Research, the Avian Flu and Bioterrorism

In their zeal to keep us all alive, it seems fair to say that public health officials love bioterrorism preparedness measures. In fact, the only thing they might love planning for more is pandemics. So last month, when researchers at two different facilities revealed they were able to mutate the virulent H5N1 avian flu strain to pass between mammals simply through the air, the NIH was highly concerned.

The discovery is alarming because avian flu is considered one of the world’s deadliest pathogens, with a 60% mortality rate. But while avian flu viruses have infected humans in the past, those infections have come directly from birds. If the virus can be mutated into an airborne pathogen, the consequences can be catastrophic.

Two research teams (one led by Ron Fouchier of Erasmus Medical Center in the Netherlands, and the other by Yoshihiro Kawaoka of the University of Wisconsin) engineered the new bird flu strains. After growing the H5N1 strain for several generations, the scientists discovered the exact genetic mutations that allowed the virus to be transmitted by air between ferrets. The results could be easily duplicated if the teams publish their studies with full details.

The National Science Advisory Board for Biosecurity (NSABB), a U.S. government advisory panel that is run out of the NIH, asked the journals Science and Nature to delay publication of the research. The NIH released the following details in a press release:

Due to the importance of the findings to the public health and research communities, the NSABB recommended that the general conclusions highlighting the novel outcome be published, but that the manuscripts not include the methodological and other details that could enable replication of the experiments by those who would seek to do harm. The NSABB also recommended that language be added to the manuscripts to explain better the goals and potential public health benefits of the research, and to detail the extensive safety and security measures taken to protect laboratory workers and the public.

The request has sparked a debate about if and when it is appropriate to have oversight of dual-use research. As defined by the NSABB, dual-use research of concern is research that is “reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment or materiel.”   A good synopsis of the bioethical implications of such research is considered by Alan Rozenshtein on lawfareblog.com.

One of the research team leaders, Ron Fouchier, responded that the NSABB’s advice amounted to one-country domination of a discussion with worldwide impact. At the same time, he conceded that the mutant strain is “probably one of the most dangerous viruses you can make.” The professor who oversees biosafety for University of Wisconsin, William Mellon, responded that the research is “society’s best defense against a pathogen that has shown time and time again that, in nature, it can adapt to human hosts with dire consequences for global public health.”

Science and Nature were slower to respond. Last month, Science Editor-in-Chief Bruce Alberts noted the journal’s initial hesitation to acquiesce to the NSABB recommendation-

“We strongly support the work of the NSABB and the importance of its mission for advancing science to serve society…At the same time, however, Science has concerns about withholding potentially important public-health information from responsible influenza researchers. Many scientists within the influenza community have a bona fide need to know the details of this research in order to protect the public, especially if they currently are working with related strains of the virus.”

Nature’s Editor-in-Chief Philip Campbell replied along the same lines:

“We have noted the unprecedented NSABB recommendations that would restrict public access to data and methods and recognise the motivation behind them. It is essential for public health that the full details of any scientific analysis of flu viruses be available to researchers. We are discussing with interested parties how, within the scenario recommended by NSABB, appropriate access to the scientific methods and data could be enabled.”

The issue at hand is as one scientist, Peter Palese, opined in Nature: “We need more people to study this potentially dangerous pathogen, but who will want to enter a field in which you can’t publish your most scientifically interesting results?”

Just last week, both teams of researchers announced in an open letter published in Science and Nature that they agreed to pause their work for 60 days. In the meantime, the teams propose to discuss the benefits and safety measures of their work in an international forum for discussion and debate within the scientific community. The researchers stated in the open letter,

“We realize that organizations and governments around the world need time to find the best solutions for opportunities and challenges that stem from the work. To provide time for these discussions, we have agreed on a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals.”

Where, when and how these discussions will take place on an international level remains to be seen, but the NSABB appears to have made its point.

An unintended effect of the recommendations is that they have called into question the role and purpose of the NSABB. The NSABB was created in 2004, as a response to the 2001 anthrax attacks and the subsequent public outcry for regulation of research with implications for bioterrorism. As past president of the American Society for Microbiology, Ronald Atlas, put it, “[t]here was a sense, whether right or wrong, that if the community did not act to protect the integrity of science, government would overreach and there would be censorship.” Instead of regulating scientific research directly, the NSABB panel of scientists was given the role of offering advisory opinions on sensitive issues.

Since 2004, the NSABB has only been asked to review six papers. Two of those papers, released in 2005, described the reconstruction of the deadly 1918 influenza virus. The NSABB recommended that the papers clearly define the public-health benefits of the research, but no other advice was given. This is partly why the NSABB’s current recommendation is unprecedented.

According to Amy Patterson, director of the NIH, a draft policy for dual-use research should be presented by the U.S. government this spring. The draft should present a comprehensive framework for the oversight of such research, and create a local review component. As she states it,

“Whatever system is put in place needs to have both aspects: some consideration up front when the work is funded, but also a component of local oversight and review. It starts with the investigator — he or she knows best what is emerging out of their work. But we also need a level of institutional review to provide a second set of eyes taking a fresh look. The earlier something is recognized, the more options for management you have.”

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, stated that the draft plan may require scientists to apply online for access to critical information, after explaining their need for details on dual-use research. As of right now, it is unclear who would judge the validity of such requests. It is worth noting that at least one other institution, the University of Maryland’s Center for International and Security Studies, has outlined potential oversight systems already.

The dilemma of dual-use research is already a global problem, and therefore requires a global solution. The World Health Organization commented after the H5N1 mutations, stating a deep concern about the possible misuses of the research. The WHO was quick to note the critical need for such scientific knowledge, but concluded that “such research should be done only after all important public health risks and benefits have been identified and reviewed, and it is certain that the necessary protections to minimize the potential for negative consequences are in place.”

As Laurie Garrett, senior fellow for global health at the Council on Foreign Relations, notes in a thorough review of international mechanisms for oversight of dual-use research, the first problem is that there are “no consistent, internationally agreed-upon regulations governing synthetic biology.” The only review that does currently exist is the “toothless” Biological Weapons Convention(BWC) from 1975, to which 165 states are party.

Last month, U.S. Secretary of State Hillary Clinton attended a BWC summit, and stated-

“The nature of the problem [dual-use research] is evolving. The advances in science and technology make it possible to both prevent and cure more diseases, but also easier for states and nonstate actors to develop biological weapons. A crude, but effective, terrorist weapon can be made by using a small sample of any number of widely available pathogens, inexpensive equipment, and college-level chemistry and biology. Even as it becomes easier to develop these weapons, it remains extremely difficult . . . to detect them, because almost any biological research can serve dual purposes. The same equipment and technical knowledge used for legitimate research to save lives can also be used to manufacture deadly diseases.”

The need for global cooperation on this issue is crucial.

In truth, it seems that pandemics fascinate most of society, and not just public health professionals. Last year saw the release of the movie Contagion, with a plot line appealing enough to enlist the acting talents of Gwyneth Paltrow and Matt Damon (for a great comparison of the movie to real-world issues, see  W. Ian Lipkin’s op-ed for the New York Times). Further, avian flu remains a present threat. Just this month, Chinese health authorities confirmed a bird-flu-related death, Indonesia reported the third death related to bird flu in three months, and there are reports of avian flu among birds in India. Given that H5N1 remains such a threat without the consideration of bioterrorism, the need for regulations on dual-use research is seemingly more apparent than ever.

Video Gamers Provide New Insights for the Design of Antiretroviral Drugs

I suppose with age comes humility and I may well owe my 17 year-old son an apology. So here it is Rich, about as publicly as I can muster: video games are not, apparently, an utter waste of time.

