Edward Wyatt in the New York Times--
http://www.nytimes.com/2012/07/27/health/policy/drug-makers-deals-with-generic-rivals-may-face-justices-review.html
--reports on a ruling of the U.S. Third Circuit Court of Appeals that brand-name drug companies paying generic companies to delay the entry of generic drugs into the market is anti-competitive. This ruling runs contrary to rulings by other courts that support these payments and makes it more likely that the U.S. Supreme Court will have to take up the issue.
Wyatt adds that a bill now stuck in the Senate to end these pay-for-delay arrangements has been estimated by the Congressional Budget Office to promise $4.8B in savings over a decade for the Federal government, and overall drug savings of $11B.
The industry point of view--which, for a change, both the brand-name and generic drug companies agree on-- is that pay-for-delay is good business and good for the consumer because it actually speeds the entries of generic drugs into the market. How so? The usual stimulus for such an agreement is a patent dispute between the two companies. The companies have two options--make a deal; or fight a lengthy court battle to resolve the patent dispute. It's more efficient and ultimately cheaper for all parties, they say, so go the out-of-court-settlement route.
As I explained in HOOKED, there might be some merit in this argument if the patent dispute were truly a serious matter. The problem is, that it usually is far from that. The U.S. Patent Office, and the FDA oversight of drug patents, have gotten so loosy-goosey over the whole business that a brand-name firm can patent all sorts of trivial features of the pill, including famously its color, and then drag out a court battle with the generic company for years. The ultimate solution to this problem is to do away not only with pay-for-delay, but also with senseless, trivial patents, and for judges to simply throw out all such lawsuits.
Friday, July 27, 2012
Friday, July 13, 2012
AAUP Chimes In: The Trend toward Tougher COI Regulations
The American Association of University Professors has announced the publication of a draft version of "AAUP Recommended Principles & Practices to Guide Academy-Industry Relationships," and asked for open comments: http://www.aaup.org/AAUP/comm/rep/industry.htm
At a total of some 300 pages, the AAUP managed to exceed the length of Freeh report on the scandal at Penn State. Disclaimer: what follows here is based on my review of the first 40 pages that give a quick summary of the recommendations and an overview of the general approach. Full disclosure: I am an AAUP member.
For those of you who aren't academics, AAUP is an organization that represents faculty interests in higher education and is, in some places, the teacher's union. The present document is an amalgam of guidelines issued by other national groups such as IOM and AAMC, along with new principles generated by AAUP. AAUP justifies a new report because many previous recommendations have been made only for portions of the university such as a medical center, and AAUP argues that the impact on the entire university community needs to be considered.
Some of the 56 recommendations are standard AAUP boilerplate about how faculty should have a say in uinversity covernance regarding industry relationships. But a lot of the report seems well worth our attention because it suggests that the trend these days is toward tougher approaches to conflicts of interest in academia.
For example, the AAUP is a staunch defender of academic freedom and therefore admits that some faculty have used this as an argument against any regulation of financial relationships with industry--that individual faculty members should be allowed to make their own choices about their relationships with drug companies, research and consulting, etc. The report replies, "Their arguments obscure the fact that academic freedom evolved as a concept not only to protect individual rights but to insulate the academy and safeguard the discovery process from powerful social forces, initially the church and later big business. Some rules are necessary to preserve freedom of research, teaching, and inquiry. At stake are the standards that govern universities, their reputations, and public trust.
"Academic freedom does not entitle faculty members to accept outside responsibilities that make it impossible to do their primary jobs. Academic freedom does not entitle faculty members to sign away their freedom to disseminate research results. Academic freedom does not entitle faculty members to ignore financial conflicts of interest that could dangerously compromise the informed-consent process and the impartiality of research."
In sum-- stringent regulations against COI in industry relationships protect the core values of academic freedom.
