Project Shows Substantial Decrease in Colorectal Surgery Infections

There was a time in medical science when doctors did not wash their hands prior to operating on their patients (some might say, that to a greater extent than seems possible, this is still the case among medical professionals and point to a number of recent studies as uncomfortable proof). This failure of doctors to wash hands in the medical forum led to the otherwise avoidable death of many of their patients. Up until the mid 1800s, medical science had simply not made the connection between bacteria, transference, infection and death.

Ignaz Semmelweis, a Hungarian physician who was Director of the maternity clinic at the Vienna General Hospital in Austria, made the connection after what is said to have been an extensive statistical analysis in the 1840s, and demonstrated that hand-washing could drastically reduce the number of women dying during childbirth. He introduced a rigorous hand scrubbing protocol and enough women stopped dying to earn him the honorific, “savior of our mothers.”

But as an article from the UK’s Science Museum, Exploring the History of Medicine, points out

Until the late 1800s surgeons did not scrub up before surgery or even wash their hands between patients, causing infections to be transferred from one patient to another. Doctors and medical students routinely moved from dissecting corpses to examining new mothers without first washing their hands, causing death by puerperal or ‘childbed’ fever as a consequence. As dissection became more important to medical practice in the 1800s, this only increased.

Semmelweis showing again that the common sense of one era is the uncommon brilliance of one bygone.

Which brings us to this latest study/project showing new solutions which decrease the risk of colorectal surgical site infection. According to the Associated Press in an article about the project,

“Almost 2 million health care-related infections occur each year nationwide; more than 90,000 of these are fatal.”

And:

“Infections linked with colorectal surgery are particularly common because intestinal tract bacteria are so abundant.”

 

According to the press release regarding the Project,

A project to reduce colorectal surgical site infections (SSIs) saved more than $3.7 million in costs for 135 avoided SSIs. The two-and-a-half year project included seven hospitals and was directed by the Joint Commission Center for Transforming Healthcare in collaboration with the American College of Surgeons.

The participating hospitals were able to reduce superficial incisional SSIs, which affect skin and underlying tissue, by 45 percent and all types of colorectal SSIs by 32 percent. The average length of stay for hospital patients with any type of colorectal SSI decreased from an average of 15 days to 13 days. In comparison, patients with no SSIs had an average length of stay of eight days.

The press release further notes that

Colorectal surgery was identified as the focus of the project because SSIs are disproportionately higher among patients following colorectal surgeries. Colorectal surgery is a common procedure across different types of hospitals, can have significant complications, presents significant opportunities for improvement, and has high variability in performance across hospitals. The project addressed preadmission, preoperative, intraoperative, postoperative and post discharge follow-up processes for all surgical patients undergoing emergency and elective colorectal surgery, with the exception of trauma and transplant patients and patients under the age of 18. Project participants studied the potential factors that contribute to all three types of colorectal SSIs – superficial incisional, deep incisional and organ space SSIs, which affect organs and the space surrounding them.

 

The AP article:

Solutions included having patients shower with special germ-fighting soap before surgery, and having surgery teams change gowns, gloves and instruments during operations to prevent spreading germs picked up during the procedures.

Some hospitals used special wound-protecting devices on surgery openings to keep intestine germs from reaching the skin.

The average rate of infections linked with colorectal operations at the seven hospitals dropped from about 16% of patients during a 10-month phase when hospitals started adopting changes to almost 11% once all the changes had been made.

The AP article further notes the timely nature of the Project’s benefits:

Besides wanting to keep patients healthy, hospitals have a monetary incentive to prevent these infections. Medicare cuts payments to hospitals that have lots of certain health care-related infections, and those cuts are expected to increase under the new health care law.