FierceBiotech IT  reports: “Video gamers uncover AIDS drug targets.” FierceBio writes:

Players of the online science game Foldit have pieced together the structure of an enzyme that could provide new targets for AIDS treatments, doing in three weeks what scientists failed to accomplish in more than 10 years.

The retroviral protease is a scissor-like enzyme that helps keep the AIDS virus going. Blocking the enzyme’s activity is a goal of drug researchers, but they first need to know the structure of the enzyme. Firas Khatib, a researcher at the University of Washington, where Foldit originated, gave players of the online game the challenge of cracking the structure of the protease that scientists had puzzled over for more than a decade. The players came up with multiple structures of the enzyme in an astonishing three weeks, giving Khatib and his colleagues enough information to revise the gamers’ work.

In addition, the gamers were able to expose “molecules on the surface of the enzyme that could be blocked with drugs to disable the function of it.”

Astonishing, really. If only they would continue to use their powers for good instead ….

The findings were published in Nature Structural & Molecular Biology and you can find the abstract here, Crystal structure of a monomeric retroviral protease solved by protein folding game players and the FierceBiotech IT article here

Video gamers uncover AIDS drug targets - FierceBiotechIT

The NIH’s Amended Conflict of Interest Regulations: A New, Weaker Approach to Intellectual Property Interests?

Yesterday, at long last, the National Institutes of Health released the final revisions to its regulations governing financial conflicts of interest on the part of applicants for federal research funds.  And there is good news.  The rule’s sunshine provisions have not, as was feared, been “gutted.”  Grant recipients will have to make their investigators’ financial conflicts of interest publicly accessible.  While an institution will not have to post the details of each conflict on its website, as was provided in the proposed regulations, if it does not it will instead have to provide the information in writing to anyone who asks for it.  Academics, advocates, federal and state prosecutors, other regulators, and members of the news media will have the access they need.  For sure, prospective patients or research participants will be less likely to come across information about investigator conflicts, but, as Kathleen Boozang explains here, it is far from clear that they would find such information helpful.

Of potentially more significance than the weakened sunshine provisions, the final regulations diverge from the proposed regulations with regard to the treatment of intellectual property.  Under the prior regulations, investigators were required to inform their institutions about relevant intellectual property rights, including copyrights, patents, and royalties in excess of $10,000.  The proposed regulations modified the definition to require disclosure of copyrights, patents, and royalties (and agreements to share in royalties) regardless of amount.  Under the final regulations, investigators do not need to tell their institutions about their intellectual property rights and interests unless and until they are in “receipt of income related to such rights and interests.”

The preamble to the final regulations is somewhat confusing.  For example, while the final regulations define significant financial interest to exclude intellectual property rights and interests that do not produce income, the agency states in the preamble that it “would expect institutional policies to require disclosure upon the filing of a patent application or the receipt of income related to the intellectual property interest, whichever is earlier.”  The preamble also contradicts itself with regard to the applicability of the rule’s $5,000 threshold, stating at one point that the threshold “applies to licensed intellectual property rights (e.g., patents, copyrights), royalties from such rights, and agreements to share in royalties related to licensed intellectual property rights,” while explaining (correctly, I think) at another point that “the $5,000 threshold would apply to equity interests and ‘payment for services,’ which would include salary but not royalties.”

The NIH’s explanation of its addition of the “receipt of income related to such rights and interests” qualifier to the definition of a significant intellectual property right or interest is especially confusing.  The agency writes that its intent was to exclude from the definition

“the rare cases when unlicensed intellectual property is held by the Investigator instead of flowing through the Institution,” because “it is difficult to determine the value of such interests.”  The agency’s point about valuation may be true, but that is an argument in favor of disclosure not against it.  With regard to equity interests, the final regulation requires investigators to disclose any equity interest in a non-publicly traded entity; the Food and Drug Administration similarly requires disclosure of equity interests “whose value cannot be readily determined through reference to public prices[.]“  The FDA also requires disclosure of any “[p]roprietary interest in the tested product,” without regard to value.

When an investigator has a proprietary interest in a product under study the potential exists for a serious conflict regardless of the interest’s current value or whether it is currently income-generating.  Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy and others have recommended a near-total ban on serving as an investigator in that case.  Such a ban cannot, of course, be implemented unless investigators are required to tell their institutions about their proprietary interests.

The Changing Landscape of Health Information Regulation

There is an impressive new issue of the American Journal of Law & Medicine out, with top names in the field participating in a symposium entitled “Marketing Health: The Growing Role of Commercial Speech Doctrine in FDA Regulation.”  I also wanted to recommend a piece from Simon Stern and Trudo Lemmens on pharma ghostwriting, which is getting a lot of play in Canada.  Titled “Legal Remedies for Medical Ghostwriting: Imposing Fraud Liability on Guest Authors of Ghostwritten Articles,” the piece could lead to some interesting litigation opportunities.  Here is the abstract:

Ghostwriting and guest authorship of medical journal articles raise serious ethical and legal concerns, bearing on the integrity of medical research and evidence used in legal disputes. Ghostwriting involves undisclosed authorship, usually by medical communications agencies or a pharmaceutical sponsor of the published research; guest authorship involves taking authorial credit for the published work without making a substantial contribution to it. Commentators have objected to these practices because of concerns involving bias in ghostwritten clinical trial reports and review articles. We also note the effects of ghostwritten articles on questions involving the legal admissibility of scientific evidence. Efforts to curb ghostwriting practices, undertaken by medical journals, academic institutions, and professional disciplinary bodies, have thus far had little success and show little promise.These organizations have had difficulty adopting and enforcing effective sanctions, for specific reasons relating to the interests and competencies of each kind of organization.

Because of those shortcomings, a useful deterrent in curbing the practice may be achieved through the imposition of legal liability on the ‘guest authors’ who lend their names to ghostwritten articles. We explore the doctrinal grounds on which such articles might be characterized as fraudulent. A guest author’s claim for credit of an article written by someone else constitutes legal fraud, and may give rise to claims that could be pursued in a class action based on the Racketeer Influenced and Corrupt Organizations Act (RICO). The same fraud could support claims of “fraud on the court” against a pharmaceutical company that has used ghostwritten articles in litigation. This doctrine has been used by the U.S. Supreme Court to impose sanctions on the authors and corporate sponsors of a ghostwritten article. We discuss the potential penalties associated with each of these varieties of fraud.

This promises to inspire some difficult legal challenges to industry practices that have long been considered undesirable as a policy matter.

Can’t Teach an Old Doc New Tricks?

Reuters reports that,

According to findings in the American Journal of Medicine, patients whose doctors had practiced for at least 20 years stayed longer in the hospital and were more likely to die compared to those whose doctors got their medical license in the past five years.

The study, which was based in Montefiore Hospital in the Bronx, NYC, examined the records of over 6,500 patients of the teaching hospital from 2002 to 2004. Over the course of the study, there were 59 different attending physicians heading up 6 different teams, consisting of said attending, a medical student, and recent med school graduates.  A junior doctor randomly assigns patients to a team. The researchers grouped patients and according to length of practice for the attending– “five years or less,
six to 10 years, 11 to 20 years, or more than 20 years.”

Reuters reports,

At first glance, compared to patients with the newest doctors, those with the most experienced physicians had more than a 70 percent increase in their odds of dying in the hospital and a 50 percent increase in their odds of dying within 30 days.

However, when the researchers took into account how sick the patients were, they
found that only the sicker patients — those with complicated medical problems — were at higher risk in the hands of the more experienced doctors.

