Informed Consent

Some Thoughts on the New Common Rule for Human Subjects Research

On January 18, 2017, in one of its last official acts, the outgoing Obama administration issued a final revised version of the Common Rule—the regulation that governs the treatment of human subjects in all federally funded research. This was the culmination of a process that began in 2011 when the Department of Health and Human Services (HHS) issued an Advance Notice of Proposed Rulemaking, or ANPRM, that envisioned major changes to the original 1991 Common Rule. Then, on September 8, 2015, HHS and 15 other federal departments and agencies released a Notice of Proposed Rule Making (NPRM) that proposed specific changes to the Common Rule and opened a 90-day public comment period.

The NPRM’s proposed changes would have greatly altered the rules for human subjects research, especially regarding biospecimens. Among the most controversial of its proposals was the expansion of the definition of regulated “human subjects research” to include research using anonymous or deidentified human biospecimens. This is a critical point because research that does not involve human subjects at all is not subject to the Common Rule’s requirements. The comments from industry, research universities, and scientific and professional organizations were highly critical of some of the proposed changes. There was an evident division between (critical) hard science and (supportive) social science (anthropologists, for example) commenters; bioethicists were generally critical, but there were opinions on both sides. In a previous GLR post, I reported on a withering critique of the biospecimen proposal from the National Academies of Sciences, Engineering, and Medicine, which argued that “continuing expansion of federal regulations on research is diminishing the effectiveness of the U.S. research enterprise.”

The January 18 final version (the “Final Rule”) adopts some of the changes proposed in the NPRM and drops others, including the controversial expansion of the definition of “human subjects” to include non-identified biospecimens. The official text of the Final Rule appears here.

As you can see, this is a daunting 500-plus-page document. However, the complete text of the Final Rule appears at pp. 459-508, with an executive summary of the new provisions at pp. 360-362. The rest of the document consists of numerous tables (cost-benefit analyses and the like) required by law and a summary of and response to every public comment made in 2015.

There have already been numerous published summaries of the differences among the original Common Rule, the NPRM version, and the Final Rule. The most comprehensive of these may be from the Council on Governmental Relations.  A second article, from the New England Journal of Medicine, summarizes and analyzes how the Final Rule differs from the NPRM from the medical research perspective. A third, from a higher education journal, focuses more on the social science perspective and links to several other analyses. A fourth piece, from Science, cites the bioethical critique of the new Final Rule.

Without trying to reinvent the wheel, here are some of the key provisions of the Final Rule that these sources point out:

Is the Final Rule Really “Final”?

The answer here is a resounding “probably.” A 1996 law called the Congressional Review Act allows the House and Senate to eliminate new agency regulations by passing a joint resolution of disapproval within 60 days of being notified of a new rule. As with an ordinary bill, the resolution would be subject to presidential signature or veto. (President Obama vetoed five such resolutions—the only times the CRA has been used.) The 60-day period apparently expired on March 20 without any congressional action, though there is debate over what it means for Congress to be “notified.”

The new administration could announce yet another rulemaking—this one intended to modify or eliminate the Final Rule. The administration could also attempt to change the practical application of the Final Rule through informal “guidance,” which was the subject of an earlier GLR post.

There is no reason to believe that any of these things will happen. The criticism of the NPRM did not follow partisan or ideological lines—just about everyone involved in research, from university medical centers to Big Pharma, opposed many of its provisions. The fixes reflected in the Final Rule seem pragmatic and not calculated to trigger political responses from either the legislative or executive branch. With the exception of some in the bioethics community, virtually all constituencies are supportive. And most importantly, no one in Congress or the administration has—as far as I can tell—expressed any interest or concern. So the prudent assumption is that the Final Rule really is final.

Why Are Some Bioethicists Unhappy?

Several prominent bioethicists have criticized the failure to require informed consent for research on anonymous or deidentified human biospecimens. Hank Greely of Stanford has called it “a predictable result of the disparity in lobbying power” between the research and subject communities. Another critic is Rebecca Skloot, the author of the best-selling The Immortal Life of Henrietta Lacks, about a poor African-American woman whose cells—without her knowledge or consent—gave rise to the HeLa cell line and, directly and indirectly, generated large amounts of money in which she and her descendants have never shared. A Lacks descendant has recently sued Johns Hopkins University in a belated effort to seek compensation. The suit faces many significant legal challenges—the biggest of which may be the statute of limitations.