Stillbirth: An Interdisciplinary Approach to ‘Closing the Knowledge and Solution Gaps’*

In an article out in the American Journal of Obstetrics and Gynecology, the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)—a Gates Foundation-funded initiative of Seattle Children’s Hospital and the University of Washington School of Medicine’s Departments of Global Health and of Obstetrics and Gynecology—reports on its efforts to develop “a research agenda related to pregnancy, childbirth, and early life[.]”  In addition to interviewing scientific thought leaders and convening a “technical team of 13 prominent researchers from multiple disciplines in the developed and developing world,” the GAPPS spoke to “18 representatives of funding organizations—including government agencies, global foundations, and other financial partners—to gain a deeper understanding of the current perspectives, attitudes, and commitments of funders toward research on pregnancy, childbirth, and early life.”

The GAPPS’ conversations with funders surfaced a number of challenges to increasing funding, including 1) “a range of understanding of the issues[,]” 2) “varying degrees of interest in the topic[,]” and 3) concern about “the challenges of progress with such a long-term and complex problem.”  The authors, to their credit, do not deny that the question (questions, really) of what causes prematurity, stillbirth, and other pregnancy and early life problems are among the “most difficult … in biomedical research today.”  The authors note that “[d]ifferent biological pathways are involved in the adverse outcomes of pregnancy, and these can be characterized at different biological levels from the genome to the exposome (the combined effects of environmental influences).”

At the level of the exposome, recently-published research by investigators from New Jersey’s own UMDNJ-Robert Wood Johnson Medical School, brings us incrementally closer to understanding the effects of ambient air pollution on stillbirth, while exemplifying the complexity of the science involved.  Ambarina Faiz and colleagues compiled data contained in “New Jersey electronic birth certificate records for live births and fetal death certificates for stillbirths linked to their corresponding hospital delivery discharge records from 1998 to 2004[,]” along with data on air pollutants from 25 New Jersey Department of Environmental Protection monitoring stations.  Their analysis of the data revealed that “[i]ncreased concentrations of ambient air pollutants during pregnancy were associated with increased relative odds of stillbirth after adjustment for known risk factors for stillbirth, mean temperature, and a neighborhood level measure of socioeconomic status.”  Numerous questions remain, though.  The authors call for “molecular studies with specific biomarkers … to define more clearly the roles of specific pollutants and to investigate possible biologic mechanisms that lead to stillbirth.”

Drawing on what it learned from funders, as well as from scientific thought leaders and from the technical team it convened, the GAPPS developed eight recommendations aimed at encouraging such research, with the ultimate goal of “making every pregnancy a healthy pregnancy[.]”  The GAPPS calls for 1) determining and publicizing the true cost of prematurity, stillbirth, and other pregnancy and early life problems, 2) establishing alliances among funders, researchers, and other stakeholders, 3) agreeing on research priorities, and 4) promoting research opportunities, particularly opportunities for “new investigators from multiple disciplines.”  While these are clearly daunting tasks, the authors report that “[s]everal interviewees observed that the Bill and Melinda Gates Foundation has an unparalleled ability to persuade, convene, and organize important players, both nationally and internationally.  In particular, they pointed to the potential for the foundation to move the concept of coordinated funding forward.”  The prospect of a new clarity about research priorities, combined with a coordinated approach to funding, is a hopeful one for all of us since “healthy outcomes in pregnancy benefit everyone, directly and indirectly.”

*I thank Catherine Finizio, the Administrator of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, for keeping me focused on this important issue.  (My prior posts are here, here, and here).  Cathy’s grandson, Colin Joseph Mahoney, was stillborn at 39 weeks gestation on November 10, 2008.

The Treatment of Neonates in Pending Legislation Permanently Reauthorizing the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act

Last week, the United States Senate took up debate of The Food and Drug Innovation and Safety Act, S 3187.  A similar bill, HR 5651, was voted out of the House Energy and Commerce committee earlier this month. In addition to re-authorizing user fees for drug and devices and newly authorizing user fees for biologics and generic drugs, the bills include provisions reauthorizing and making permanent both the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). As reported here, S 3187 and HR 5651 are expected to pass the House and Senate in the coming weeks and to go to a conference committee in June. Lawmakers hope to present the final version of the legislation to President Obama before the Fourth of July.