So… the good news here is that only sicker patients are at higher risk in the hands of the more experienced doctors. Those with complicated medical problems are more likely to die if seen by a more experienced doctor. Although I feel as though I should write this again, I fear it still won’t fully resonate. But let me try in simple, quasi-mathematic terms:  More sick + More Experienced Doctor = More Death.

No, it’s still not working for me, but Reuters spoke with Dr. Niteesh Choudhry of Harvard Medical School, who was not involved in the study but is said to have offered the following:

The problem, he said, is not with the capability of the more experienced doctors, but rather, their familiarity with more current guidelines and practices. The results suggest the need to rethink the way doctors are continually educated in the years after completing their certification, he added.

There’s more, and you can read it here.

Contractual Liability and Clinical Trial Reimbursement in Italy

Contractual Liability and Clinical Trial Reimbursement in Italy

By: Christopher J. Asakiewicz, Esq. and Anna Pinkhas, Esq. [1]

In the Italian Ministerial Decree of July 14, 2009 (the “Decree”) the Ministry of Labour, Health and Social Policy sets forth a number of statutory requirements relating to insurance in human clinical trials conducted in Italy. In order to safeguard the clinical participants the Decree expanded on and formulized into law a requirement previously established by the European Union, which provides that a clinical trial can be initiated in the Member States only when provisions have been made for insurance or indemnity to cover the liability of the investigator and sponsor towards clinical trials subjects. [2] However prudent and protective of clinical participants the Decree is, its implementation into Italian law has led to significant delays in the negotiation of the indemnification clauses in clinical trial agreements because of improper interpretation, an interpretation that delays the introduction of possible life saving medicines into the country and the European marketplace.

Indemnification is a critical part of the clinical trial agreements between clinical trial sponsors, investigational sites and, sometimes, the principal investigator. Generally, indemnification language in any agreement seeks to impute liability to a contractual party for acts or omissions and to defend, hold harmless and compensate the other party for any loss that such party may suffer during the performance of the contract that results from said acts or omissions. Indemnification provisions in a clinical trial agreement differ among varying sponsors and investigational sites. Generally, the provisions are mutual. A mutual indemnification provision will have the sponsor indemnify for personal injury or illness to study patients that relates to the study or the study drug, and likewise, the other party will indemnify the sponsor for any negligence or willful misconduct for which it is responsible.

Drafting and negotiating an indemnification clause can be both difficult and tedious, as the clause’s meaning is particularly important during litigation. Frequent confusion, however, between indemnification and study subject reimbursement further complicates and delays negotiations. A clinical trial agreement generally also includes a provision where the sponsor agrees to reimburse the institution for any reasonable and necessary medical expenses incurred by the investigational site for the treatment of patients’ illness or injuries related to the study or the study drug.  The purpose of such subject injury language is to address reimbursement of expenses incurred to treat an adverse event. [3] This reimbursement language is meant to swiftly compensate such injuries without regard for party fault so the patient can receive care immediately or continue to receive the highest standard of care.

Indemnification, on the other hand, is to assume responsibility and the costs incurred in litigation or from claims that resulted from the fault attributable to the wrongdoing of the indemnifying party. Although these two scenarios are clearly distinguishable, confusion arises over the Italian regulation because of misunderstanding about the nuances of indemnification as compared to subject injury reimbursement. The Decree states that the promoter, or the sponsor, of the clinical trial shall provide insurance to cover “any civil liability of investigator and promotor of the clinical trial, without excluding any damage which may be unintentionally caused by accident e/o be attributed to negligence, imprudence or inexperience.” [4] In other words, the clinical trial sponsor is required by the Decree to be insured to sufficient limits for not only willful or reckless conduct, but also for negligent unintentional acts or omissions. [5] Many Italian sites interpret this language to mean they are not responsible for their own negligence and therefore remove their indemnification obligation of the sponsor, the promotor, from the clinical trial agreements. However, the Decree only governs reimbursement to study subjects by the insured in the event of injuries, and does not limit contribution as well as the investigational site’s indemnity of the sponsor for those third party claims which fault is attributable to either it or its actors.

Article 1 states: “The insurance policy is to grant specific cover in connection with the reimbursement of damages caused to the subjects by the clinical trial activities throughout the entire duration thereof.”

[6] The Decree’s purpose is therefore not to forgive or excuse liability, but only to safeguard participants by ensuring that a damaged party obtains reimbursement immediately. It is incorrect to interpret the legislation’s purpose as being a limit on the scope of the Institution’s liability with respect to its own actions, as the Decree further states “[t]his restriction shall not in any event impair the right of the damaged party to seek reimbursement of damages from the person liable therefor.” [7] Exclusion language which relates to negligence, imprudence or inexperience of the investigator serves to make the insurance policy a no-fault policy, assuring participants appropriate compensation and reimbursement for their injuries or illness without having to litigate the cause of the injury or prove fault. [8]

The patient’s clinical trial injury and treatment expenses will be immediately reimbursed by the policy. But, as the Decree does not limit the remedies at law, and corresponding insurance policy’s only purpose is to compensate the participant immediately, the site can still be held liable by a court for its actions. In the situation, when the sponsor was required to compensate, but is not the determined cause, the sponsor is entitled seek contribution or indemnity for such actions’ expenses from those actors responsible. The Italian Civil Code also supports the notion that the site can still be held liable, as Article 2053 provides that any willful or negligent conduct, causing an unjust harm to third parties, obliges the tortfeasor to compensate the damages. [9]

To resolve this confusion between indemnification and clinical trial injury reimbursement, the authors recommend that a sponsor with sites operating in Italy, (i) obtain an insurance policy covering all treatment expenses incurred by patients and associated with injuries related to the study drug or protocol procedures, and (ii) ensure that any indemnification provision in the clinical trial site’s contract does not exclude the institution or the investigators from liability. The Italian Civil Code and Decree are both in agreement that those persons liable for causing harm to a third party are obligated to compensate for those damages. The sponsor through clinical trial insurance can therefore immediately reimburse the patient’s costs, then, in accordance with the mutual indemnification, the sponsor or the insurer may seek to subrogate or recoup through contribution such expenses which are attributable to the investigational site or investigator and outside the sponsor’s control. [10]

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[1] DISCLAIMER: Both authors are admitted to practice law in the state of New Jersey and draft and negotiate international clinical agreements as well as counsel on patient disclosures for pharmaceutical companies. The views and opinions expressed are solely those of the authors and shall not be attributed to any other party, company or entity. The expressed opinions are for informational purposes only, and not meant to nor intended to be an advertisement, solicitation, legal advice, authority nor services of any kind to any Client, including any person or entity in any state, country or sovereign nation. Such information is not meant to create an attorney-client relationship. the reader must not act nor rely upon these materials without seeking professional legal counsel.

[2] See Art. 3(2)(f) Directive 2001/20, of the European Parliament and of the Council of  4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, 2001 O.J. (L 121) 34, 37 ( “provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor. “); See also Art. 3(1)(f) Decreto Legislativo, 24 June 2003, n. 211, G.U. 09 Aug 2003 (It.) (”provision has been made by the trial sponsor for insurance to cover the third-party liability of the investigator and the sponsors in the event of claims for damages by trial subjects.”).

[3] “adverse event” means any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

[4] Art. 1(2) Decreto Ministeriale 14 July 2009, n. 213, G.U. 14 September 2009 (It.) (Italian Ministerial Decree, Minimum requirements for insurance policies which safeguard participants to clinical trials of medicinal products.).

