Questions about Deaths in Cancer Trials using Gene-Altered Cells

Posted on Jan 9, 2017

This article was originally posted on The Center for Genetics and Society’s site here.

In the past month, the media has reported seven patient deaths of subjects enrolled in separate gene therapy clinical trials being conducted by Juno Therapeutics and by Ziopharm Oncology, Inc., both aimed at immunotherapy-based cancer treatments that have sparked widespread hope. Despite these deaths, the trials continue to move forward.

Media coverage of trials related to gene therapy has portrayed the clinical research rollercoaster.  Just this past week, The New York Times ran an unusually lengthy and high-profile series of articles in the Sunday paper about immunotherapy treatments for cancer, some involving genetic modification of immune cells. The articles describe the promising aspects of engineering one’s own immune system to fight cancer, including dramatic stories of tumors “melting away” and promises of complete remission.

Yet commentary on the ethical implications of these events has been scant, and these events raise a number of concerns about what bioethicists call “therapeutic misconception” – vulnerable patients seeking enrollment in a clinical trial with the mistaken belief that the gene therapy is approved by the FDA to be safe and effective. The clinical trial deaths also highlight lingering questions about transparent reporting of adverse events to the FDA and appropriately navigating financial conflicts of interest.  Instead, numerous articles have focused on how these deaths impact the bottom line: corporate stock prices.

The excitement has been building for some time. In June 2015, MIT Technology Review described Juno’s experimental T-cell immunotherapy for leukemia as “Biotech’s Coming Cancer Cure” and profiled the “miracle” recovery of 20-year old leukemia patient Milton Wright III. Wright signed up for the clinical trial because “they hyped it up, like it was going to be amazing” and MIT Technology Review has characterized Juno’s immunotherapy trials as “remarkable.”

Some scientists are hopeful for a breakthrough, particularly for patients whose cancer has returned after multiple rounds of traditional chemotherapy. For vulnerable patients seeking a “miracle cure,” such characterizations blur the distinction between approved therapy and clinical research that may or may not produce a viable therapy. As a disclaimer, I have not seen any of the informed consent documents from Juno or Ziopharm. But whatever these documents say, media descriptions of a “coming cancer cure” make it challenging to fully convey the risks to sick people with few other options who are considering enrolling in clinical trials as a last-ditch treatment effort. This is precisely the kind of situation that the term “therapeutic misconception” addresses.

We must cautiously tread when describing Phase I and Phase II clinical trials to patients who are simultaneously acting as research subjects, and take care not to inflate our words when we discuss this research in the media. Despite the misleading name, these early gene therapy trials are not approved therapies, but experiments to assess safety, dosing tolerability, and effectiveness. The goal for this stage of research is not to provide a treatment for this specific person, but rather to contribute to generalized knowledge. It focuses on asking: Will this method of gene therapy work? Is it safe? Are there adverse risks so severe or frequent which constitute an unacceptable level of risk?

It is not clear whether the patients recognize the uncertainty of benefit, especially when measured against the magnitude of risk. Gene therapy poses a distinct, and an arguably riskier, profile of possible adverse effects compared to drugs alone because it can permanently alter the recipient’s cells and holds the potential for severe latent adverse effects such as cancer, immunologic, neurologic, and autoimmune complications.

When unexpected serious adverse reactions do occur that are related to the trial, the sponsor must report these to the FDA. Several months ago in May 2016, Juno reported one death to the FDA of a subject who was enrolled in one of its CAR-T protocols for leukemia, asserting: “It is not clear what caused the death, and a change at this time is not warranted.” In July, Juno reported two more deaths, this time stating that they resulted from compounding factors (a chemotherapy drug Fludarabine used in conjunction with the CAR-T protocol). Juno subsequently updated its statement, disclosing there have been four total deaths from its CAR-T protocols.