On one issue that I have been harping on for many years, the report is similarly uncompromising. It accepts as a guiding principle that the mere disclosure and "management" of COI is seldom the right way to proceed, and that as a rule, eliminating and avoiding COI is much better--while formal plans for managing COI should be adopted for the minority of cases where it is indeed unavoidable without serious harm to vital public interests.
The AAUP also implicitly rejects the argument that since all faculty are biased in one way or another, "intellectual COI" is ubiquitous and therefore special regs to limit financial COI are unneeded:
In short, this draft report considers some key arguments against tougher COI regulations, rejects them, and proceeds to recommend a fairly uncompromising set of guidelines. The way AAUP operates, this report can never become a standard uniform set of regulations for all universities; rather the hope is that individual universities will turn to this report for general guidance as to their policies and then craft policies that take local needs and issues into account--in some cases, the report admits, perhaps adopting more lenient standards.
"Of course, faculty investigators also have biases—whether they arise from scholarly debates, personal affinities, or political and religious commitments. Faculty status does not confer independence from the activities and interests of the communities in which faculty members live and work. The heart of the matter, however, is that faculty not be contractually obligated to represent positions at odds with their professional judgment and public commitments, or placed in compromised situations, financial and otherwise, that are more likely to produce bias."
The AAUP is very clear that public trust in the academy and its research is at stake, for example:
"When corporations, or nominally nonprofit funding agencies, effectively bribe faculty members to, for example, publish articles with doubtful product claims, dubious economic assessments, or attacks on well-established science, the faculty betray their professional and public responsibilities."
At a total of some 300 pages, the AAUP managed to exceed the length of Freeh report on the scandal at Penn State. Disclaimer: what follows here is based on my review of the first 40 pages that give a quick summary of the recommendations and an overview of the general approach. Full disclosure: I am an AAUP member.
For those of you who aren't academics, AAUP is an organization that represents faculty interests in higher education and is, in some places, the teacher's union. The present document is an amalgam of guidelines issued by other national groups such as IOM and AAMC, along with new principles generated by AAUP. AAUP justifies a new report because many previous recommendations have been made only for portions of the university such as a medical center, and AAUP argues that the impact on the entire university community needs to be considered.
Some of the 56 recommendations are standard AAUP boilerplate about how faculty should have a say in uinversity covernance regarding industry relationships. But a lot of the report seems well worth our attention because it suggests that the trend these days is toward tougher approaches to conflicts of interest in academia.
For example, the AAUP is a staunch defender of academic freedom and therefore admits that some faculty have used this as an argument against any regulation of financial relationships with industry--that individual faculty members should be allowed to make their own choices about their relationships with drug companies, research and consulting, etc. The report replies, "Their arguments obscure the fact that academic freedom evolved as a concept not only to protect individual rights but to insulate the academy and safeguard the discovery process from powerful social forces, initially the church and later big business. Some rules are necessary to preserve freedom of research, teaching, and inquiry. At stake are the standards that govern universities, their reputations, and public trust.
"Academic freedom does not entitle faculty members to accept outside responsibilities that make it impossible to do their primary jobs. Academic freedom does not entitle faculty members to sign away their freedom to disseminate research results. Academic freedom does not entitle faculty members to ignore financial conflicts of interest that could dangerously compromise the informed-consent process and the impartiality of research."
In sum-- stringent regulations against COI in industry relationships protect the core values of academic freedom.
On one issue that I have been harping on for many years, the report is similarly uncompromising. It accepts as a guiding principle that the mere disclosure and "management" of COI is seldom the right way to proceed, and that as a rule, eliminating and avoiding COI is much better--while formal plans for managing COI should be adopted for the minority of cases where it is indeed unavoidable without serious harm to vital public interests.
The AAUP also implicitly rejects the argument that since all faculty are biased in one way or another, "intellectual COI" is ubiquitous and therefore special regs to limit financial COI are unneeded:
In short, this draft report considers some key arguments against tougher COI regulations, rejects them, and proceeds to recommend a fairly uncompromising set of guidelines. The way AAUP operates, this report can never become a standard uniform set of regulations for all universities; rather the hope is that individual universities will turn to this report for general guidance as to their policies and then craft policies that take local needs and issues into account--in some cases, the report admits, perhaps adopting more lenient standards.