[5] See Art. 2(2) D.M. n. 213/2009 (It.) (”Insurance shall provide for an insured limit for the reimbursement of damages not lower than Euro 1 million per participant, although the following minimum limits for each individual protocol are required, not less than: a) Euro 5 million if trial participants are less than or equal to 50; b) Euro 7 million five hundred thousand if the trial participants are more than 50 but less than 200; c) Euro 10 million if the trial participants are more than 200.”).

[6] Art. 1(2) D.M. n. 213/2009 (It.) (emphasis added).

[7] Art. 1(6) D.M. n. 213/2009 (It.) (emphasis added).

[8] “no-fault insurance” is any type of insurance contract under which insured’s are compensated for losses, regardless of fault in the incident generating said losses.

[9] Art. 2043 Codice civile [C.c.] (It.) (Italian Civil Code).

[10] See Blacks Law Dictionary (9^th ed. 2009) (1) (SUBROGATION “1. The substitution of one party for another whose debt the party pays, entitling the paying party to rights, remedies, or securities that would otherwise belong to the debtor.”).

The Limits of Disclosure as a Response to Finanacial Conflicts of Interest in Clinical Research

Seton Hall University School of Law’s Center for Health & Pharmaceutical Law & Policy has issued a White Paper, “The Limits of Disclosure as a Response to Financial Conflicts of Interest in Clinical Research,” in which the Center agrees that public policy should encourage researchers and institutions to make information about their financial relationships with industry available to the public, but-contrary to many other commentators’ recommendations- concludes that disclosure of financial information should not routinely be required as part of the informed consent process.

While reiterating the Center’s prior recommendations for direct measures to eliminate, reduce, and manage problematic financial relationships in clinical research, the Center notes that, despite “the importance of transparency as an ethical value, incorporating financial issues into the informed consent process would provide few, if any benefits to research subjects and could in fact cause significant harms.”

The Center notes the problem of “information overload,” as clinical research informed consent documents have already become “long and complex, thereby confusing and overwhelming potential research participants,” and evidence indicates that “participants are often unable to sift through the morass of information to tease out the content they find salient or material.” In addition, qualitative studies have shown that “brief concise statements about financial interest within informed consent documents were rarely understood, and sometimes only served to confuse potential participants.

The Center concludes that, if a conflict of interest is so serious that its disclosure would lead a reasonable person to refuse to participate in a study, the proper remedy is to eliminate the conflict. It is therefore essential to ensure that information about financial interests is made available to institutional review boards (IRBs) and conflicts of interest committees, so that they can ensure that any problematic conflicts are eliminated before a study begins.

The Center notes that its conclusion that financial conflicts of interest should not be routinely disclosed as part of the informed consent process is not inconsistent with the California Supreme Court’s decision in Moore v. Regents of the University of California.

While Moore creates the possibility that, in the right set of circumstances, a physician’s failure to disclose research-related financial interests could give rise to liability, it does not mean that any and all financial relationships with industry must necessarily be disclosed. Rather, as in any informed consent claim, liability would depend on the plaintiff’s ability to establish the element of causation–i.e., that, if the omitted information had been disclosed, a reasonable person in the plaintiff’s position would not have consented to the procedure. As explained above, under the Center’s proposed framework, any conflict serious enough to affect a reasonable person’s decision about enrollment would already have been eliminated before the research began.

“The Limits of Disclosure as a Response to Financial Conflicts of Interest in Clinical Research” may be found at http://law.shu.edu/HealthLawPublications.

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy is a think tank that fosters dialogue, scholarship, and policy solutions to critical issues in health and pharmaceutical law. As part of its mission, it convenes policymakers, consumer advocates, the medical profession, industry, and government in the search for concrete solutions to the ethical, legal, and social questions presented in the health and pharmaceutical arenas. The Center also runs a compliance training program covering the state and federal laws governing the development and marketing of drugs and medical devices.

Exploitations of Immortality

Rebecca Skloot’s remarkable book The Immortal Life of Henrietta Lacks has quite a following among health lawyers. As an excerpt from the book explains,

Henrietta Lacks was a poor Southern tobacco farmer who worked the same land as her slave ancestors, yet her cells — taken without her knowledge — became one of the most important tools in medicine. The first “immortal” human cells grown in culture, her cells — known as “HeLa cells” — are still alive today, though she has been dead for more than 60 years.

If you could pile all HeLa cells ever grown onto a scale, they’d weigh more than 50 million metric tons — as much as a hundred Empire State Buildings. HeLa cells were vital for developing the polio vaccine; uncovered secrets of cancer, viruses, and the effects of the atom bomb; helped lead to important advances like in vitro fertilization, cloning, and gene mapping; and have been bought and sold by the billions. Yet Henrietta Lacks remains virtually unknown, buried in an unmarked grave.

Skloot tells the story of the Lacks family, which never shared in the prosperity based on the HeLa cells. This is old news for any property student familiar with Moore v. Regents, but it’s particularly poignant in this context.

Now Skloot has worked to share the book’s proceeds with the Lacks family. As a recent news article explains,

Since the book’s debut a year ago, it has earned rave reviews, prizes, a movie deal with HBO and a steady spot on best-seller lists. And Ms. Skloot is making good on her pledge to share the financial windfall with the Lackses. Soon after the book came out, she created the Henrietta Lacks Foundation to help Mrs. Lacks’s descendants, some of whom suffered from the whirlwind of publicity, misinformation and scam artists surrounding HeLa cells, not to mention a lack of insurance to pay for any of the medical advances Mrs. Lacks’s cells made possible. . . .

The foundation — which is still in the process of applying for nonprofit status — is paying for a high-tech hearing aid for Mrs. Lacks’s youngest son, Zakariyya; truck repairs for her middle son, Sonny; new teeth for her granddaughter Kimberly; braces for her great-granddaughter Aiyana Rodgers; and, yes, tuition, books and fees for five of her grandchildren and great-grandchildren.

Whatever one thinks of the proper compensation for research subjects, it is disheartening to consider the economic difficulties of the Lacks family. (How can a society that spends, on average, $1425 per year on care and maintenance of its pets, not provide dental care for all?)

I think part of the answer lies in our constant striving for “innovation,” and the comparative devaluation of dissemination of innovation. My colleague Gaia Bernstein has written about these trends in several contexts. I have also worried about the lack of a US industrial policy for distributing the gains of innovation. I first came to these conclusions in the context of a paper I wrote on “immortal stem lines,” almost a decade ago. As the abstract argued:

[I]nnovations that now look benign might lead to an era of untrammeled biotechnological manipulation of our lives. For example, the same technology used to eliminate disease-causing genes or to clone embryos may eventually be deployed to produce genetically engineered children. That could, in turn, entrench class differences, since only the wealthy could afford the most desirable genetic enhancements. . . . Public debate on regenerative medicine must acknowledge this inequality. Societies and individuals can invest in it in good conscience only if they are seriously committed to extending extant medicine to all.

Without more attention to those at the bottom of the economic heap, the biotech project might recall these haunting lines from John Bunyan’s “The Pilgrim’s Progress:” “Now he had not run far from his own door, but his wife and children perceiving it, began crying after him to return, but the man put his fingers in his ears, and ran on, crying, Life! Life! eternal life.” Gary Shteyngart’s recent novel imagines a world where a company that sells modern-day “immortalization services” only takes on clients who promise to prioritize payments for the company’s “dechronificaiton” over any claims by relatives for help. They don’t even consider the possibility that those seeking endless self-preservation might be tempted to give to charity instead. Michel Houllebecq’s much worse novel, The Possibility of an Island, carries the trope further, imagining a future where the wealthy simply clone themselves into the future rather than worrying about reproducing.