The BPCA and the PREA are often described as taking a carrot and stick approach.  The BPCA is the “carrot,” providing a drug’s manufacturer with six additional months of protection from generic competition in return for studying the drug in children.  The PREA is the “stick,” requiring, as I explained here, “that, as a condition of FDA approval of a new drug application or supplemental drug application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, drugs be studied in children. Applicants must submit a ‘pediatric assessment’ which evaluates the drug’s safety and effectiveness for use in children and ‘supports dosing and administration’ for any pediatric sub-populations for which the drug is found to be safe and effective.  The PREA also requires applicants to request approval of the formulations appropriate for those sub-populations for which the drug is found to be safe and effective.”

While not without their flaws, the BPCA and the PREA have increased our knowledge of the safety and effectiveness of drugs when used in children.  As Daniel Frattarelli of the American Academy of Pediatrics testified before Congress earlier this year, as a “direct result of BPCA and PREA[,]” “we have gone from a situation where about eighty percent of time, the drugs we were using in children did not have FDA-approved pediatric labeling to today where that number is down to about fifty percent.”

In addition to reauthorizing permanently the BPCA and PREA, both S 3187 and HR 5651 make minor changes to the laws, addressing some but not all of the concerns raised in the Institute of Medicine’s February 2012 report, Safe and Effective Medicines for Children: Pediatric Studies Conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. For example, the IOM suggested that “[m]ore timely planning, initiation, and completion of pediatric studies would benefit children[,]” and both bills require that companies submit the pediatric research plans required under PREA earlier in the process than they currently do.  The bills also include provisions designed to, in the words of one of the sponsors of HR 5651, “increase[] transparency on the status of pediatric clinical trials required under PREA” and to provide FDA the necessary enforcement tools to ensure that trials are completed on time.

One problem that the IOM discussed in its report that is only partially addressed in the draft legislation is the need for more studies of drugs in neonates, that is, infants up to four weeks old.  Per the IOM, “[f]rom 1998 through 2010, only 23 of the more than 350 labeling changes resulting from [studies conducted pursuant to the BPCA and the PREA] included information from studies with neonates.”  There were also “five products [that] had been studied in neonates and companies had received exclusivity, but no information from the neonatal studies was added to the labeling.”

The draft legislation incorporates the following provisions relating to neonates:

• Both the House and the Senate bills provide that if the FDA issues a request pursuant to the BPCA and “does not request studies in neonates, such request shall include a statement describing the rationale for not requesting studies in neonates.”

• Both the House and the Senate bills require that the reports that the FDA will be required to make to Congress every five years include a discussion of “the efforts made by the Secretary to increase the number of studies conducted in the neonatal population (including efforts made to encourage the conduct of appropriate studies in neonates by companies with products that have sufficient safety and other information to make the conduct of the studies ethical and safe)[.]“

• The House bill includes a provision that would ensure that the Pediatric Review Committee (PeRC), which is responsible for carrying out the BPCA and PREA, has as a member an agency employee with expertise in neonatology.

• The House bill also includes a provision requiring that the staff of the Office of Pediatric Therapeutics, which is “responsible for coordination and facilitation of all activities of the Food and Drug Administration that may have any effect on a pediatric population or the practice of pediatrics or may in any other way involve pediatric issues, including increasing pediatric access to medical devices[,]” 21 U.S.C. § 393a, include “one or more additional individuals with expertise in neonatology[.]“

Ensuring that individuals with expertise in neonatology serve on the Pediatric Review Committee and staff the Office of Pediatric Therapeutics will not guarantee that studies in neonates are conducted where appropriate.  The IOM concluded in its report that it did not have enough information to know whether additional expertise would have made a difference in the quality of the FDA’s review of studies in neonates.  It also wrote, however, that it “had some concerns about whether sufficient expertise in neonatology and neonatal pharmacology was brought to bear on some requests, for example, those for bacterial conjunctivitis and GERD.”   Common sense suggests that expertise in neonatology is a necessary but not sufficient condition for high quality review; the bill that comes out of conference committee should incorporate the two provisions from the House bill.