In response, the FDA temporarily (and very briefly) suspended the clinical trial, causing a fleeting plummet in Juno’s stock prices. Juno quickly submitted a modified protocol that removed Fludarabine, updated the trial brochure, and amended the patient consent form to the FDA. The FDA deemed these modifications acceptable and expediently lifted the hold within days, despite the alarming disclosure. Juno’s trial – and stock prices  – were back in business.  Articles (here and here) characterized these deaths and the corresponding swift response as a “bump in the road,” myopically questioning how it would impact the clinical trial progression and corporate financial outlook. Minimizing patient deaths that may have resulted from the gene therapy rather than their underlying illness is dehumanizing and ethically inappropriate, even if we reason that these patients were near the end of life.

One biotech analyst questioned FDA’s decision to quickly lift the clinical trial hold, observing, “They are trying to referee a game while the rules are still being written. And it appears to be causing some deaths that should have been avoided.”

Ziopharm made similar headlines in the past few months relating to its Phase I clinical trials designed for glioblastoma patients. Ziopharm partnered with the synthetic biology company Intrexon, and has been studying a gene therapy technique using a genetically engineered virus that is directly injected into the subject’s tumor. According to Ziopharm, the third subject died 15 days after beginning the trial of an intracranial hemorrhage. Prior to this report, two other enrolled subjects also died, albeit months after the initiation of one of the trials. According to a press release, Ziopharm maintains the intracranial hemorrhage death “is an isolated case” and the other patient deaths were unrelated, and attributed those outcomes to pre-existing illness, stating, “these patients are all, unfortunately, medically fragile.”

The problem with reporting adverse events, including deaths, to the FDA resides in a substantial loophole that awards discretion to the investigator to decide whether the adverse event is serious and whether it reasonably resulted from the gene therapy. Although the investigator theoretically stands in the best position to sort through the noise of the confounding variables of underlying illness or other drugs the subject may be taking, this nonetheless creates a troublesome reliance upon the corporation whose stock price and profitability are tenuously tied to clinical trial performance. This creates an undeniably powerful motivation to shift the blame of any adverse outcomes.

As Professor Osagie K. Obasogie has noted, profit motives remain entrenched in medical research, which can further complicate relationships where industry and medical care become intertwined. The arrangement between Ziopharm and MD Anderson Cancer Center exemplifies such enmeshment: Ziopharm and Intrexon executed a deal with MD Anderson to provide $100 million in stock, and recently appointed MD Anderson physician Dr. Laurence Cooper as Ziopharm’s newly minted CEO.  Similarly, Science’s recent profile of competitor Dr. Carl June’s work at the University of Pennsylvania also flagged the potential conflict of interest arising from its partnership with Novartis to develop gene therapies for which June would hold a financial stake arising from related patents.

Despite assertions that these relationships will be managed according to institutional conflict of interest policies, such heavy financial ties heighten the stakes and necessarily raise concerns about independent judgment and transparency. The call to uphold ethical tenets of research is nothing new, particularly when there is a frantic competition to bring an FDA-approved product to market. Back in 2007, Obasogie raised similar concerns after a patient death in a gene therapy trial for arthritis: “Time is money; in the rush to get products to market, patient safety can inadvertently take a backseat.”

These vulnerable patients have a stake, too. We must ask the right questions to see whether they appreciate the risks they decide to undertake. We must stop blindly accepting these dismissals of deaths and assurances that conflicts of interests are mitigated, especially when there is so much riding on clinical trials’ success.


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The Problem of Transparency and Human Genome Editing

Posted on Jun 4, 2016


In the past several weeks, human genetic modification has been dominating headlines.  This time, the controversy surrounded the closed door meeting between 130 scientists, attorneys, entrepreneurs, and government officials to discuss the creation of a synthetic human genome.  The project, called “Human Genome Project-Write Testing Large Synthetic Genomes in Cells” aims to synthesize a complete human genome in a cell line within ten years, with the future goal of translating such basic science into clinical applications.  Rather the modifying the human genome through editing technology such as CRISPR, synthetic creation would allow scientists to make extensive and radical changes throughout the genome.