"Of course, faculty investigators also have biases—whether they arise from scholarly debates, personal affinities, or political and religious commitments. Faculty status does not confer independence from the activities and interests of the communities in which faculty members live and work. The heart of the matter, however, is that faculty not be contractually obligated to represent positions at odds with their professional judgment and public commitments, or placed in compromised situations, financial and otherwise, that are more likely to produce bias."
The AAUP is very clear that public trust in the academy and its research is at stake, for example:
"When corporations, or nominally nonprofit funding agencies, effectively bribe faculty members to, for example, publish articles with doubtful product claims, dubious economic assessments, or attacks on well-established science, the faculty betray their professional and public responsibilities."
Thursday, July 12, 2012
"Dualities of Interest"-- the Latest Fig Leaf?
Medical anthropologist Joan E. Paluzzi has written a study (subscription required) on the incestuous relationships between drug companies and disease-specific patient advocacy organizations, often mediated by physician experts ("key opinion leaders") with major financial interests in the drug firms. She looks particularly at three disease areas-- osteoporosis, diabetes, and restless leg syndrome.
There's not a whole lot new for readers of HOOKED but she uses as her title one interesting phrase which I had not heard before. The American Diabetes Association published in 2010 (in the journal Diabetes Care) an update to their "Diabetes Standard of Care." The committee that wrote these guidelines had 15 members, and a separate document lists 77 separate relationships these docs had with pharmaceutical firms and other industry folks. Now, simple-minded people like me would have imagined these relationships to be conflicts of interest, but the ADA hastened to assure readers that no such thing could possibly be the case. Instead, they headed the list "Dualities of Interest."
As Paluzzi comments, "That these relationships were explicitly characterized as 'dualities' (implying a state of complementarity) rather than the long-accepted representation of 'conflicts' of interest (which highlights the potential for vested self-interest) is understood here as an attempt to normalize or, at least, to minimize perceptions of potentially unethical conduct."
As I say, this particular manner of applying lipstick to a pig is one I had not previous been aware of--no doubt just showing how far out of the loop I am.
Paluzzi JE. "Dualities of interest": the inter-organizational relationships between disease-specific nonprofits and the pharmaceutical industry. International Journal of Health Services 42:323-339, 2012.
There's not a whole lot new for readers of HOOKED but she uses as her title one interesting phrase which I had not heard before. The American Diabetes Association published in 2010 (in the journal Diabetes Care) an update to their "Diabetes Standard of Care." The committee that wrote these guidelines had 15 members, and a separate document lists 77 separate relationships these docs had with pharmaceutical firms and other industry folks. Now, simple-minded people like me would have imagined these relationships to be conflicts of interest, but the ADA hastened to assure readers that no such thing could possibly be the case. Instead, they headed the list "Dualities of Interest."
As Paluzzi comments, "That these relationships were explicitly characterized as 'dualities' (implying a state of complementarity) rather than the long-accepted representation of 'conflicts' of interest (which highlights the potential for vested self-interest) is understood here as an attempt to normalize or, at least, to minimize perceptions of potentially unethical conduct."
As I say, this particular manner of applying lipstick to a pig is one I had not previous been aware of--no doubt just showing how far out of the loop I am.
Paluzzi JE. "Dualities of interest": the inter-organizational relationships between disease-specific nonprofits and the pharmaceutical industry. International Journal of Health Services 42:323-339, 2012.
Tuesday, July 3, 2012
Inside Paxil Study 329, Courtesy the Justice Department
I've previously discussed the now-infamous Study 329, which took discouraging data on the efficacy and safety of paroxetine (Paxil) in kids and spun it into an article claiming excellent results:
http://brodyhooked.blogspot.com/2011/11/will-brown-university-investigate.html
Thanks to the U.S. Justice Dept. complaint in the suit recently settled by GlaxoSmithKline for a record $3B: http://www.justice.gov/opa/documents/gsk/us-complaint.pdf
--we can follow the history of this study in more detail, based on the internal GSK documents discovered during the proceedings, and see just how the data were manipulated for marketing purposes.