What specific harms to subjects are the critics worried about? The possible harms seem to fall into three broad categories: privacy-related, emotional, and financial. On the privacy issue, Skloot has noted that Mrs. Lacks ultimately lost her anonymity, and that she and her family endured the public disclosure of personal medical information. That’s a rare event, as Skloot has acknowledged. In fact, it’s hard for me to see realistic invasion-of-privacy concerns in the current research environment, regardless of how the Common Rule treats biospecimens. When I ask the question—Is there a measurable probability that someone will have the means and motive to re-identify my DNA sample and then use that information to harm me?—my answer is no.

Skloot has also drawn on the Lacks family’s experience to catalogue the possible emotional harms, including “the shock of learning they were part of research” and being drawn into “debates over who controlled samples” and how those samples could be used. I wouldn’t judge someone else’s reaction to these consequences, but I would discount it by the current probability of similar things happening—and Skloot deserves much of the credit for bringing attention to the issue and thereby reducing that probability.

I think the most serious consequence is what Skloot has called “questions over profits.” A lot of people and institutions made money from Henrietta Lacks’s cells. She didn’t get any of it, and she was never told that the research was going on. The same thing has happened in a couple of other notorious cases, most infamously the 1990 California case of Moore v. Board of Regents. This bothers me. If I’m considering giving you a biospecimen and you think you might use it for money-making purposes, you should tell me. Some people might refuse your request outright; I would personally want the opportunity to negotiate for a piece of the action.

Curiously—to me—the research and bioethics communities have almost uniformly rejected the ideas that an informed consent document is a contract and, especially, that money can be used as an inducement to contribute a research biospecimen (though they do approve of token payments as compensation for the subject’s inconvenience). A few years ago, several colleagues and I published two articles advocating a contractual model for biospecimen contributions to biobanks. The key idea was a sliding scale of compensation: the more control over the sample that the subject ceded to the researcher, the more the subject would get paid.

The reaction, in print and at conferences where we presented the papers, was very negative. Allowing subjects to treat their DNA as a commodity seemed to be viewed as per se unethical. I remember one anonymous journal reviewer—who advocated rejecting the article—writing that we had totally ignored the lessons of the Henrietta Lacks case. We thought that we had come up with a way to prevent the same thing from happening in the future. The lesson I took away from the whole experience was that, to our critics, subject autonomy was little more than a rhetorical construct.

How Much Does the Final Shape of the Common Rule Really Matter?

At least with respect to research using biospecimens, the answer may be: not all that much. The reason is that many, many people are regularly consenting to the use of their biospecimens without ever becoming aware of it.

I owe this realization to Jean Cadigan, a medical anthropologist at UNC Medical School, who co-teaches my Biotechnology and Life Sciences course at UNC Law School. In a recent class, Jean led us through a fascinating exercise about consent to research in teaching and research hospitals (most use very similar forms, so these comments could apply to almost any university medical center). First, she showed us an elaborate, carefully crafted informed consent video used by a university-affiliated biobank. The biobank offers all the protections that the Common Rule requires and more. Then we looked at a specific consent for treatment form. By way of preamble, I should note that I and family members whom I’ve accompanied to various hospitals have had to sign this kind of document on several occasions in exigent circumstances. I’ve never read one—and I bet you haven’t either. I’m a lawyer and I teach this stuff, but the consent form is the last thing on my mind in the emergency room. I’ll scribble my name on anything they put in front of me just to get the treatment started.

But what would I find if I did read it? In the example we looked at, at the end of a long paragraph entitled “Consent for Use and Release of Information,” I’d see that the patient gives the hospital permission “to release any information about me, my health, the health services provided to me . . . (4) as otherwise described in the Notice of Privacy Practices and as permitted by law.” Then, if I dug up that Notice (as Jean did for our students), I’d find that the hospital (taking advantage of a HIPAA exception) asserts the right, “without [the patient’s] authorization or an opportunity to agree or object,” to use or disclose personal health information or “surplus specimens” (anything they take out of your body that they don’t put back in) as long as “the use and/or disclosure relates to research.”

The bottom line appears to be that, however the Common Rule treats biospecimens, the research world will still be awash in unwittingly donated—and not anonymized—tissue samples. This makes the anguish over the Final Rule, and the ethical aversion to our contractual model, seem like rearranging the deck chairs on the Titanic.

