We have discussed how our current policy of letting corporations sponsor and run the clinical research meant to assess their own products has lead to widespread manipulation of research to make their products look better, and sometimes suppression of research that cannot be manipulated into making their products look good.  This should make health care professionals, policy makers, and the public extremely skeptical of every over-hyped new "innovation."  So far, there seems to be no public skepticism about this latest, and seemingly most expensive pharmaceutical "triumph."

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 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.


References
1.  Chung RT, Baumert TF.  Curing chronic hepatitis C - the arc of medical triumph.  N Engl J Med 2014:  Link here.
2.   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.
3.  Afdhal N et al.  Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.  N Engl J Med 2014: Link here.
4.  Orinusi A Meissner EG, Lee YJ et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.  JAMA 2013; 310: 804.  Link here.
5.  Lawitz E, Poordad FF, Hyland RH et al.  Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised phase 2 trial.  Lancet 2013; 383: 515.  Link here.
6.  Gane EJ, Stedman CA, Hyland RH et al.  Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.  Gastroenterology 2013.  Link here.
7.  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.

ADDENDUM (21 April, 2014) - Also see the post on "breakthrough cures?" by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog. 

Finally, An Article in a Large Circulation Medical Journal with Systematic Data about Leaders of Academic Medicine Conflicted by their Service on Health Care Corporate Boards

Background - a New Species of Conflict of Interest

Since 2006, we have posted repeatedly about  what was then a new species of severe conflicts of interest.  This occurs when leaders of academic medical institutions or other health care non-profit organizations or non-governmental organizations (NGOs) also serve as members of boards of directors of for-profit corporations  whose products and actions have major effects on health care.

Most recently, we discussed the cases of the current CEO of the National Quality Forum and past CEO of the American Board of Internal Medicine who was found to be on the board of for-profit hospital group purchasing organization Premier Inc, and had been on the board of its privately held but for-profit predecessors.  We then discussed the case of the incoming president of the US Institute of Medicine and former Chancellor of Health Affairs at Duke University who was on the boards of Alnylam Pharmaceuticals, Medtronic and Pepsico.  We next discussed the case of the current Dean of medicine at the University of Illinois who is on the board of Novartis. 

We also recently posted about the first time these sorts of severe conflicts of interest issue have been addressed in a large circulation medical journal.  A commentary in JAMA called for many such conflicts to be banned.

A Small Study of the Prevalence of a New Species of Conflict of Interest

Now JAMA has just published a research letter which examined the prevalence of board members of large, for-profit, publicly held pharmaceutical companies who also were among the leadership of academic medical centers. [Anderson TS, Dave S, Good CB et al. Academic medical center leadership on pharmaceutical company boards of directors.  JAMA 2014; 311: 1353-5.  Link here.]

The authors looked at public data about 2012 board membership of the 47 biggest publicly held companies based on global prescription drug sales. They tabulated those who were also leaders at (apparently only US) academic medical centers. 

The most important findings were:
- 19/47 companies (40%) had at least one board member who was a leader of an academic medical center (AMC)
- 16/17 US based companies had at least one board member who was also a leader of a US AMC
-  pharmaceutical company board members included 2 university presidents, 6 deans of medicine, 6 hospital or health system executives, 7 clinical department chairs or center directors
-  28 board members were also members of boards of trustees or directors of US hospitals, medical schools, or their parent universities.

Comments

We have been trying to raise awareness of this issue since 2006.  Now we have some idea of the size of the problem.

Keep in mind that this study did not attempt to determine the prevalence of academic medical center leaders on boards of smaller pharmaceutical companies, privately held companies, biotechnology or device companies, or other health care and health care related companies (e.g., for-profit hospital systems, health insurance companies, for-profit contract research organizations, for-profit medical education and communication companies, large companies with major health care components, etc, etc, etc)  It also did not attempt to determine the prevalence of leaders of other important health care non-profit organizations (e.g., hospitals and hospital systems, insurance companies, professional societies, patient advocacy groups, accrediting boards, etc, etc, etc) on health care or related corporate boards.  It also did not address leaders of health care organizations outside of the US.  So this study likely greatly underestimates the overall prevalence of and the number of people involved in what we first called a "new species of conflict of interest."

But it is a start.  And publishing it in JAMA will begin to make more health care professionals, policy makers, and researchers, and more of the public at large aware of the problem.

As I said before, it is very nice to see that the issue of what we once called a new species of conflict of interest finally has made the big time.  Whether it now gets any more traction remains to be seen.  Unfortunately, since conflicts of interest can be so profitable for the directly affected parties, I fully expect they will continue to oppose any restrictions.  The money they have made will likely be used to deploy marketing and public relations personnel and legal counsel to counter any attempts to try to make this aspect of health care more honest.

As we have said again and again, the web of conflicts of interest that is pervasive in medicine and health care is now threatening to strangle medicine and health care.  Furthermore, this web is now strong enough to have effectively transformed US health care into an oligarchy or plutocracy.  Health care is effectively run by a relatively small group of people, mainly professional managers plus a few (lapsed?) health care professionals, who simultaneously run or influence multiple corporations and organizations.

For patients and the public to trust health care professionals and health care organizations, they need to know that these individuals and organizations are putting patients' and the public's health ahead of private gain. Health care professionals who care for patients, those who teach about medicine and health care, clinical researchers, and those who make medical and health care policy should do so free from conflicts of interest that might inhibit their abilities to put patients and the public's health first.

Health care professionals ought to make it their highest priority to ensure that the organizations for which they work, or with which they interact also put patients' and the public's health ahead of private gain, especially the private gain of the organizations' leaders and their cronies.

ADDENDUM (3 April, 2014) - see also comments by Paul Levy on the Not Running a Hospital blog, on the 1BoringOldMan blog, and by Ed Silverman (welcome back!) on the WSJ Corporate Intelligence blog. 

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.