Study 329, directed by Dr. Martin Keller of Brown University, was one of 3 clinical studies in children and adolescents that were all interpreted by GSK scientists between August and October, 1998 to be discouraging. Study 329's protocol specified two primary endpoints, and on neither measure did Paxil do better than placebo. The study also logged in 11 serious adverse reactions to Paxil, much more than in the placebo group, including 5 with agitated or suicidal behavior, the major risk for which eventually the FDA issued a black-box warning for the SSRI class of antidepressants.
Undaunted, GSK contracted in April 1998 with Scientific Therapeutics Information, Inc. to prepare an article for journal publication based on 329. As we know from other sources, STI writers basically wrote the paper and later did revisions, with minimal input from the supposed scientific authors, meaning that the paper was largely if not completely ghostwritten. As part of the laundering process, STI decided to downplay the primary endpoints and instead inserted 8 "efficacy measures," none of which had been specified in the original study protocol. By what's called data-dredging, STI was able to show that Paxil was statistically better than placebo on 4 of the 8 newly invented measures.
Initially the purported authors sent the paper to JAMA, claiming in the abstract that Paxil was "a safe and effective treatment for major depression in adolescents." In December, 1999 JAMA rejected the paper, and reviewers' comments indicated that the scientific reviewers had seen through the fog and realized that there were no solid data to show the superiority of Paxil. One internal memo then indicated that GSK and Dr. Keller agreed to send the manuscript to "a less demanding journal."
Even the less-demanding Journal of the American Academy of Child and Adolescent Psychiatry originally couldn't swallow the revised manuscript that Keller and company sent them in June 2000. Their reviewers detected some of the same problems as the earlier JAMA review. GSK had STI go back to work responding to the reviewers' comments and eventually JAACAP accepted the manuscript in February 2001.
According again to the Federal complaint, even with the recommended changes, GSK and STI (with the willing acquiescence of Dr. Keller and his co-authors, we presume) managed to slip in a number of incorrect and misleading statements. The abstract stated that the drug "is generally well tolerated and effective for major depression in adolescents." The article mentioned the primary endpoints but failed to make clear that by neither was Paxil statistically superior to placebo. The article falsely implied that Paxil was superior on one of the primary endpoints by deliberately conflating one of the later "efficacy measures" with that endpoint. The article consistently downplayed all the measures where Paxil failed to show superiority to placebo and focused on the few, invented-later measures where a statistically significant result had been found.
More important, the 11 patients with serious adverse reactions due to Paxil, and the 5 of them with specifically suicidal or agitated symptoms, magically disappeared. In the revised manuscript the investigators suddenly decided that only one of the reactions (headache) was actually caused by Paxil, and the other bad outcomes were unrelated to the drug. When the FDA got its hands on the raw data from 329, it eventually determined that 10 of 93 patients taking Paxil had experienced a potentially suicidal reaction--a far different and scarier picture than that portrayed in any of the drafts or in the final manuscript.
To be sure that child psychiatrists heard the correct marketing message, GSK sponsored 8 "Forum" meetings at lavish resorts such as Rio Mar Beach Resort in Hawaii and Renaissance Esmerelda Resort in Palm Springs, CA. The psychiatrists who attended had their airfare and hotel paid plus a $750 honorarium, and in many cases their spouses were also paid for (a practice supposedly prohibited in the 2002 PhRMA code of conduct). The hired speakers who told them how wonderful Paxil was for treating kids received $2500 honoraria in addition.
