Of Evergreening and Efficacy, Part II

By Ryan Abbott

I wrote earlier this month about the case between Novartis and the Union of India, in which the Supreme Court of India affirmed denying a patent for Novartis’ anti-cancer drug Glivec. Adriana Benedict added an insightful post about the case last week.

In my last post, I talked about the theory behind the decision and what it means for a drug to be therapeutically efficacious. Today and tomorrow, I thought it would be interesting to focus on the practical outcome of the case. In other words, what does this case mean for the access to medicines more generally, both in India and around the world?

Judging by recent public comments, this will be a landmark case. On the Novartis website, where the company is hosting an impressive array of resources devoted to the Glivec patent case, it states that this “decision discourages innovative drug discovery essential to advancing medical science for patients.” Eric Althoff, a Novaris spokesman said, if “innovation is rewarded, there is a clear business case to move forward. If it isn’t rewarded and protected, there isn’t.” On the opposite side of the spectrum, Indian Trade Minister Anand Sharma called the ruling “a historic judgment” that reaffirmed the position of Indian law requiring substantive innovation for patent protection. The Supreme Court itself noted that the “debate took place within a very broad framework. The Court was urged to strike a balance between the need to promote research and development in science and technology and to keep private monopoly (called an ‘aberration’ under our constitutional scheme) at a minimum.”

Despite the controversy, this case won’t necessarily have a wide ranging impact. It involved some unusual elements, which require historical background in India’s patent system to understand.

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Caplan on the Myriad Patent Case

[Posted on behalf of Art Caplan]

On January 7, 1610 Galileo Galilei, the Italian physicist and astronomer, aimed his new invention, the telescope, at the sky and became the first human to observe three of the moons orbiting the planet Jupiter.  His discovery created a sensation since he had shown that there were objects in the universe that were not circling the Earth – throwing into doubt the view that his church, the Roman Catholic church, taught that the Earth was the center of the universe.

If Galileo had been alive today he might have been working for a private science company.  If so there is little doubt that they would have insisted he seek a patent for the marvelous telescope that revealed amazing secrets about the world.  If that company had been Myriad genetics they might have insisted that he not only patent the telescope but also everything he found when he looked through it, including Jupiter and its moons.  In a way, that is what Myriad did when in 1994 it, along with the University of Utah, sought a patent on an association scientists had discovered between a set of genetic mutations and a high risk of developing breast cancer.

The patents Myriad received have earned the company a pretty penny.  They have had a monopoly over all genetic testing for breast cancer for nearly two decades.  Doctors and patients have complained bitterly that Myriad’s high priced tests have limited access for many women and hindered efforts to conduct research that might have more rapidly improved the accuracy of testing.

I think the Myriad patents should not have been awarded.  Nor should any patent that relies solely on looking at genes as they exist in nature and finding associations with the risk of getting a disease.  The standard for a patent is not discovery but making something useful out of a discovery.  Patenting genes is too close to trying to patent the moons of Jupiter which Galileo discovered but did not create.  Myriad’s early patent arguably hindered the willingness of others to aggressively explore better tests for a terrible disease.  Other patents on other gene sequences could have the same effect.

If Myriad discoveries the equivalent of the genetic testing telescope then great—let them have their patent.  But finding what is out there in nature be it Jupiter, the moon, or a sequence of genes gets you a place in history but not a patent.

Twitter Round-Up (3/31-4/6)

By Casey Thomson

This week’s slightly belated round-up concerns palliative care across cultures, the threat and problems of over-prescribing, and Big Pharma’s failure to create prices with the patient in mind. Read on for more from this week’s round-up.