As the IOM emphasizes, industry-funded research conducted pursuant to the BPCA and the PREA will never be enough to build an adequate evidence base for drug treatment of neonates, because the BPCA and the PREA only apply to relatively new drugs.  This has a disproportionate effect, because, as the IOM explains, “[m]any drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.”  The IOM discusses an ongoing study of caffeine citrate, which is used to treat apnea of prematurity, which is following children treated with the drug through the age of twelve.  As the IOM notes, “[t]he study, which was funded by the Canadian Institute for Health Research, illustrates the importance of long-term studies of the benefits and risks of neonatal therapies and the importance of public funding for such studies, particularly for long-marketed drugs.”

An Uncertain Future for ICD-10

On February 14, 2012, Marilyn Tavenner, the acting Administrator of CMS, told reporters that CMS will “re-examine the timeframe” of the planned conversion to the ICD-10 code standard.  Presently, covered entities under HIPAA must fully convert from the ICD-9 coding system to ICD-10 by October 1, 2013.

ICD-10, which stands for the International Classification of Diseases, 10^th Revision, is a coding system that providers use for billing purposes and medical researchers also use for statistical analysis.  ICD-10 consists of 68,000 codes that will expand upon the 13,000 codes currently being used with ICD-9. The codes, each representing a separate medical service or diagnosis, are used by providers and hospitals when they submit their bills to the insurer. The providers receive payment for their services based upon the codes and the terms of their reimbursement agreement. From these codes, medical researchers are able to evaluate kind and frequency of care; with more than five times as many descriptive codes in the new system, many researchers and evidence based medicine proponents are said to look forward to the far greater depth of analysis the new coding system will offer. The United States already lags behind many countries in ICD-10 implementation and it is said that this compliance extension will widen the gap even further.

Two days after Ms. Tavenner’s announcement, HHS issued a news release stating that “HHS will initiate a process to postpone the date by which certain health care entities have to comply with ICD-10.” Kathleen G.  Sebelius, the Secretary of HHS, states in the news release that “we have heard from many in the provider community who have concerns about the administrative burdens they face in the years ahead. We are committing to work with the provider community to reexamine the pace at which HHS and the nation implement these important improvements to our health care system.”

HHS’s news release leaves a lot of questions unanswered. There is no hint at which “certain health care entities” will be granted an extension for compliance and how far off the new deadline will be. HHS claims they will “initiate a process,” which leads many to believe a formal rule making process with public comments will occur. This process could possibly take years to complete, which undoubtedly has caused a giant sigh of relief for providers and institutions across the country that feel ill-prepared for the 2013 deadline. Analysts at Health Care IT News estimate that the deadline could be pushed off a year or two if there is a formal rule-making process.

As the news of Ms. Tavenner’s announcement spread, members of the industry sent out messages cautioning that a complete overhaul of the current plan is unlikely.  Ms. Tavenner’s announcement, which happened at the American Medical Association (AMA) Advocacy Conference in Washington, D.C., was fittingly met with applause by AMA members. The AMA has publicly and vehemently opposed the current October 1, 2013 deadline.  In a January 17, 2012 letter addressed to Speaker of the House John A. Boehner, the Executive Vice President and CEO of the AMA James L. Madara M.D. pleaded with Speaker Boehner to stop the implementation of ICD-10. In the letter, Dr. Madara argues that the conversion “will create significant burdens on the practice of medicine with no direct benefit to individual patient care, and will compete with other costly transitions associated with quality and health IT reporting programs.” Of course, Dr. Madara is referring to the task of implementing an electronic health records (EHR) system in accordance with CMS’s meaningful use criteria, which entitles a covered entity to receive incentive payments from CMS. Dr. Madara also cites to what he deems to be the competing tasks of dealing with financial penalties for non-participation in Medicare programs, including e-prescribing and the Physician Quality Reporting System.