In my article on immortality, I reach conclusions similar to those of Andre Gorz in The Immaterial. Whenever we come across a project that

will enable ‘us’ to free ‘ourselves’ from the contingency of our factuality. . . . to recreate and transcend ‘ourselves’ or even abolish the human condition[,] [t]his re-creation might be said the be the supreme stage of self-production. But it is a grammatical mirage. . .. [There is a] difference between the natural body and the body reprogrammed by science. . . .

In my own words, from my 2002 article:

Artificial-intelligence [based immortality] projects are unconvincing because their products lack bodies, and therefore cannot experience the sense-perceptions that are fundamental to human consciousness. Given the inevitable decay and profound importance of the brain, perpetual rounds of organ replacement seem only to offer their beneficiaries a series of lives, and not really a chance to maintain a coherent one. Neither the inorganic nor the organic forms of immortality offered by these two families of technologies offers indefinite life that is recognizably human or continuous with that of the person who employs them.

Nevertheless, I expect the “immortality project” will continue to attract followers. John Gray’s book “The Immortalization Commission” follows the Soviet elite who wished for a this-worldly resurrection. He sees similar aspirations today:

The hopes that led to Lenin’s corpse being sealed in a Cubist mausoleum have not been surrendered. Cheating aging by a low-calorie diet, uploading one’s mind into a super-computer, migrating into outer space [are all present day aspirations] . . . Longing for everlasting life, humans show that they remain the death-defined animal.

Today it is not a communist elite that is likely to continue the immortality project, but rather those billionaires who believe their lifespans should be as much longer than the average Joe’s as their fortunes eclipse his bank account. There is a slight chance the innovations they fund can “trickle down” to all, but in a world of limited resources, new variations on cryonics may not be the best place for funds to be allocated.

A “Sputnik Moment”? Hopes for Renewed Drug Development With A Little Help From Our NIH Friends

In his State of the Union Address, President Obama tried to spark the “creativity and imagination” of the American people when he proclaimed

[t]his is our generation’s Sputnik moment.  Two years ago, I said that we needed to reach a level of research and development we haven’t seen since the height of the Space Race.  And in a few weeks, I will be sending a budget to Congress that helps us meet that goal.  We’ll invest in biomedical research, information technology, and especially clean energy technology… an investment that will strengthen our security, protect our planet, and create countless new jobs for our people.

Now I don’t know what came first — the chicken or the egg — but President Obama’s speech about investing in biomedical research and technological innovation follows National Institutes of Health (NIH) Director Francis Collins’ proposal to create a National Center for Advancing Translational Sciences (NCATS) to encourage drug discoveries and facilitate translational research in compounds overlooked by or abandoned by pharmaceutical manufacturers.  So does Dr. Collins’ proposal qualify as a “Sputnik moment”?

You might not have realized it, given those never-ending TV and magazine advertisements for prescription products (whose side effects sometimes sound worse than their benefits, but that’s another blog post), but pharmaceutical manufacturers have reduced their investment in researching and developing drugs.  According to the New York Times, pharmaceutical manufacturers spend over $1 billion developing a drug, with some “typically spend[ing] twice as much on marketing as on research” though that’s “a business model that is increasingly suspect.”  (For a brief overview of the research and development process, click here.)  The Pharmaceutical Research and Manufacturers of America (PhRMA) estimates that its members spent $45.8 billion in 2009 in research alone.

Even so, the number of drugs approved by the Food and Drug Administration (FDA) has dropped over the last 15 years and that’s not due to a lack of scientific information or higher FDA standards.  In November 2010, Forbes health blogger Matthew Herper reported on  the annual meeting of the American Society of Human Genetics at which Dr. Collins

implored his colleagues in genetics to work to develop new treatments for rare diseases. His point was that the NIH and the Food and Drug Administration are increasingly able to handle preclinical and early clinical drug development, and that with these first steps taken medicines are more likely to be brought to market by large pharmaceutical companies.

Mr. Herper also noted that a few organizations, such as the Cystic Fibrosis Foundation and the Multiple Myeloma Research Foundation, have taken a similar route in pushing along research  until a pharmaceutical manufacturer picks up the slack.  Then a month later, Arthur H. Rubenstein, dean of the University of Pennsylvania School of Medicine and chair of the NIH Translational Medicine and Therapeutics Working Group, told the Wall Street Journal Health Blog, “[b]asic science has exploded but it has not translated into benefit for the public.  The question was what to do about it.”

In stepped NIH to ease, in the words of the WSJ Health Blog, the “mounting frustration that a wealth of new information about the molecular basis of diseases hasn’t produced more new therapies.”  On December 7, 2010, NIH’s Scientific Management Review Board (SMRB) voted 12-1 in favor of adding NCATS to NIH.  Dr. Collins notified Health and Human Services Secretary Kathleen Sebelius of the decision.  Then on January 14, 2011, Secretary Sebelius sent a letter to Congress.  However, the decision to add NCATS  meant dismantling one of the 27 NIH centers and institutes, per the requirements of a 2006 law (”27″ is the “magic number”).  The lone SMRB dissenter, Jeremy Berg, director of the National Institute of General Medical Sciences, said he was “concerned that the implications for the rest of NIH hadn’t been adequately discussed.”

And therein lies some of the controversy.  NIH envisions NCATS as a link between basic discovery research and therapeutics care by:

• providing a visible, central locus for access to resources, tools, and expertise related to translational medicine;
• streamlining and improving the process of therapeutics development;
• serving as a catalyst, resource, and convener for collaborative interactions by supporting novel and innovative partnerships between multiple key stakeholders, including academia, government, industry, venture capitalists, and non-profit organizations;
• expanding the pre-competitive space by, among other things, enabling and providing incentives for greater sharing of scientific information and publication of negative results;
• supporting and strengthening translational medicine and therapeutics research, including providing access to services and resources for high-throughput screening, assay development, medicinal chemistry, and preclinical modeling;
• training translational research investigators; and
• enhancing communication among all stakeholders.

PhRMA Senior Vice President David E. Wheadon supports NCATS because

[c]ollaboration — including industry, NIH and academia — is one element driving innovation in drug development, particularly early stage — and ‘bold and ambitious’ proposals, such as Dr. Collins’, will be key to how we collectively progress in discovering novel compounds for addressing patients’ unmet medical needs….

The fact remains that biopharmaceutical research companies today and in the future will play a pivotal role: Our companies create the vast majority of new medicines from start to finish and, for the remainder, in close collaboration with academia and NIH, fulfill the critical final phase that transforms promising molecules into actual medicines for patients.

The WSJ Health Blog notes that NCATS isn’t NIH’s first foray into developing drugs.  In 2009, NIH created the Therapeutics for Rare and Neglected Diseases (TRND) program for basic research on rare diseases.  This early stage of drug development, WSJ Health Blog notes, is “expensive, time-consuming… prone to failure” and often not worth the effort for pharmaceutical manufacturers since the related market is small.

However, this time NIH must restructure several programs to accommodate NCATS, including the Molecular Libraries screening program, TRND, and the National Center for Research Resource’s (NCRR) Clinical and Translational Science Awards.  NCATS would house all three programs, along with the in-the-works Cures Acceleration Network (a drug-development program created by the Patient Protected and Affordable Care Act).

Staff members and researchers connected with the NIH community aren’t too thrilled over the restructuring, particularly with respect to NCRR.  If you visit Feedback NIH, the online forum for public commentary on NIH initiatives, you can read through the 1,100+ lengthy NCATS-related comments.  You’ll also see the “Separating Fact & Fiction” post by Dr. Francis Collins, which begins:

[b]y now, many of you have read the recent New York Times article or related news coverage, about NIH’s plan to establish the National Center for Advancing Translational Sciences (NCATS).