  • Alex Smith (@AlexSmithMD) retweeted a piece on the lessons learned by Dr. Vvjeyanthi “V.J.” Periyakoil on how to approach palliative care for patients from a variety of backgrounds in ways that both extend life and fulfill the desires of the patient (in particular, reducing pain). (4/3)
  • Alex Smith (@AlexSmithMD) also retweeted an opinion piece in the NYT about the growing trend towards self- and over-medication, and the problems of overextending definitions of medical ‘conditions.’ As the piece’s author summarized: “The D.S.M. would do well to recognize that a broken heart is not a medical condition, and that medication is ill-suited to repair some tears.” (4/3)
  • Daniel Goldberg (@prof_goldberg) retweeted a link on two new wrongful death lawsuits against the NFL, which claim that the NFL withheld knowledge of the risks associated with concussions from players, that have been added to the string of other brain injury lawsuits filed against the league. (4/3)
  • Daniel Goldberg (@prof_goldberg) additionally retweeted a blog post on the striking results of a new study comparing male and female mortality amongst counties in the United States. While male mortality increased in only 34% of counties from 1992-1996 to 2002-2006, female mortality increased in 42.8%. This brings up questions concerning the cause of this demographic and largely geographic inequality, and what such a differential could mean on the health of dependents (children). (4/3)
  • Daniel Goldberg (@prof_goldberg) posted another article that put the recent New York “True Cost” campaign in historical context. The article called the campaign a “modern manifestation of…anxieties about the ‘contagion’ of working class and poor communities,” comparing it to the World War II-era venereal disease campaigns and the case of Typhoid Mary as all moralizing weapons aiming to instill shame rather than promote actual solutions to public health concerns. (4/4)
  • Arthur Caplan (@ArthurCaplan) linked to his own discussion of the problem with Novartis and India, noting that emphasis has been wrongly placed on patents when the concern should be on pharma’s hesitancy to create a pricing strategy that can provide medications for those who cannot afford huge prices. This unwillingness to do so, he claims, is violating a moral obligation. (4/4)

Industry-Provided Meals, Gifts — Still Happening?

One of my primary areas of research is in conflicts of interest (COI). I generally focus on the financial relationships between physicians/researchers and the pharmaceutical industry. See Here Here and Here.

However, COI researchers and policy makers need to expand our scope to include other health care professionals who have relationships with other key health care industries, other than pharma and device companies. In this blog, I focus upon the relationships between discharge planners and long-term care providers (including home care, skilled nursing facilities and others). Long-term care is a growing part of health care expenditures, and represents an area where patients’ preferences and best-interests should be the primary obligations of discharge planning professionals — who are not biased due to industry marketing.

As I reflect back upon my almost two decades in health care, as a clinician, researcher and bioethicist, I am amazed at how pervasive marketing activities are in hospitals… other than seeing drug reps visiting doctors (in fact, this was banned in the hospital I worked). For example, during my first clinical internship, at a rural hospital near Atlanta, home care agency marketing reps were often bringing food and providing educational/marketing materials to the Case Management/Social Work office. We all hung out together. Same thing happened in NYC; although I was not directly involved in discharge planning, home care and post-acute care providers bestowed small gifts, food and other marketing materials – obviously, with the hope of building goodwill, and hoping that as a clinical social worker, I would indirectly influence referrals to their businesses. In addition to gifts and marketing, representatives from these health care companies were often ever-present in the inpatient units to help the Case Managers and other clinicians with the necessary paperwork, insurance reviews, and overall referral facilitation. From what I understand, this type of post-acute care industry “detailing” still occurs in American Hospitals with frequency.

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John Robertson on Cohen and Adashi on Made-to-Order Embryos for Sale

By John Robertson

Glenn Cohen and Eli Adashi have an interesting Sounding Board piece in the latest NEJM[i] on made-to-order embryos for sale.  A California clinic offering this option has garnered enormous publicity.  It might, however, have stimulated more bioethical thinking than actual demand for its services.

