Ebola Outbreak Shines a Light on Compassionate Use

coleman_carl_lg2The Ebola outbreak, which has claimed nearly 1,000 lives since its emergence in West Africa in December 2013, has brought renewed attention to policies surrounding the “compassionate use” of unapproved medications – i.e., the provision of unapproved medications to individuals outside the context of clinical trials.   The issue rose to the forefront early last week when it was reported that two American aid workers in Liberia were treated with an “experimental drug that has never before been tested for safety in humans.”  Both workers appeared to respond well to the drug, known as ZMapp.  The drug was also provided to a Spanish priest, who died shortly thereafter; it was unclear whether he took the drug before he died.  Following some controversy over the fact that the first three recipients of the drug were all foreign aid workers, on Tuesday it was reported that the drug’s manufacturer had sent its remaining stocks of the drug to Liberia for the treatment of two African doctors.

The FDA recognizes three broad categories of compassionate use, which are grouped under the general label of “expanded access.”  These include expanded access for individual patients, including for emergency use; expanded access for intermediate-size patient populations; and expanded access for large patient populations under a treatment IND or treatment protocol.  All of these categories are limited to patients who have serious or immediately life-threatening diseases or conditions for which no comparable or satisfactory alternative treatment exists.  The FDA must determine that the potential benefits of the unapproved drug outweigh the potential risks, and that the risks “are not unreasonable in the context of the disease or condition to be treated.”  In addition, the FDA must determine that allowing expanded access “will not interfere with the initiation, conduct or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.”

The FDA typically grants most requests for expanded access.  When requests are denied, they most frequently involve emergency requests to use drugs that are not already undergoing clinical trials – precisely the situation facing ZMapp.  On the one hand, it is understandable that the FDA would be cautious in allowing expanded access when no safety information exists and when there is no time to perform an exhaustive assessment.   On the other hand, patients who are expected to die in a short time because they have no treatment alternatives may reasonably decide that they are willing to assume a high level of risk.  Moreover, if clinical trials have not even been initiated, allowing expanded access cannot possibly interfere with the trials’ completion.  While there is some possibility that systematically allowing expanded access in emergency situations would interfere with the initiation of trials, the manufacturer would have its own incentives to initiate trials once the expected demand for the drug is sufficiently high.

For now, all of these questions are moot, as existing supplies of ZMapp have reportedly been exhausted.   When more supplies become available, further requests for expanded access are certain to arise.  However, granting access to the drug through compassionate use programs is not a long-term solution.  As an ethics panel convened by the World Health Organization concluded on Tuesday, the ideal way to introduce new Ebola medications is “in the best possible clinical trials under the circumstances in order to definitely prove their safety and efficacy or provide evidence to stop their utilization.”

Clinical trials of Ebola treatment will of course raise difficult questions in their own right.  Unlike with expanded access, where everyone obtains the medication they have expressly requested, in a clinical trial some participants may be assigned to control groups that receive different medications or even placebos.  Because no effective treatment for Ebola currently exists, placebo-controlled trials of new Ebola treatments would appear to be consistent with the ethical principles in the Declaration of Helsinki.  Yet, particularly after American and Spanish foreign aid workers received the first doses of the experimental medications through compassionate use programs, asking African patients to enroll in placebo-controlled trials would surely be controversial.  As the WHO panel delicately put it, the goal should be to devise “ethical ways to gather data while striving to provide optimal care under the prevailing circumstances.”   The challenge will be to figure out effective strategies for carrying this out.

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Kathleen Boozang on Death with Dignity Legislation Currently Pending in New Jersey

dean-kathleen-boozang-176x220There’s a fair chance the New Jersey Assembly will take up the Death with Dignity Act before the legislators head off to the Jersey Shore for the summer.  The topic is appropriate for this blog, entitled Health Reform Watch, because physician-assisted suicide (PAS) is a kind of desperate attempt at reforming end-of-life care.  The frustration with the limited extent to which we’ve been able to improve end-of-life care over the last three decades is understandable.  I suggest, however, that even with the enactment of practitioner orders for life sustaining treatment (POLST) legislation, New Jersey has not been sufficiently creative or aggressive in attempting to change end-of-life care practices in the state, and the legislature should be focused on other initiatives to achieve that end.  Based on the experiences of Oregon, Washington, and Vermont, there is no reason to expect that a Death with Dignity law would contribute meaningfully to an improvement in end-of-life care for New Jerseyans.