ICD-10 opponents also cite to the industry’s recent failure to comply with the January 1, 2012 deadline to comply with the transition to Version 5010, a HIPAA electronic transactions upgrade that is necessary to support ICD-10, as evidence that the industry is not ready for the ICD-10 change. In November 2011, CMS gave in to industry pressures to extend the 5010 compliance deadline an additional ninety days. It is undeniable that providers are already subject to tremendous demands under HIPAA and the HITECH Act, on top of Medicare cuts, which are placing significant financial stress and compliance burdens on the industry. It is not surprising that ICD-10 has met a lot of resistance from providers. However, it is no secret that providers and institutions are consistently successful lobbyists for their concerns and beliefs and it remains to be seen how CMS will proceed with the scheduled ICD-10 implementation and what compromises will be made.

Proponents of the ICD-10 system argue that the new coding system will create significant positive changes in the industry because it will help collect important data that will improve the quality of patient care, decrease costs, and collect statistics for medical research.  CMS and the Center for Disease Control and Prevention believe that the new codes will create more accurate and exact descriptions of diagnoses and inpatient procedures, which will improve efforts to track care, detect emerging health issues and improve quality. A report from Deloitte, a consulting firm, reported that the increased size and scope of the ICD-10 codes is expected to provide potential benefits in cost and quality measurement, public health, research, and organizational monitoring and performance measurement.  Whether a provider supports the change or not, Deloitte echoes the sentiment of many that advance planning is essential. Providers and institutions that have already invested time and money into the ICD-10 implementation are frustrated and upset by CMS’s decision to “reexamine” the current compliance deadline.  After all, no provider wants to see its large investment in the ICD-10 system put to waste.

The fact is that no one, perhaps even CMS and HHS, is certain about the date of the future ICD-10 implementation plan so perhaps the smartest choice for providers is to proceed with steps to continue the ICD-10 implementation. Considering the prospect of the financial disincentives attached with non-compliance, it seems like a risky choice for any provider to sit around and wait and see what may happen, especially when the ICD-10 implementation cannot happen overnight.  There are providers that started the ICD-10 conversion process back in 2009 when it was first introduced and they still have not completed the task. Unfortunately for providers, the ICD-10 conversion requires time, manpower, training, testing with payers, and significant technological changes that will carry high administrative and financial costs.  The Medical Group Management Association (MGMA), which opposes the ICD-10 implementation, estimates that it will cost a ten doctor practice more than $285,000 to convert to ICD-10, with software upgrades accounting for only $15,000 of that amount. According to the MGMA, the bulk amount would be for increases in claims queries, reductions in cash flow, and increased documentation time.  What it comes down to is that if a provider wants to be paid for its services, noncompliance with ICD-10 is not an option. The risk for successful claims processing and receiving payments in a timely fashion is present, but adequate preparation and testing well before the compliance deadline is the best way to combat this significant risk.

One thing is certain – until HHS releases a new rule and schedule for ICD-10 implementation, opponents will continue to argue that the costs to adopt the new system are too high, the task too onerous, and the rewards too speculative to justify such an undertaking.  Unless the industry comes together to find a solution for an easy transition, this could be a bumpy road until the ICD-10 transition is complete.