According to one of the co-organizers, Harvard Geneticist George Church, the meeting merely constituted a “thought experiment” and the organizers made an executive decision to close the meeting to the public, asserting they would subsequently publish the discussion from the meeting in a prominent scientific journal that required a pre-publication embargo on publicly sharing the content of the meeting.


Stanford’s Drew Endy not only declined to attend based on the meeting’s intentional secrecy, but posted to his Twitter a copy of the meeting invitation, which stated the organizers instituted the media ban as a mechanism avoid media scrutiny and “to permit attendees to speak freely and candidly.”  Endy, along with Northwestern’s Laurie Zoloth published a response in Cosmos Magazine noting that “when the first people at the table mostly have significant and direct material interests in the proceeding, everyone, not just those in the room, risk out-of-control competition between public and private interests, ethical conflicts of interest, and temptations to manipulate human subject consent.”


Endy advocated for “pluralistic, public, and deliberative discussions” to encourage transparency of purpose and content.  Marcy Darnovsky  from The Center for Genetics and Society posited the meeting served as a step to privatize efforts toward genetic modification.  According to the Center for Genetics and Society, billionaire attorney and entrepreneur Randal Kirk plans to expand his empire of life sciences corporations focused on genetic modification (projects that currently include genetically modified salmon, genetically modified mosquitoes, and human gene therapy research) to include research projects designed to synthetically create human ova and alter the human germline.


We have seen the impact of closed meetings and the power by which interested stakeholders with deep pockets and a vested interest in promoting a technology can direct public opinion like a puppet master through strategic media campaigns, assert “conclusions” professing basis in scientific evidence, proclaim consensus despite the existence of divisive questions within the scientific community, and strong arm regulation and policy without public transparency.  Perhaps most problematically, few members of the public are even aware of this complex history behind the curtain of genetically modified food so eloquently and meticulously presented by attorney Steven Druker in Altered Genes, Twisted Truth In his book, Druker raises several notable points, each of which are pertinent to the discussion relating to human genetic modification: we must analytically examine the current state of science rather than accepting inflated promises, comprehend the danger of failing to consider unintended effects within the organism and its ecosystem, and scrutinize the implication of inherent unpredictability when altering genetic structures.


Indeed, the Committee on Science Technology, and Law Policy and Global Affairs at the International Summit on Human Gene Editing noted that the current gene editing technology CRISPR is highly unpredictable: it can alter DNA at other unintended locations other than its target, which would impact genetic structure and function at other locations on the genome.  This process could activate other genes including cancer causing genes,  inactivate essential genes, or cause chromosomal rearrangements.  One team from Guangzhou Medical University China who conducted gene editing on non-implantable embryos using CRISPR reported dismal preliminary results: only 4 of the 26 embryos the team used produced the desired mutation that scientists believe confers HIV resistance and the embryos demonstrated signs of mosaicism.  Furthermore, Geneticist Eric Lander observed inducing this particular mutation simultaneously confers an increased risk of West Nile virus and aptly summarized: “We are terrible predictors of the consequences of the changes we make…we don’t understand the genome enough to make changes in the long run.”


Despite a United Nations prohibition on the modification of the human genome and other nations that legally prohibit human genetic modification, the US does not have federal regulations prohibiting human genetic modification, whether achieved through genome editing or synthetic human genome creation.  It is also foreseeable that any obstacles arising out of federal funding limitations could be easily circumvented though private funding or successful lobbying to ease or even erase such restrictions.