First, let’s get one matter out of the way:  I do not believe that the proponents of Death with Dignity legislation are motivated by a desire to reduce the cost of end-of-life care.  The patient suicide movement has been around for a very long time, and has always, in my view, been grounded in the philosophical belief in patient autonomy and an expansive view of a right to control the means and timing of one’s death.  Experience in those states where PAS is legal is that too few people take advantage of physician-assisted suicide for its availability to make a dent in health care costs.  If anything, reducing healthcare costs is more likely to be a reason supporting improvements to end-of-life care, although nationally, it’s not clear one way or the other whether reforming end-of-life care will actually reduce Medicare costs – the labor-intensive care required for several months of hospice is expensive.  New Jersey could be different.  Certain indicators suggest that patients dying in New Jersey receive more aggressive treatment than almost any other state in the country. Because that’s not how the majority of people want to die, it could be that in New Jersey, improving care of the terminally ill would save Medicare dollars.  If that’s a side benefit, all the better.  My primary point in this regard is that I don’t think it’s fair to accuse proponents of PAS of being motivated by potential cost savings; proponents of reforming the care of the chronically and terminally ill are more likely to cite costs as a factor in their search for reform.  Ultimately, I believe that both sides are motivated primarily by the desire to provide patients and their families with compassionate, holistic, and high-quality care in the last years and months of life.  That will not be accomplished by physician-assisted suicide. Read more

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Direct to Consumer Genetic Testing and the Over-Production of Genetic Information

bernstein-gaia-lgCross Posted at HealthLawProf Blog

23andMe, the Internet genetic testing company, which offered genetic testing for health conditions and ancestry, has received extensive publicity in recent months. In November 2013, the FDA ordered 23andMe to stop marketing its health-related genetic test results to customers because their product is a “device”, which requires FDA approval. In its letter to 23andMe the FDA focused on the harms of consumers’ interpretation of genetic test results without the appropriate medical guidance.

And for sure, consumers’ independent interpretation of genetic results is potentially harmful. But, another important concern not addressed by the FDA is the need to regulate and constrain the production of genetic information in the first place – at the time that a consumer decides which tests to take. Direct to consumer genetic testing companies, like 23andMe, usually offers a battery of multiple tests that the consumer purchases without careful selection of what information is desirable to her. And, although genetic information can help improve and control health outcomes, not all genetic information is made equal and not all tests results are similarly desirable for all people. In my essay Direct to Consumer Genetic Testing: Gatekeeping the Production of Genetic Information, I discuss the problem of indiscriminate production of genetic information and argue for the need for a medical gatekeeper not just for the interpretation of genetic test results but earlier on to guide consumers through the selection of tests.

The guidance of a medical practitioner (particularly a genetic counselor) at the test selection stage is important to avoid the production of genetic information that is unsuitable for the specific person who wants to undergo testing. First, some people may prefer not to know certain genetic information about themselves because there are no effective preventive measures, and they do not want to live with the knowledge that they are likely to incur a certain genetic disease. For example, currently, the most effective prevention for breast cancer is a mastectomy. Some women would welcome the information and the ability to prevent the disease. But, others may not view this as a preventive measure they can endure and would prefer not to undergo a genetic test for the breast cancer genetic mutations. Second, some genetic tests convey little information. Certain positive genetic test results indicate only a slightly higher probability of incurring the disease than the likelihood in the general population. Finally, some genetic tests may lack solid scientific validity, whether due to the state of the science or the effect of many mutations and environment factors that act in conjunction. For all these reasons, catering the selection of genetic information to the person testing can be as important as regulating the interpretation of the results stage.