While we are pleased that the news media have recognized NIH’s efforts as a significant development for translational research, the Times article contains some misleading statements that we would like to clarify. Those statements suggest that a much larger shakeup of NIH is underway than is actually contemplated.

So, to set the record straight, we want to share with you what we know at this point in time…

(internal links removed).  The “we” includes Members of the Institute and Center Directors NCATS Working Group.  The post attempts to clear up concerns about budget cuts (House Republicans have already promised to cut the discretionary spending that supports NIH), the security of existing programs, and the misconception that NCATS will be a drug company.

Despite the negative responses, Dr. Collins remains optimistic.  In an interview with ScienceInsider, he emphasized that

the NIH director is called upon to look for scientific opportunities that aren’t being met and to figure out how to make them happen, and that sometimes requires moving things forward at a rapid pace, and that affects a lot of people.

And of course change is always distressing, especially if people aren’t quite sure where it’s going. So I understand the anxiety that currently exists.

But let’s wait a year and see when this has all taken shape how people feel at that point. Will they say at that point that projects or programs at NCRR got dealt a bad deal? I bet they won’t. Will they say they’re excited about the translational science opportunities that are taking shape in the form of this new center? I bet they will.

Perhaps if purse strings weren’t so tight and the healthcare reform debate was settled — or if NIH wasn’t limited to 27 centers and institutes — the creation of NCATS might not upset so many people.  Yet has Dr. Collins displayed a little of that “Sputnik moment” spirit by accelerating the development of drugs for diseases and other areas overlooked by pharmaceutical manufacturers?  Sure.  Just don’t expect him to take us to the moon.

Guatemala and Tuskegee, Winter Man Rides Again

Recent news of STD experiments by U.S. Public Health Service researchers on vulnerable Guatemalans back in the 1940s  gives rise for pause. The Wall Street Journal’s Health Blog reports:

In an article published online in the Journal of the American Medical Association, the CDC’s Thomas Frieden and NIH’s Francis Collins say the unpublished research — which involved intentionally infecting prison inmates, soldiers, sex workers and the mentally incapacitated with syphilis and other STDs — clearly violated ethical standards.

And that

The two say that “regulations safeguarding humans participating in research have been enacted” since the studies were conducted, from 1946-48. Federally funded research projects that could expose human subjects to harm must be overseen by an institutional review board, and researchers are almost always required to get informed consent, they write.

This is true, regulations safeguarding humans participating in research have been enacted. But it’s important to remember that such atrocities–and they are atrocities–were not just relegated to the forties. Although 1948 seems a very long time ago, 1972 does not.

The Tuskegee Syphilis Experiment/Study was conducted by the U.S. Health Service between 1932 and 1972 in Tuskegee Alabama. Poor African-American sharecroppers with syphilis were recruited to document the progression of the disease. They were left untreated.

“The Public Health Service, working with the Tuskegee Institute, began the study in 1932. Nearly 400 poor black men with syphilis from Macon County, Ala., were enrolled in the study. For participating in the study, the men were given free medical exams, free meals and free burial insurance. They were never told they had syphilis, nor were they ever treated for it. According to the Centers for Disease Control, the men were told they were being treated for ‘bad blood,’ a local term used to describe several illnesses, including syphilis, anemia and fatigue.”

Although penicillin became the standard treatment for syphilis by 1947, the Tuskegee researchers continued the study for another 25 years, withheld penicillin  from the study subjects, and “prevented participants from accessing syphilis treatment programs available to others in the area.”

As a result, numerous men died from the disease, many spread it to their wives, and a number of children were born with congenital syphilis. The study was stopped, 40 years after it started, only after a newspaper got wind of it.

John Charles Cutler, M.D. “was a senior surgeon, and the acting chief of the venereal disease program in the United States Public Health Service.” He was involved in the studies in both Guatemala and Tuscegee. “In ‘The Deadly Deception,’ the 1993 Nova documentary about the Tuskegee experiments, Dr. Cutler states, “It was important that they were supposedly untreated, and it would be undesirable to go ahead and use large amounts of penicillin to treat the disease, because you’d interfere with the study.”

The utilitarian calculus can be a monstrous thing. That there are laws now to protect against the practice does not relieve me of the dread at the thought that we actually need laws for such a thing.  The inclination alone is reason for pause. In old Lakota Sioux medicine wheel teachings, Hyemeyohsts Storm says that intellect without compassion produces Winter Man– which freezes everything it touches. But I don’t think that’s a standard academic text.

A Sokal Hoax for Docs

Via Ezra Klein, a revealing anecdote about the power of “thought leadership:”

In the early 1970s, a group of medical researchers decided to study an unusual question. How would a medical audience respond to a lecture that was completely devoid of content, yet delivered with authority by a convincing phony? To find out, the authors hired a distinguished-looking actor and gave him the name Dr. Myron L. Fox. They fabricated an impressive CV for Dr. Fox and billed him as an expert in mathematics and human behavior. Finally, they provided him with a fake lecture composed largely of impressive-sounding gibberish, and had him deliver the lecture wearing a white coat to three medical audiences under the title “Mathematical Game Theory as Applied to Physician Education.” At the end of the lecture, the audience members filled out a questionnaire.

The responses were overwhelmingly positive. The audience members described Dr. Fox as “extremely articulate” and “captivating.” One said he delivered “a very dramatic presentation.” After one lecture, 90 percent of the audience members said they had found the lecture by Dr. Fox “stimulating.” Over all, almost every member of every audience loved Dr. Fox’s lecture, despite the fact that, as the authors write, it was delivered by an actor “programmed to teach charismatically and nonsubstantively on a topic about which he knew nothing.”

It’s one more rationale for more disclosure of sources of influence in the medical profession . . . and ostensibly more objective, “algorithmic” authorities.

Originally posted at Concurring Opinions. Photo credit, Jerry Angelica.

The Ethics of Modern Drugs and Clinical Trials

A recent article in the New York Times raised an interesting question: are traditional, randomized, controlled trials of new genetically targeted cancer drugs unethical?

The piece recounts the story of two cousins, both diagnosed with melanoma.  After enrolling in the last phase of clinical study, the computer lottery selected one cousin to receive PLX4032, experimental “superpills.” The second cousin, now deceased, was relegated to a “notoriously ineffective” course of chemotherapy.

Randomized, controlled trials have become the gold standard in clinical research, comparing competing treatments to determine which extends life most.  The structure of the trial, with an experimental group and control group, is premised on the idea that the comparative effectiveness of the experimental treatment is unknown.  Therefore, one half of the participants in the clinical trial receive a believed to be less effective therapy for a greater good: researchers come to know definitively which treatment is more effective and future patients benefit from that knowledge.

Critics point out that these new drugs are so much more effective than prior treatments that time-consuming clinical trials are futile: the Phase III trial for PLX4032 would cost $100 million and take at least two years before possibly receiving F.D.A. approval.  That is a huge cost, in terms of lives and money, to “prove” what has already been demonstrated in early clinical testing.  Physicians are forced to forego an opportunity “to give patients symptomatic relief, even if the drug turned out not to prolong life.”

Dr. Paul B. Chapman of Sloan-Kettering, a medical oncologist at Memorial Sloan-Kettering Cancer Center and leader of the trial states in the article:

My goal is to find out as quickly as possible in as few patients as possible whether this works.  If we never know, then we’re never going to be able to build on anything.

Making patients’ tumors go away is gratifying.  But that’s not the businss I’m in.  I’m in the business of making people live longer.  That’s what I want to do.