This weekend at the American Society of Law, Medicine and Ethics Annual Heath Law Professors Conference Law Professor John Robertson repeated Church’s label, asserting that we are likely to see “exciting” efforts to “correct disease” fairly soon but efforts for enhancement are a distant “thought experiment.”  I disagree.   Corporations need not offer perfectly accurate technology, but instead appeal to a market by advertising a product’s technological promise.  As we’ve seen in current genomic technologies, this translates into technology premised upon manufacturer advertisements of accuracy and validity which may or may not produce the desired advertised outcome.


The community of interested stakeholders must rise as a leader to promote thoughtful governance, particularly given the transnational and global nature of this research.  Public transparency of the scientific community’s goals and agendas are imperative given our current juncture-  private corporations are poised to create synthetic ova, presently occurring experiments create chimeras integrating human DNA into animals, and Bill Skarnes of the Wellcome Trust Sanger Institute predicts the utilization of human genetic modification for clinical use in humans within the next five years.  Failing to intervene with prudent regulation at this juncture will have unimaginable and irreversible consequences.



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Media Misstates the Message: Investigate CDC Whistleblower’s Claims

Posted on Apr 22, 2016

Media headlines are abuzz around the decision to pull the documentary Vaxxed: from Conspiracy to Cover-Up from the Tribeca Film Festival.  As a disclaimer, I have not viewed the film.  What is deeply troubling, however, is how numerous media outlets (here and here) have misconstrued the film’s message calling for an examination of vaccine safety and efficacy.  Instead, headlines and news content repeat erroneous assertions that are contrary to scientific evidence and focus exclusively on the controversial Dr. Andrew Wakefield as a red herring. (If you are interested in learning the full story about the Wakefield controversy and the role of the media, you can read it in this book).   Both the science and the law relating to vaccination are nuanced and evolving.  When vaccines go through the approval process at the FDA, approval is premised upon data submitted by the vaccine manufacturer showing that the product is safe, effective, and its benefits outweigh the risks.  Glossing over this complex process and improperly labeling any questions pertaining to safety and efficacy as “anti-vaccine” effectively stunts the scientific process as an evolution and pursuit of developing knowledge.

Based on its website, the film intends to address statements made by Dr. William Thomson PhD, senior scientist at the CDC who revealed he was instructed by fellow CDC senior scientists to eliminate highly unfavorable data from studies they conducted examining links between vaccination and neurological injury.  The conclusions of these studies (DeStefano 2004, Thompson 2007,  Price 2010)  have been widely cited and touted by Dr. Paul Offit MD as “definitive” proof demonstrating vaccine safety.  What did that excluded data show?  According to conversations between Thompson and biology Professor Dr. Brian Hooker PhD, the data demonstrated a substantial differential rate of adverse reactions to the MMR vaccine based on sex and race: African American boys who received the vaccine according to the American Academy of Pediatric Schedule had a 3.4 fold increase in risk of autism.  Barry published a book summarizing conversations he had with Thompson including full transcripts of lengthy discussions related to alleged data manipulation and conflicts of interest between industry and the CDC.  You can read a summary written by attorney Robert Kennedy Jr. JD LLM here and the book containing full transcripts here.

Not only is this statistic alarming, but what’s more concerning is lack of mainstream media coverage and public knowledge of this incident and other information that calls into questions vaccine safety from a variety of angles.    CBS Reporter Sharyl Attkisson has referred to the topic of vaccine safety and efficacy as the “most censored and misreported story of the century.” To find that information requires digging through other media channels, such as Attkisson’s website, attorney Robert Kennedy Jr. JD LLM’s work, MIT Senior Research Scientist Stephanie Seneff PhD’s findings, or assessments by physicians Dr. Mark Hyman MD and  Dr. Kelly Brogan MD.

Combing through the research rather than accepting the common meme reveals numerous safety questions about which there has been no open dialogue pertaining to studies demonstrating: long term central nervous system damage including seizures, learning disabilities, and neurological disorders; an increased risk of severe allergies and asthma; the onset of chronic arthritis; and death.  Further, numerous studies (examples here and here) and federal whistleblower claims against Merck point to compelling evidence undermining assumptions of efficacy and the veracity of manufacturer claims of efficacy prior to FDA submission for approval.  Such evidence threatens the massive profits of the global vaccine market, which constituted estimated $24 billion in 2014 (see here and here).