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Consent to Arbitration is Not a Health Care Decision: South Carolina Supreme Court Invalidates Nursing Home Arbitration Agreement Executed by Health Care Surrogate

coleman_carl_lg2Nursing homes commonly include arbitration agreements in their admissions materials. These agreements require residents to bring any disputes against the facility to a professional arbitrator, as opposed to a court. Many advocates maintain that arbitration disadvantages nursing home residents, particularly in malpractice cases, and that their use in the admissions process takes advantage of a vulnerable population. Nonetheless, efforts to challenge such agreements have failed in light of the Supreme Court’s decision in AT&T Mobility LLC v. Concepcion, which held that the federal Arbitration Act (FAA) preempts state laws that “prohibit[] outright the arbitration of a particular type of claim.” Following Concepcion, the Supreme Court unanimously overturned a decision by the West Virginia Supreme Court that had found that nursing home arbitration agreements are inherently unconscionable, concluding that “a categorical rule prohibiting arbitration of a particular type of claim … is contrary to the terms and coverage of the FAA.”

Yet, as demonstrated by the South Carolina Supreme Court’s recent decision in Coleman v. Mariner Health Care, Inc., there is still one situation in which nursing home arbitration agreements are open to challenge: when the agreements are signed by a third party appointed to make health care decisions for the patient by operation of law.

Coleman involved a wrongful death suit brought by the surviving sister of a nursing home resident who had been admitted to the facility after already having lost decision-making capacity. The resident’s sister – the plaintiff in the wrongful death lawsuit – signed the admissions forms based on the authority granted to her under South Carolina’s Adult Health Care Consent Act. One of the forms the sister signed was an arbitration agreement.

Denying the nursing home’s motion to compel arbitration, the court concluded that the arbitration agreement was not valid because it exceeded the scope of the sister’s authority under the Adult Health Care Consent Act. According to the Court, the statute specifically limited surrogates’ authority to making health care decisions and associated financial arrangements. Because an agreement to arbitrate was not a health care or related financial decision, it exceeded the scope of the sister’s authority.

The dissent argued that the majority’s decision conflicted with Concepcion because it had the effect of treating a specific type of arbitration agreement – i.e., one entered into by a surrogate decision-maker – as inherently unenforceable. In response, the majority asserted that it was simply recognizing the legislature’s intent to limit the scope of surrogates’ decision-making authority to narrowly defined areas. It other words, the rationale for the majority’s decision was not that arbitration agreements entered into by surrogates are unenforceable because they are specifically disfavored; instead, it was that surrogates may not enter into any agreements that do not directly deal with “health care decisions” or the associated financial costs.

Of course, the majority’s narrow interpretation of the Adult Health Care Consent Act is not the only possible way to read the statute. If the surrogate has the authority to consent to an individual’s admission to a facility, it does not seem like much of a stretch to conclude that this authority implicitly includes all decisions reasonably related to the admission – including those related to how any subsequent disputes with the facility will be resolved. It is true that, in this case, the arbitration agreement was a “separate” document that “concerned neither health care nor payment,” but it could just as easily have been included as a term in the underlying contract for admission. It seems hyper-technical to say that the surrogate’s authority to consent to arbitration depends on whether the agreement is contained in the admissions agreement itself as opposed to a stand-alone document.

Yet, even if the court could have interpreted the scope of the surrogate’s authority more broadly, its decision remains consistent with Concepcion because it does not amount to “a categorical rule prohibiting arbitration of a particular type of claim.” Instead, the court was simply applying the general legal rule that arbitration agreements, like any agreements, must be entered into by an individual with the legal capacity to contract. At least in South Carolina, this means that nursing homes can no longer rely on arbitration agreements for residents who are admitted based on surrogate consent.

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Potential Effects of Clinical Trial Data Sharing on Biopharmaceutical Innovation

P18We are very pleased to welcome Dana Darst, a Master of Science in Jurisprudence candidate in Health Law and Intellectual Property Law here at Seton Hall, to the blog today.

In recent years, biopharmaceutical research and development organizations have established partnerships with academic institutions and start-up biotechnology companies to drive external innovation, complementary to their own in-house advancements in life sciences.  Companies such as Pfizer, Johnson & Johnson and Bayer have opened innovation centers of excellence globally, in start-up biotechnology- and academia-rich hubs such as Boston, San Francisco and Shanghai, as part of an effort to accelerate new product development and commercialization.  

More recently, the industry has commenced driving innovation via sharing clinical study protocols and patient-level treatment information at the request of qualified external researchers.  An objective of this undertaking is to enhance public health via data transparency.  This may increase efficiencies by helping researchers avoid unnecessary use of resources for new studies, when relevant clinical outcomes data exists from previous studies.  In addition, it may reduce risks for future research subjects.