In contrast, Dr. David E. Fisher, a leading melanoma biologist at Massachusetts General  said of the controlled trial:

My personal view is it’s nuts.  I don’t know anyone who hasn’t shuddered at the concept that we can’t let patients on the control arm cross over because we need them to die earlier to prove a point.

The trend towards more targeted and effective drugs changes the framework for evaluating the ethics of clinical trials.  Promising new treatments however, have sometimes been proven to be less effective.  Therefore, the question remains for medical researchers and the F.D.A.: when will early clinical results be so persuasive that a traditional, controlled trial is unnecessary?

The Downfall of Mammography?

Mammography’s reputation as gold standard in breast cancer screening took another hit this past month.  As the New York Times reported last week, research studies demonstrate that the radiation emitted by mammography can actually increase the incidence of cancer. Two nuclear technologies, breast-specific gamma imaging (B.S.G.I.) and positron emission mammography (P.E.M.), expose “patients to a risk of radiation-induced cancer that is comparable to the risk from an entire lifetime of yearly mammograms starting at 40.”

While digital mammography has an average lifetime risk of inducing 1.3 fatal breast cancers per 100,000 women aged 40 at exposure, a single B.S.G.I. exam was estimated to involve a lifetime risk 20 to 30 times greater in women aged 40, and the lifetime risk of a single P.E.M. was 23 times greater.

Moreover, mammography only increases a woman’s risk for breast cancer while B.S.G.I. and P.E.M. increase the risk of cancer in other organs, such as the intestines, kidneys, bladder, gallbladder, uterus, ovaries and colon, the study said.

That’s right, the risk of breast cancer is greater in those women that regularly receive mammograms.  At a November 30, 2009 conference, researchers reported that “for young women who have a high risk of breast cancer because of genetic mutations or family history, the radiation from yearly mammograms may make the risk even higher.”  Meta-analysis of prior research pertaining to high-risk women (0.5 - 1% of the population) with a median age of 45 found that “those women who had had mammograms or chest X-rays (which use a lower radiation dose than mammography) were more likely to have breast cancer.”

Researchers Question the Value of Mammography

The great mammogram debate began on October 21, 2009, when a Journal of the American Medical Association article stated that mammography is not as effective as anticipated:

[S]creening may be increasing the burden of low-risk cancers without significantly reducing the burden of more aggressively growing cancers and therefore not resulting in the anticipated reduction in cancer mortality… There are several reasons that may help to explain why screening has not led to a more significant reduction in deaths from these 2 diseases in the United States. First, screening increases the detection of indolent cancers. Second, screening likely misses the most aggressive cancers.

The “increasing burden of low-risk cancers” can be characterized by the high rate of false positive tests, resulting in over-treatment. As a prior HealthReformWatch post reported:

The recent analysis of all the available evidence from multiple studies published in the British Medical Journal shows that if 2,000 women are screened with mammograms regularly for ten years, only one single woman’s life will be prolonged, but 500 will have at least one false positive and ten will be diagnosed with a “cancer” that would never have become a real disease if it had been left alone.

The New York Times reports that since the mammograms became widely used in the 1980s, the diagnosis of ductal carcinoma in situ (D.C.I.S.), what many believe to be a breast cancer precursor, has increased significantly with more to more than 50,000 women in the U.S. each year.  However, the diagnosis of these borderline breast legions has raised concerns that 17 percent of diagnoses are false positives.

Researchers at Dartmouth College succinctly summed up the deficits of mammography.  In addition to the discomfort of x-ray mammography:

• The rate of false negatives from x-ray mammography range from 4% to 34%
• X-ray mammography is less sensitive in women with dense breast tissue (a common among trait among young women who are at high-risk for developing the most aggressive breast cancers)
• Seventy-five percent of biopsied lesions resulting from suspicious mammogram findings turn out to be benign (a false-positive)

It would be surprising if the Food and Drug Administration (FDA) approved an imaging modality with such poor results today.  However, the FDA never approved x-ray mammography for the diagnosis of breast cancer; it was grandfathered by the Medical Device Amendments of 1976 because it was already in clinical use.  The mammogram does not detect cancer directly, but is a measurement of tissue abnormalities such as microcalcifications, architectural distortions, masses, and asymmetrical densities.

The only mammography device to pass the pre-market approval (PMA) process is the T-Scan 2000 ED by Mirabel Medical Systems, a form of impedance imaging.  Research into impedance imaging has received attention because it does not emit radiation, can more accurately image dense breast tissue, and can differentiate between tissue types without biopsy.  Despite producing greater sensitivity in clinical trials than x-ray mammography or ultrasound, it has not become a primary imaging method.

So When Should Mammography Be Used?

The rumblings of debate turned into a roar when the U.S. Preventive Services Task Force (USPSTF) changed its breast cancer screening recommendations.  The Task Force listed many of the foregoing problems, including false positives, overdiagnosis, and radiation exposure, in support of its decision.  Despite the evidence that more effective screening measures are needed, the response in support of x-ray mammography was overwhelming.  As HealthReformWatch reported:

A number of professional and advocacy groups have responded to the Task Force’s November 16 recommendation.   The ACS continues to recommend annual screening using mammography and clinical breast examination for all women beginning at age 40.  The American College of Radiology issued a frankly titled statement, “USPSTF Mammography Recommendations Will Result in Countless Unnecessary Breast Cancer Deaths Each Year” and labeled the recommendations “cost cutting.”  And the American Congress of Obstetricians and Gynecologists continues to recommend a screening mammography every 1-2 years for women aged 40-49 years and every year for women 50 and over, as well as to recommend BSE.

The editors of Annals of Internal Medicine, which published the Task Force recommendations, responded in an editorial titled, When Evidence Collides With Anecdote, Politics, and Emotion: Breast Cancer Screening.  ”Although prevention is vital to public health, none of the previous guidelines grabbed the public’s attention as much as the Task Force’s recommendation against “routine screening mammography in women aged 40 to 49 years.”  Results of an Annals‘ website survey suggested that clinicians are more likely than the general public to be influenced by the Task Force recommendations.  In response, the editors took a position in support of the new recommendations:

Unfortunately, only a fraction of abnormalities initially detected on mammography and subsequently treated truly represents a life saved rather than unnecessary or premature treatment. Sadly, it is also true that many women who have cancer detected by screening die of the disease despite early detection and treatment… Breast cancer prematurely claims the lives of many, but it is wrong to mislead women about the effectiveness of current screening methods. Women deserve to make decisions about screening for breast cancer armed with the best available information about potential benefits and harms.

One survey respondent wrote, “This Task Force has performed a vital service for years. It brings a welcome dose of science to the politics of screening.” The editors heartily agree… Because the USPSTF issued recommendations that were politically unpopular among some constituents, there have been calls to curtail this independent body’s work. If the USPSTF sinks in turbulent waters whipped up by emotion, anecdotes, and politics, Americans should mourn its loss.

Politics and Science in the Breast Cancer Screening Debate

But what role do politics actually play in breast cancer screening?  According to Dr. Barron Lerner of Columbia University College of Physicians & Surgeons, a big one. In an interview with Kaiser Health News, he recounted:

In the late 1990s, Congress passed a bill that mandated that women who had a mastectomy would have their reconstructive surgery paid for. If you think about this, this really doesn’t happen in most areas except for breast cancer, where Congress would act, and say, “This is something we’re forcing insurance companies to do.” But it speaks to the powerful nature of the breast-cancer lobby.

One other time a report came out criticizing mammograms… the House voted 430 to nothing [ed. note: it was 424-0] — to rebuke that scientific report. So, politics is always intruding into the world of breast cancer….