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ACMG Backs Down a Bit

57 sauceA year ago, the American College of Medical Genetics and Genomics (ACMG) released its Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. As I reported in a July 2013 post, the core recommendation was this: “The ACMG recommends that for any evaluation of clinical sequencing results, all of the genes and types of variants in the Table should be examined and the results reported to the ordering physician.” Specifically, the ACMG recommended that whenever a lab does whole genome or whole exome sequencing on a patient, it should examine all 57 [now 56] genes on the list included in the Recommendations and report any clinically significant findings to the ordering physician. It would then be the duty of that physician “to provide comprehensive pre- and post-test counseling to the patient.” Most controversially, the ACMG recommended that the test findings “be reported without seeking preferences from the patient and family and without limitation due to the patient’s age.” As I characterized it in the July post, “patients should be given the 57-gene screening whether they want it or not and told the results even if they say they don’t want them.”
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Filed under Genetic Testing/Screening, Genomic Policymaking, Genomic Sequencing, Genomics & Medicine, Informed Consent

Revisions to the Ethical Standards for Research

HelsinkiThe World Medical Association published revisions to the Declaration of Helsinki (DoH) in JAMA on October 19, 2013. As noted previously on the Genomics Law Report, the DoH was adopted in 1964 and is considered a foundational guiding document for ethical medical research. The DoH has been revised six times previously, and these are the first revisions since 2008. The revised DoH was announced following the Working Group’s public consultation from April to June 2013 on the text of proposed changes, though the Working Group has apparently spent at least two years contemplating revisions and consulting with experts. In the United States, the DoH has been an important foundational document promoting the creation of institutional review boards (IRBs) but has had relatively little practical influence since it was effectively abandoned by the administration of former President George W. Bush. Nonetheless, the DoH continues to exert significant influence over international ethical standards.
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Filed under Genomic Policymaking, Genomics & Medicine, Genomics & Society, Informed Consent, International Developments, International News

Genomic Research Ethics: Special Rules for HeLa Cells

In her 2010 book The Immortal Life of Henrietta Lacks, Rebecca Skloot told the story of Henrietta Lacks and the cell lines derived from her cervical tumor biospecimen (cell lines known to scientists simply as “HeLa cells”). To make a long story short, in 1951 physicians at Johns Hopkins Hospital took a biopsy from a patient, Henrietta Lacks, and from that biospecimen developed the first human cancer cell line. The biospecimen was taken without Lacks’ knowledge or informed consent. No laws were broken in the creation of the HeLa cell lines that are now recognized (pdf) as “the most widely used human cell line in the world.” She died in 1951, and it was reportedly not until 1973 that her family learned about the HeLa cells (two years after Henrietta Lacks’ name was published as the source of HeLa cells in a scientific journal). As the table below shows, this incident occurred long before the adoption of regulations and ethical guidelines for biomedical research that, today, generally require researchers to obtain voluntary, informed consent from individuals before performing biomedical experiments.
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Approved North Carolina State Budget Includes Funds to Compensate Sterilization Victims

Jennifer K. Wagner, J.D., Ph.D., is a solo-practicing attorney in State College, PA and a research associate at the University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technologies.

Sterilization_statesNearly a year and a half ago, the GLR reported that North Carolina was one step closer to compensating the victims of its sterilization program. North Carolina’s eugenics program started with legislation in 1919 and was not officially abolished until 1977 (though the program’s sterilizations were performed between 1929 and 1974). The program victimized more than 7500 individuals and the number of victims surviving in 2010 was estimated at approximately 2950.
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DNA DTC: The Return of Direct to Consumer Whole Genome Sequencing

This morning, Gene By Gene, Ltd. – better known as the parent company of the popular genetic genealogy provider Family Tree DNA – formally announced a corporate reorganization that includes the debut of a new division, DNA DTC. (Apparently the news was also announced earlier this month at the Family Tree DNA Conference, although the company waited until today to launch press releases.)

The announcement from Gene By Gene is newsworthy for several reasons, including:

1. The Return of True DTC Whole Genome and Whole Exome Sequencing. According to DNA DTC, the company offers a range of products “utilizing next generation sequencing including the entire exome (at 80x coverage) and the whole genome.” The company’s website, while fairly spartan, appears to bear this out. Whole exomes ($695 at 80x coverage) and genomes ($5,495 at 30x coverage) are both listed as available products.

Now, Gene By Gene is not, as its Wikipedia page claims (as of this writing), “the first commercial company to offer whole genome sequencing tests.” Knome earned that honor more than four years ago, when it started selling whole genome sequences for $350,000; an astounding price, either low (given the cost of the first human genome was $3 billion) or high (given that, well, it was $350,000) depending on your perspective. Gene By Gene probably does represent, however, the only commercial company currently offering a whole genome sequence in a truly direct-to-consumer (DTC) manner.