On January 30, 2014, Janssen Research and Development, LLC (a Johnson & Johnson subsidiary) and The Yale School of Medicine’s Open Data Access Project (YODA) announced a pioneering partnership model for sharing clinical trial data.  Under their agreement, YODA will review all clinical trial data requests on Janssen’s behalf, as an independent third-party.  In a press release, J&J’s Chief Medical Officer, Joanne Waldstreicher, MD, stated that their collaboration will “[e]nsure that each and every request for access to [their] pharmaceutical clinical data is reviewed objectively and independently.”  She further stated that “[t]his represents a new standard for responsible, independent clinical data sharing.”  Other biopharmaceutical companies sharing clinical trial data do so by reviewing data requests directly as they are received from qualified external researchers.  Also, some have voluntarily adopted the Principles For Responsible Clinical Trial Data Sharing, jointly published by the Pharmaceutical Research Manufacturers of America (PhRMA) and European Federation of Pharmaceutical Industries and Associations (EFPIA), and implemented on January 1, 2014. 

Under the PhRMA-EFPIA guidelines, “Biopharmaceutical companies are committed to enhancing public health through responsible sharing of clinical trial data in a manner that is consistent with the following Principles”: (1) Safeguarding the privacy of patients, (2) Respecting the integrity of national regulatory systems, and (3) Maintaining incentives for biomedical research.  The guidelines provide a framework for life sciences companies to request patient-level data and study protocols.  Additionally, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have proposed policies to increase transparency of clinical trial data.  As Carl Coleman discussed here, both agencies have addressed the importance of patient and study de-identification.

So, what potential implications might clinical trial data sharing have on biopharmaceutical innovation? The Institute of Medicine (IOM) et al. recently published a report, Discussion Framework for Clinical Trial Data Sharing: Guiding Principles, Elements and Activities, as a framework for further discussion and public comment on how data from clinical trials might best be shared.  It provides four guiding principles for consideration which include (1) respecting individual participants, (2) maximizing benefits to participants in clinical trials and to society, while minimizing harm, (3) increasing public trust in clinical trials, and (4) carrying out sharing of clinical trial data in a manner that enhances fairness. 

The report does not provide conclusions or recommendations, which are expected to be developed and published approximately 17-months from the project’s start in August 2013. However, the IOM Committee, which includes a diverse group of representatives from government, charitable foundations, academia, healthcare institutions and private industry, has posed several potential implications of trial data sharing for consideration. 

Potential Benefits

From a societal perspective, sharing clinical trial data could increase accuracy, reduce bias and provide a more comprehensive picture of a drug’s benefits and risks.  In addition, data sharing could potentially improve efficiency and safety of the clinical research process.  For example, it could reduce potential duplication of efforts and costs of future studies, and help to avoid unnecessary harm to patients.  Furthermore, it may provide additional information to healthcare professionals and patients that can be utilized to make better informed decisions. 

Potential Harms

Alternatively, data sharing could lead to invasions of patient privacy or breaches of confidentiality, which may ultimately harm participants, either socially or economically.  Moreover, it could reduce incentives for study sponsors to invest their limited resources (e.g. time, budget, FTEs) on additional trials, which could ultimately inhibit innovation.  As the IOM Committee explains:

For example, data sharing might allow confidential commercial information (CCI) to be discerned from the data.  Competitors might use shared data to seek regulatory approval of competing products in countries that do not recognize data exclusivity periods or that do not grant patents for certain types of research. 

Conclusion

Sharing clinical study protocols and patient-level trial data could have benefits for society and healthcare, which outweigh the risks.  The IOM is planning to include an analysis of risks and benefits in their final report.  As academic, life sciences and start-up biotech entities increasingly share industry-driven trial data, a prudential approach should be taken to protect the confidentiality and intellectual property of all stakeholders involved.  Specifically, data should be adequately redacted prior to disclosure to eliminate confidential information—as recommended by the EMA and U.S. FDA.  Biopharmaceutical Innovation is driven by authors and inventors that rely on exclusive, protected rights granted for limited times.  As the IOM committee works toward establishing guidelines, adherence to their guiding principles to address these protected rights will be vital.  

To obtain additional information or provide public comments on the IOM project, visit their website at: http://www8.nationalacademies.org/cp/projectview.aspx?key=49578.

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