(Slow) Progress Towards Uncovering Sex-Linked Differences in Drug and Device Safety and Efficacy

In 2000, the General Accounting Office (since re-named the Government Accountability Office) reported that more women than ever were being included in clinical trials funded by the National Institutes of Health.  In fact, the GAO noted, over 50% of the participants in the trials that NIH funded in fiscal year 1997 were women.  At the same time, the NIH had made much less progress implementing the requirement that certain clinical trials it funds be designed to reveal sex-linked differences in a treatment’s safety and efficacy.  In 2012, sex-linked differences in responses to treatments are still not being studied in research funded by the government or by the private sector.  In a summary released last month of an Institute of Medicine workshop on the problem, Theresa Wizemann reports that “[e]ven when women are included in clinical trials, the results are often not analyzed by sex” despite “growing acknowledgement that men and women have substantial and widespread biologic differences.”

As its title — “Sex-Specific Reporting of Scientific Research” — suggests, a focus of the IOM Workshop was whether medical journals could drive reform in this area by requiring that authors report sex-specific data.  Wizemann writes that because “[r]esearchers are eager to have their papers published in high-profile journals[,]” “editorial policies implemented by those journals can be effective in modifying behavior.”  But several participants in the IOM Workshop noted that studying population subgroups poses “methodologic and analytic” challenges.  In many cases, Wizemann reports, “achieving statistical significance for subgroup analyses would require unattainable or unjustifiable numbers of participants.”  Workshop participant Gregory Curfman, who is the Executive Editor of the New England Journal of Medicine, “cautioned against editorial policies that require trials to be designed to reach valid statistical conclusions for males and females separately[,]” because “[s]uch editorial policies would create a ‘steep mountain to climb for investigators and for funding agencies[.]‘”

The participants in the Workshop seemed to be largely in agreement that journals could not, acting alone, re-shape “research culture to embrace consideration of sex differences as part of sound study design.”  There are steps that journals could (and should, I think) take short of dictating study design, though, including requiring study authors to tabulate and make available raw sex-specific data to facilitate future studies that draw on data from multiple trials.

Government agencies and other funders have a role to play too.  The NIH should more stringently enforce the statutory requirement that certain later-stage trials it funds be designed to evaluate sex-linked differences, and the FDA should take similar action with regard to trials funded by drug and device companies.

A study published last year by Sanket Dhruva, Lisa Bero, and Rita Redberg in the journal Circulation highlighted how little progress the FDA made on the device side over the last decade.  In 1994, the FDA issued a directive requiring that every time it makes a decision on an application for approval to market a new device, it issue a Summary of Safety and Effectiveness Data (SSED) that includes, among other things, a “gender bias” statement addressing the following two questions: (1) Did the proportion of men and women in the clinical trial reflect the distribution of the disease? and (2) Were there any sex-linked differences in safety or effectiveness?  Dhruva and colleagues reviewed all of the of the SSEDs for all of the cardiovascular premarket approval applications submitted and approved between 2000 to 2007 and found (1) that women were underrepresented in the underlying clinical trials and (2) that less than half (41%) of the SSEDs included the required “gender bias comment or analysis.”  Nearly a third (28%) did not even report the percentages of men and women enrolled in the studies supporting the application.  And, there was no improvement over time; “[t]here was no change in the presence of gender bias comments or analyses over the 8-year period” studied.

The FDA has been working for several years to address the problem and in December of 2011 it released a draft guidance in which it “strongly recommends” that device companies work closely with the agency to “investigate and report differences in study outcomes of treatment by sex.”

The Guidance provides clear direction for companies regarding (1) increasing the percentage of enrollees in device trials who are women, (2) designing studies to allow for the “consideration of sex and associated covariates” such as body size, (3) analyzing study data for sex-linked differences, and (4) “reporting sex-specific information in summaries and labeling for approved devices.”  Whether these strong recommendations translate into strong and consistent agency action remains to be seen, but the Guidance is an excellent start.  As Carolyn Clancy, the Director of the Agency for Healthcare Research and Quality, who participated in the IOM Workshop, emphasized, “[b]etter data on women would be better data for everyone,” allowing for more specific clinical practice guidelines and better-tailored care of individual patients.

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.

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