As New York University School of Law Research Scholar Mary Holland JD has noted, the law recognizes vaccines’ risks despite appropriate manufacturing and administration.  Vaccines are classified as “unavoidably unsafe” products; that is, they will necessarily expose some individuals to risk of injury and death.  In 1986 Congress passed the National Childhood Vaccine Injury Act as a means to shield manufacturers from mounting liability claims via private litigation while compensating victims of vaccine injury.  In 2011,  the Supreme Court in Bruesewitz v. Wyeth held that the Act preempts all design-defect claims against vaccine manufacturers, which precludes injured parties from seeking private remedy from the manufacturer.

In a powerful dissent, Justice Sotomayor stated:

“Vaccine manufacturers have long been subject to a legal duty, rooted in basic principles of products liability law, to improve the designs of their vaccines in light of advances in science and technology… the majority’s decision leaves a regulatory vacuum in which no one—neither the FDA nor any other federal agency, nor state and federal juries—ensures that vaccine manufacturers adequately take account of scientific and technological advancements. This concern is especially acute with respect to vaccines that have already been released and marketed to the public. Manufacturers, given the lack of robust competition in the vaccine market, will often have little or no incentive to improve the designs of vaccines that are already generating significant profit margins.”

Excluding information such as Thompson’s allegations from both public and policy discussions has implications for determining the extent and acceptability of risk for adverse events.  Notably, it also disables consideration of the risk of adverse events based on distinct classes and differential responses based on sex, genetic variation, or use during pregnancy.  FDA’s regulatory structure assumes that until a vaccine is given to the general population, all potential adverse events cannot be anticipated.  Many vaccines undergo Phase IV studies and the FDA relies upon the Vaccine Adverse Event Reporting System (VAERS) to identify adverse events after marketing begins.  According to former FDA Commissioner Dr. David Kessler MD, since VAERS’s inception in 1990 about 35.2 million adverse events have been reported, yet Kessler estimated only this accounts for only 1% of all serious adverse events that occurred.

Without an open and frank conversation about the meaning of evidence demonstrating increased risks or decreased efficacy, we face as a society troubling public health implications for which as Justice Sotomayor warned,  no one will be held accountable.

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Read the Fine Print Before You Send Your Spit to 23andMe

Posted on Apr 7, 2016

Our genomic sequence constitutes the most sensitive and personal of information: uniquely identifying us, revealing our propensity to develop certain diseases and conditions, and exposing familial connections of close genetic relatives. In recent years, Big Data has taken firm hold in numerous sectors, revolutionizing the volume and velocity at which businesses can collect, curate, and use digital information. Consumers can track what they eat, their fertility, whether they are exercising, and how much they are sleeping. Combining these pieces of data with genomic and health information such as family history, health conditions, disease state, and demographic information constitutes a gold mine for scientific research.

23andMe capitalized on the quantified self movement and consumers’ effusive willingness to collect and share personal data, transforming it into a highly profitable venture. Within the past year, 23andMe rapidly reinvigorated its business model, introducing Food and Drug Administration-compliant Carrier Screening Reports as part of its new Personal Genome Service, introduced on online recruitment platform for disease specific research cohorts, and publicized multimillion dollar partnerships with pharmaceutical giants such as Genentech.

In numerous media interviews, 23andMe CEO and cofounder Anne Wojcicki beams with positivity about how this model will revolutionize health care; empowering consumers with an awareness of the secrets of their genome while accelerating the speed of research and drug discovery. As one article in theSan Francisco Chronicle characterized it, “23andMe wants to do for health what Google has done for the search: make massive quantities of information digital, accessible, and personal.” 23andMe made this vision a reality by digitalizing and compiling genotypic-phenotypic data into a searchable format for interested investigators to run queries in its Research Portal, an online searchable database of over genotyped individuals with more than 225 million phenotypic data points, including demographic, clinical information, and family history.