In the early 1990s, there was some suggestion that if you did something called a bone marrow transplant, or stem cell transplant — which was a very aggressive treatment for metastatic breast cancer — that women live longer… The power of that lobby was so strong that insurance companies began to pay for the procedure, even though it was still experimental and its value hadn’t been proven….

It turns out that when the randomized studies came through and we got good data — at the end of the 1990s — that treatment was, in fact, no better than standard chemotherapy and caused more harm along the way. So it was not indicated at all. But, again, this was an example of Congress, or the government, sort of sticking its foot where it shouldn’t — trying to do the right thing, trying to insure access for all women who have a serious disease. But if you don’t look at the data and you’re acting based on your heart, or your gut instinct, you often make the wrong decision.

In supporting some breast cancer treatments, some lobby groups divert important resources away from important goals (e.g., development of an x-ray mammography alternative) and waste them on every promise of hope (e.g., extensive x-ray screening despite evidence of its negative effects).  The most recent example involves the new drug Avastin.

As the Fiscal Times reports, the FDA gave “accelerated approval” for the marketing of Avastin in 2008.  Two confirmatory trials submitted earlier this year led an FDA advisory committee decision to withdraw agency approval.  The first study showed that Avastin did not delay patient death and a second study indicated that patients on Avastin actually died more quickly than those on chemotherapy alone.  In spite of these findings, Susan B. Komen for the Cure chief Nancy G. Brinker and Sen David Vitter, R-La, have called upon the FDA to continue its approval of Avastin.  The FDA has yet to issue a decision.

Would You Like Statins With That?

As we wrote on this blog the other day about research which raised questions about the efficacy of statins for those who have not yet experienced a heart attack– an off label prescription–the WSJ pointed to a new paper in the American Journal of Cardiology from authors at  Imperial College, London, U.K., which suggests that  statins should be made available free of charge to consumers along with the purchase of fast food. The press release from Imperial College can be found here.

Low level doses of statins may be purchased over the counter in England.

In a prior post, I  wrote about meeting with a cardiologist who suggested I commence taking statins because of my various cardio risk factors. A point, however uncomfortable at the time, made ultimately moot by the favorable results of my stress test, echocardiogram and calcium scoring. I had, prior to my surprisingly clean bill of cardiac health, relented mentally to the prospect of what would become a life long prescription. Of statins, I wrote:

“If one has risk factors, it is prophylactic and is prescribed to reduce the risk of heart attack, stroke and other heart diseases. It is doubtful whether once I start taking this drug I will ever stop. There is no foreseeable time (while alive) that I will wish to stop reducing the risk of heart attack or stroke. And that I suppose is the essence of the onset of age– piling up prescriptions. A daily regimen that will follow one to the grave–only the dosages or the brand names changing as each day welcomes a regimen of pills. In short, this prescription feels like the onset of dependence. The forward guard, if you will. A harbinger of a pharmaceutical future.”

One might say I didn’t take the news well. But crucial to my decision to relent were the words of my cardiologist and another heart doctor. I wrote:

Seeing my, shall we say, chagrin, the cardiologist told me that, like over 50% of the cardiologists he knows, he takes a statin. “We’ve seen the data.” Another recently told me  “Yeah, I take it. They should put it in the water.”

And now, apparently, in burgers.

But, we wrote of some  important (and conflicting) recent findings regarding statins here at HRW last week:

A LA Times article has recently highlighted the problems of off label prescriptions.  In the article, it has come to light that the off label use of statins, one of the world’s most prescribed medication, may not have the efficacy that many doctors had previously thought.  The LA Times reports,

Statins were initially approved by the Food and Drug Administration for the prevention of repeat heart attacks and strokes in patients with high cholesterol who had already had a heart attack. And used for that purpose - called “secondary prevention” - the drugs are powerful and effective medications, driving down patients’ risk of another heart attack or stroke by lowering their levels of LDL (or “bad”) cholesterol.

Then physicians came to believe statins could also reduce the risk of a first heart attack in people who have high LDL cholesterol but are nonetheless healthy. This use of statins - called “primary prevention” - has driven the growth in the market for statins over the last decade.

Statins certainly decrease rates of heart attack in people who have clear signs of cardiovascular disease but it’s not so clear they work that way in people who are healthy. In spite of that uncertainty, statins’ use for primary prevention has sky rocketed.

One wonders how so many physicians came to believe that statins could also reduce the risk first time heart attacks.  Dr. John Abramson, from Harvard Medical School, attributes statins’ off label growth to a “conspiracy of false hope.”  He states, “[t]he public wants an easy way to prevent heart disease, doctors want to reduce their patients’ risk of heart disease and drug companies want to maximize the number of people taking their pills to boost their sales and profits.”

So, with all these interests pushing for statins’ off label use, it should not be a great surprise that extensive research has not been performed regarding statins’ primary preventive effects- and conflicting results have emerged.  The LA Times reports,

In the first of three studies published in the Archives last month, medical researchers found that, contrary to widely held belief, statins do not drive down death rates among those who take them to prevent a first heart attack. A second article cast significant doubt on the influential findings of a 2006 study, called JUPITER, that has driven the expansion of statins’ use by healthy people with elevated blood levels of C-reactive protein, a measure of inflammation. A third article suggested potential ethical, clinical and financial conflicts of interest at work in the execution of the JUPITER study and concluded the widely hailed trial was “flawed” and raises “troubling questions concerning the role of commercial sponsors.”

So??? Statins anyone?

Doctors, Patients and a Failure to Communicate

“What we have here is a failure to communicate.”  Fans of Cool Hand Luke (and who is not?) will recall the phrase in graphic detail–and for those of you without that memory, the video will provide.

A recent study highlighted in the Wall St. Journal’s Health Blog points to both a discrepancy in perception between hospital doctors and their patients and a failure to communicate.

The study was conducted by Douglas P. Olson, MD and Donna M. Windish, MD, MPH. The authors noted as “Background” in the study abstract that:

Hospital surveys indicate lack of patient awareness of diagnoses and treatments, yet physicians report they effectively communicate with patients. Gaps in understanding and communication could result in decreased quality of care. We sought to assess patient knowledge and perspectives of inpatient care and determine differences from physician assessments.

The results of the study were derived from two validated questionnaires given to inpatients treated by “house doctors” over a course of roughly eight months at one hospital.The corresponding doctors were also queried. Eighty-nine patients and 43 doctors participated.

According to WSJ:

The survey — which the authors note is limited by its reach (one institution), patient characteristics (older, indigent and less-educated than average), and general responses, rather than one-to-one-patient-physician comparisons — is published in the Archives of Internal Medicine.

The results? From the abstract:

• Only 18% of patients knew their main doctor by name.
• Sixty-seven per cent of doctors believed their patients knew them by name.
• Fifty-seven per cent of patients knew their diagnosis.
• Seventy-seven per cent of doctors believed their patients knew their diagnosis.
• Fifty-eight per cent of patients thought that physicians always explained things in a comprehensible way.
• Twenty-one per cent of doctors stated they always provided explanations of some kind.
• Sixty-six per cent of patients reported receiving a new medication in the hospital, 90% noted never being told of any adverse effects of these medications.
• Ninety-eight per cent of doctors stated that they at least sometimes discussed their patients’ fears and anxieties.
• Fifty-four per cent of patients said their doctors never did this.

Interestingly enough,the WSJ article notes that the

responses didn’t significantly differ by sex, age, race, language or payment source, for the patients, or level and type of training, for the doctors.

Only 57% of patients knew their diagnosis? Which is to say that 43% did not? 90% not told of potential adverse reactions to new medication?

Res Ipsa Loquitur.

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