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Filed under Direct-to-Consumer Services, FDA LDT Regulation, General Interest, Genetic Testing/Screening, Genomic Sequencing, Genomics & Society, Industry News, Informed Consent, Privacy

Patenting and Personal Genomics: 23andMe Receives its First Patent, and Plenty of Questions

Earlier this week 23andMe, the Silicon Valley-based personal genomics company, was awarded its first patent: US Patent Number 8,187,811, entitled “Polymorphisms associated with Parkinson’s disease”.

23andMe co-founder Anne Wojcicki announced the issuance of the patent via a post on the company’s blog late Monday evening, attempting to strike a tenuous balance between her company’s oft-championed philosophical devotion to providing individuals with “unfettered access to their genomes” and its desire to commercialize the genomic information so many of those very same individuals have shared, free of charge, with 23andMe. With its new patent, 23andMe also injected itself into the middle of what Wojcicki herself described as the “hot debate” surrounding the patentability of “inventions related to genetics.” Wojcicki’s announcement appeared to catch more than a few of the company’s customers by surprise, sparking concern about the company’s intentions on 23andMe’s blog, Twitter and elsewhere, along with rapid and pointed commentaries from Stuart Hogarth and Madeleine Ball, among others.

Of the various questions asked of and about 23andMe and its new patent, these may be the three most common: Where did this patent come from, and why didn’t I hear about it before? What does 23andMe’s patent cover? How is 23andMe going to use its patent? Let’s take each question in turn.


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Filed under Biobanking, Direct-to-Consumer Services, General Interest, Genetic Testing/Screening, Genomics & Society, Industry News, Informed Consent, Legal & Regulatory, Myriad Gene Patent Litigation, Patents & IP

On Genetic Rights and States: a Look at South Dakota and Around the U.S.

SD H.B. 1260, introduced in South Dakota on January 26, 2012, is an act that would govern the use of genetic information. By any standards – and especially by legislative standards – the two-page bill (pdf) is succinct and should not be considered a state variation of GINA, as the bill does not speak to non-discrimination issues.

The bill’s brevity should not, however, be mistaken for a narrowness of purpose. In under 200 words, the South Dakota bill, if passed, would (1) grant property rights to individuals in their DNA samples and genetic information, (2) prohibit surreptitious testing, (3) call into question many forensic and law enforcement uses of DNA, (4) eliminate newborn blood spot screening without explicit consent and (5) impose broadly worded informed consent requirements on all collections and uses of individual genetic data. So much for inefficient government.
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Alabama’s “Genetic Information Privacy Act” & the Ongoing Need for Personal Genomics Leadership

Jennifer K. Wagner, J.D., Ph.D., is a solo-practicing attorney in State College, PA and a research associate at the University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technologies.

Thanks to technological innovation and a corresponding decline in cost, an increasing number of individuals are finding themselves with the task – or at least the opportunity – of accessing and interpreting their own genetic information. Over the past year, several state legislatures have taken notice.

Following on the heels of legislation passed or proposed in California, Vermont and Massachusetts, the Alabama House of Representatives is considering a bill by Representative Henry (pre-filed on January 23, 2012 and scheduled for first read on February 7, 2012) titled the “Genetic Information Privacy Act” (2012 AL H.B. 78). While the bill is relatively brief, its effects as written may reach far beyond those intended.

A New Bar for Informed Consent. First, the bill in its current form would require signature on separate informed consent documents to obtain, retain, or disclose genetic information. As drafted the bill would provide an exception for the insurance industry, permitting a single, integrated informed consent document if the genetic information is being obtained, retained, or disclosed “for the purpose of obtaining insurance” (Page 4, Line 25).


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North Carolina One Step Closer to Compensating Victims of its Eugenics Program

Jennifer K. Wagner, J.D., Ph.D., is a solo-practicing attorney in State College, PA and a research associate at the University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technologies.

Almost a year ago, North Carolina Governor Bev Purdue set up a Task Force charged with determining how the state should compensate victims of its eugenics program. The Final Report (pdf) by that Task Force was submitted to the Governor on January 27, 2012. If the state legislature takes action to implement the Task Force’s recommendations, North Carolina will become the first state (of the 32 states that had eugenics programs) to compensate the victims of its involuntary sterilization program.


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