An exciting prospect for research scientists, but also attractive to many other business as well. The sheer amount of information 23andMe’s database makes it appealing to a number of external parties, including data brokers, the pharmaceutical industry, employers, health insurers, and law enforcement. Entities may want to use the data for predictive modeling and draw inferences to market a product, decide suitability for employment, deny life insurance coverage, or target suspects pursuant to a criminal investigation. These uses of the data pose significant informational risks: shame, embarrassment, discrimination, or being subjected to law enforcement investigations. Perhaps surprisingly, many of these secondary uses of the data are currently permitted by law.

Just how much information does 23andMe collect? Much more than consumers may imagine unless they read the fine print. Purchasing the test and submitting DNA creates a potentially indelible electronic record of your genomic sequence in 23andMe’s database, along with a composite mosaic of additional health, lifestyle, and consumer generated personal details. In addition to the information the consumer actively sends, 23andMe employs numerous techniques to collect and track additional details through social media, web beacons, and consumer IP addresses such as compiling personal photos, place of employment, a record of every website the consumer clicks on, and real time tracking of the consumer’s location.  23andMe uses this data internally for marketing purposes and shares the data for research if the consumer provides consent.

But- the fine print also contains a provision that permits 23andMe to unilaterally modify its privacy policy at any time, effectively changing current promised limitations. Wojcicki’s positive intentions aside, she is not the sole party controlling the data. If 23andMe follows in Google’s footsteps, then the private information may not stay private. Indeed, Google Ventures managing partner Bill Maris (a financial supporter of 23andMe) has dismissively challenged, “What are you worried about? Your genome isn’t really secret.” If 23andMe modifies its policy to widely sell consumer data without consent, the lightning nature of electronic data sharing means Pandora’s Box is open.

How is this possible? In addition to expediting the process for research, 23andMe also challenged the traditional regulatory and ethical requirements that ordinarily correspond to collecting and disseminating private genomic and health information. The massive paradigm shift to collecting genomic and health information in the commercial arena, as opposed to the health care setting, means the transaction may occur outside the scope of regulatory structures designed to ensure informed consent when subjects provide DNA and to protect health data privacy.

The HIPAA (Health Insurance Portability and Accountability Act) Privacy Rule does not apply to consumer curation of health data or any associated protections related to privacy, security, or minimizing access. Similarly, unless a commercial entity conducts research that is supported by a federal department or agency, such as NIH funding, regulations set forth in the Common Rule will not govern that entity’s practice. Even though 23andMe receives NIH funding, 23andMe currently asserts that its data-mining analysis does not constitute research on human subjects under the current version of the Common Rule because it de-identifies the data. This stance is significant because it means 23andMe believes any consent it obtains to retain, use, and share consumer data is not necessary for regulatory compliance, but rather constitutes a transactional courtesy.

The traditional informed consent dialogue intended as a means to convey risks and benefits shifts dramatically when the consent process occurs online via consumer interaction with a website clickwrap interface rather than a physical contact person from the research team. Clicking through to purchase the test constitutes an entangled package consisting of a service, agreeing to receive medical information, and research.Recent litigation over 23andMe’s model of presenting its terms reiterates that just because you don’t read the fine print does not mean you can claim those terms are unfair and erase your decision.

Consumers may be blinded by the genomic technological imperative to know and widely share their genetic profile or assuaged by notions of altruism highlighting their contribution to important scientific research. They may bypass reading the fine print, or alternatively, they may not fully appreciate the implications of the transaction. Read the policies closely, and read them carefully, to assess whether the benefits outweigh such looming informational risks.

Read more:http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=7767&blogid=140#ixzz459gNnJck

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