On the bioethical side, Glenn and Eli survey the relevant issues and conclude that what is most “new and unique here is the lack of clear legal guidance as to the parentage of the embryos in question.”[ii]  My impression is different– existing laws give sufficient support about parentage, if anyone wants to use them.  The clinic creating the embryos from separate gamete donations will have dispositional control of them, but no parenting questions arise until the embryos are gestated and brought to term.  True, there are few state laws on embryo donation as such. But in states with no specific embryo donation laws, those who have commissioned gestation will most likely have rearing rights and duties once a child is born until they arrange for an adoption.[iii]

Nor would the gamete donors in such states be able to claim rearing rights or be subject to rearing duties after such a birth.   Most states recognize gamete donor relinquishment of rearing rights and duties in resulting children with their consent to donation.  After the birth of a child, the gamete donors ordinarily would have no right to change their mind and acquire rearing rights or be subject to rearing duties, whether the donation was of sperm or egg separately or both combined into an embryo.

One aspect of this transaction that is ethically unique is that divvying up embryos created from the same egg and sperm donor would lead to different recipients giving birth to full rather than half siblings, as is the usual situation with gamete donation (it could happen with excess embryos donated after successful IVF by an infertile couple, but that is rarer). Whether it creates a higher risk of full sibling consanguinity would depend on clinic practices in distributing embryos from the same batch to different recipients.  As Glenn and Eli note, donor registries might solve this problem, but none yet exist in the United States.

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More Thoughts on the Preemie Study and IRB Review

By now, most of you have heard about the controversial study that sought to evaluate how much oxygen to give premature newborns to preserve both their lives and their sight.  Below, Laura Stark lays out some of the key details about the study and OHRP’s response, and concludes that part of the problem may have been a result of the difficulties associated with approving multi-site research.

Maybe so, but let me offer a more fundamental challenge: perhaps IRBs are just ineffective – or not as effective as we hope they would be – at protecting human subjects.  In retrospect, it looks like all 23 IRBs that reviewed the study, all of which were applying the same regulatory standards, failed to do what OHRP, many news outlets, and as awareness grows, much of the public thinks they ought to have done to protect the babies and families involved in this study.  How could they all have gotten it wrong?  Are the regulations insufficient?  Are the procedures insufficient? Is it all just a matter of interpretation?

These questions lead to another fundamental issue: the lack of empirical evidence on IRB effectiveness.  We have data on whether IRBs follow the regulations, data on adverse events, data on OHRP warning letters, data on IRB-imposed research burdens and delays – but these all nibble around the edges of the real questions: what are IRBs supposed to be doing, are they doing it well, and how would we know?  The counterfactual – a world without IRB review – is pretty tough to study, but I’m working with a group of colleagues at the Petrie-Flom Center and elsewhere to think through some empirical methods to get at precisely these issues.  And we’d love to hear your thoughts!

Finally, as a side note, one point that seems to be getting lost in coverage of this preemie story is that although there seems to have been some major problems with the consent process, the study question itself was a very important one to ask.

Human Subjects Case Unfolds

Institutional Review Boards are in the top news at outlets such as the New York Times, as a research debacle unfolds. I looked through the documents that are publicly available to figure out what happened and what to expect.

Researchers at 22 universities or hospitals in the US enrolled premature babies in a randomized controlled trial between 2004 and 2009. This was the second part of a broader study, but the first part of the study “raised no concerns” according to the US Office of Human Research Protections on page 2 of its determination letter to the lead institution, University of Alabama-Birmingham. OHRP is the federal agency in charge of enforcing human-subjects regulation.

For the second part of the study, though, OHRP found that all 23 IRBs that approved the study (at 22 research sites) violated federal regulations: IRBs should have made researchers tell the parents that they knew their babies would be at higher risk of death, neurological damage, or blindness if they enrolled in the study (pages 2 and 10 of UAB letter). OHRP has only posted a determination letter for UAB at this point, but it explains that at all of the sites, the agency found violations with consent documents “similar to those described” to UAB. The UAB IRB is in especially hot water because it seems first to have first approved the 2.5-page template consent form, which the other institutions used (page 5). If you read the last page of UAB’s letter, you can make a good guess at who may officially be getting bad news from OHRP soon.

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