Talking of speakers' bureaus, another media summary of the complaint:
http://finance.yahoo.com/news/glaxosmithklines-gsk-3-billion-whistleblower-154800879.html
--reported that GSK had enrolled 49,000 health professionals to be on its speakers' bureau for Paxil and other drugs. Two conclusions are possible: 1) there are 49,000 really excellent and scientifically informed speakers out there whose talents are needed to inform their fellow practitioners; or 2) a "speaker's bureau" is really nothing but a disguised bribe to get all those docs to prescribe a lot of the drugs they are paid to speak about.
Hat tip to Dr. Roy Poses of Health Care Renewal blog for sending me the link to the full complaint (all 76 pages, for anyone who wants some fun reading).
http://brodyhooked.blogspot.com/2011/11/will-brown-university-investigate.html
Thanks to the U.S. Justice Dept. complaint in the suit recently settled by GlaxoSmithKline for a record $3B: http://www.justice.gov/opa/documents/gsk/us-complaint.pdf
--we can follow the history of this study in more detail, based on the internal GSK documents discovered during the proceedings, and see just how the data were manipulated for marketing purposes.
Study 329, directed by Dr. Martin Keller of Brown University, was one of 3 clinical studies in children and adolescents that were all interpreted by GSK scientists between August and October, 1998 to be discouraging. Study 329's protocol specified two primary endpoints, and on neither measure did Paxil do better than placebo. The study also logged in 11 serious adverse reactions to Paxil, much more than in the placebo group, including 5 with agitated or suicidal behavior, the major risk for which eventually the FDA issued a black-box warning for the SSRI class of antidepressants.
Undaunted, GSK contracted in April 1998 with Scientific Therapeutics Information, Inc. to prepare an article for journal publication based on 329. As we know from other sources, STI writers basically wrote the paper and later did revisions, with minimal input from the supposed scientific authors, meaning that the paper was largely if not completely ghostwritten. As part of the laundering process, STI decided to downplay the primary endpoints and instead inserted 8 "efficacy measures," none of which had been specified in the original study protocol. By what's called data-dredging, STI was able to show that Paxil was statistically better than placebo on 4 of the 8 newly invented measures.
Initially the purported authors sent the paper to JAMA, claiming in the abstract that Paxil was "a safe and effective treatment for major depression in adolescents." In December, 1999 JAMA rejected the paper, and reviewers' comments indicated that the scientific reviewers had seen through the fog and realized that there were no solid data to show the superiority of Paxil. One internal memo then indicated that GSK and Dr. Keller agreed to send the manuscript to "a less demanding journal."
Even the less-demanding Journal of the American Academy of Child and Adolescent Psychiatry originally couldn't swallow the revised manuscript that Keller and company sent them in June 2000. Their reviewers detected some of the same problems as the earlier JAMA review. GSK had STI go back to work responding to the reviewers' comments and eventually JAACAP accepted the manuscript in February 2001.
According again to the Federal complaint, even with the recommended changes, GSK and STI (with the willing acquiescence of Dr. Keller and his co-authors, we presume) managed to slip in a number of incorrect and misleading statements. The abstract stated that the drug "is generally well tolerated and effective for major depression in adolescents." The article mentioned the primary endpoints but failed to make clear that by neither was Paxil statistically superior to placebo. The article falsely implied that Paxil was superior on one of the primary endpoints by deliberately conflating one of the later "efficacy measures" with that endpoint. The article consistently downplayed all the measures where Paxil failed to show superiority to placebo and focused on the few, invented-later measures where a statistically significant result had been found.
More important, the 11 patients with serious adverse reactions due to Paxil, and the 5 of them with specifically suicidal or agitated symptoms, magically disappeared. In the revised manuscript the investigators suddenly decided that only one of the reactions (headache) was actually caused by Paxil, and the other bad outcomes were unrelated to the drug. When the FDA got its hands on the raw data from 329, it eventually determined that 10 of 93 patients taking Paxil had experienced a potentially suicidal reaction--a far different and scarier picture than that portrayed in any of the drafts or in the final manuscript.
To be sure that child psychiatrists heard the correct marketing message, GSK sponsored 8 "Forum" meetings at lavish resorts such as Rio Mar Beach Resort in Hawaii and Renaissance Esmerelda Resort in Palm Springs, CA. The psychiatrists who attended had their airfare and hotel paid plus a $750 honorarium, and in many cases their spouses were also paid for (a practice supposedly prohibited in the 2002 PhRMA code of conduct). The hired speakers who told them how wonderful Paxil was for treating kids received $2500 honoraria in addition.
Talking of speakers' bureaus, another media summary of the complaint:
http://finance.yahoo.com/news/glaxosmithklines-gsk-3-billion-whistleblower-154800879.html
--reported that GSK had enrolled 49,000 health professionals to be on its speakers' bureau for Paxil and other drugs. Two conclusions are possible: 1) there are 49,000 really excellent and scientifically informed speakers out there whose talents are needed to inform their fellow practitioners; or 2) a "speaker's bureau" is really nothing but a disguised bribe to get all those docs to prescribe a lot of the drugs they are paid to speak about.
Hat tip to Dr. Roy Poses of Health Care Renewal blog for sending me the link to the full complaint (all 76 pages, for anyone who wants some fun reading).
Monday, July 2, 2012
Breaking News: A Record Fine for GSK
I usually don't do breaking news on this blog but was searching the NPR website for something else just now when this story popped up:
http://www.npr.org/2012/07/02/156118688/drug-maker-glaxosmithkline-fined-record-3-billion
The story also causes me to depart from my usual fill-in-the-blank approach to drug company settlements in federal prosecutions, since this one has several peculiar features.
Peculiar feature #1: The $3B settlement is, I believe, a new record, as previous highs have been less than $2B.
Peculiar feature #2: Several different drugs and offenses are involved. It appears to be related to off label marketing in connection with the antidepressants paroxetine (Paxil) and buproprion (Wellbutrin), and failure to report safety concerns with the diabetes drug rosiglitazone (Avandia). The specific offense regarding Paxil was marketing the drug for teens, as we have discussed before, such as:
http://brodyhooked.blogspot.com/2008/06/alison-basss-side-effects-another-hall.html
Peculiar feature #3: The news release indicates that GSK actually admitted fault, which most companies don't in such cases. ("Wer're shelling out a billion bucks to get the Feds off our backs, but we deny that we actually did anything wrong.")
More details will probably be forthcoming.
NOTE ADDED 7/3/12: I misspoke above when I said that previous high settlement amounts for fraud charges have been below $2B; Pfizer paid a $2.3B fine in September 2009. See ProPublica's concise summary of recent fraud cases, http://www.propublica.org/special/big-pharmas-big-fines.
http://www.npr.org/2012/07/02/156118688/drug-maker-glaxosmithkline-fined-record-3-billion
The story also causes me to depart from my usual fill-in-the-blank approach to drug company settlements in federal prosecutions, since this one has several peculiar features.
Peculiar feature #1: The $3B settlement is, I believe, a new record, as previous highs have been less than $2B.
Peculiar feature #2: Several different drugs and offenses are involved. It appears to be related to off label marketing in connection with the antidepressants paroxetine (Paxil) and buproprion (Wellbutrin), and failure to report safety concerns with the diabetes drug rosiglitazone (Avandia). The specific offense regarding Paxil was marketing the drug for teens, as we have discussed before, such as:
http://brodyhooked.blogspot.com/2008/06/alison-basss-side-effects-another-hall.html
Peculiar feature #3: The news release indicates that GSK actually admitted fault, which most companies don't in such cases. ("Wer're shelling out a billion bucks to get the Feds off our backs, but we deny that we actually did anything wrong.")
More details will probably be forthcoming.
NOTE ADDED 7/3/12: I misspoke above when I said that previous high settlement amounts for fraud charges have been below $2B; Pfizer paid a $2.3B fine in September 2009. See ProPublica's concise summary of recent fraud cases, http://www.propublica.org/special/big-pharmas-big-fines.
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