Not Lost in Translation: ISSCR Guidelines 2016

by Alexey Bersenev on May 15, 2016 · 0 comments

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One of the biggest news this week was a release of final updated 2016 version of the Guidelines for Stem Cell Science and Clinical Translation (you can download pdf version here). Everyone who involved in stem cell research and/ or clinical translation of stem cell-based interventions should read this document! I think, ISSCR did a great job in getting this information together thorough task force of 25 experts and feedback from 85 external consultants. There was a public commenting period, so, everyone had an opportunity to contribute to the guidelines development. Importantly, new ISSCR Guidelines include a number of controversial issues, which were not previously covered comprehensively, such as gene editing of human embryos, mitochondrial replacement therapy, donor consent for pluripotent stem cell banking, patient sponsored and pay-to-participate trial and other topics.

A few general comments:

  1. There is no clear scope in the Guidelines. So, sometimes it is not very clear to what category of “stem cell stakeholders” does it apply. The Guidelines indicate that “code of conduct applicable to all researchers in the field”. But what about patients and advocates, industry professionals, regulators and policy makers, communicators and physicians? The Guidelines frequently calls for collaboration of all stakeholders, but specifically written for stem cell researchers.
  2. It is not very clear to me if the Guidelines apply to all types of stem cells. When I was reading it I had a feeling that the whole document was written with pluripotent stem cells (iPS/ ES cells) in mind. Some statements and recommendations may not be applicable to adult stem cells in general or to minimally manipulated cells, for example (emphasis mine):

    Recommendation 3.2.2.2: Risks for tumorigenicity must be rigorously assessed for any stem cell-based product, especially if extensively manipulated in culture, genetically modified, or when pluripotent.

    So, if I have subset of CD34+/CD45RA- cells, freshly isolated from apheresis and infused within few hours, why ISSCR wants me to do tumorigenicity studies? FDA will be fine without it.

  3. Lack of definitions. One of the most frequently used in Guidelines term “stem cell-based interventions” begs a definition. “Stem cell-based product” is not defined as well. It is missing, even in glossary section. What is “stem cell intervention”? Is administration of bone marrow mononuclear cell fraction in myriad of diseases stem cell-based intervention? Some developers say yes, some – no. It will be good to know ISSCR position on it.
  4. Cell processing and manufacture section mostly describes current regulatory requirements, some of which are not even guidelines, but laws. I think, in this case would be better just refer directly to particular FDA/EMA documents, where cell manufacturing requirements outlined much better.
  5. ISSCR is very very critical of (1) patient-sponsored and pay-to-participate trials and (2) clinical translation via medical innovation, but the ISSCR may be (rarely) OK with it in certain situation with number of conditions. So, the Guidelines are not very permissive, but not totally prohibitive for these controversial things.

Now I’d like to share some quotes and my thoughts about new topics from the document, related to transparency, data reporting and communication. Let’s start from transparency:

Researchers and clinicians pursuing stem cell research should promote timely exchange of accurate scientific information to other interested parties. Researchers should communicate with various public groups, such as patient communities, to respond to their information needs, and should convey the scientific state of the art, including uncertainty about the safety, reliability or efficacy of potential applications. Researchers and sponsors should promote open and prompt sharing of ideas, methods, data, and materials.

That’s exactly what stem cell researchers do not do or do very badly right now. They do not promote exchange of information to another parties, they do not communicate it to anywhere, unless asked by mass media, journalists or institution’s PR office. Will stem cell researchers change with this Guidelines?

Next quote (emphasis mine):

Accompanying the enormous attention paid by the media and the public to cellular therapies is the problematic trend towards initiation of clinical application and trials far in advance of what is warranted by sound, rigorous, and dispassionately assessed preclinical evidence.

So, too much attention from public is problematic for stem cell researchers, because they feel pressure to start trials earlier than evidence of benefit are available. The blame on public pressure, not on researchers themselves. Don’t they want to be the first, have a “scientific glory”, enjoy grants money and attention? And what about regulators safeguard, who gives “green light” to the trials? Next quote from section 3.5.2:

The stem cell research community benefits from providing patients and the general public access to scientific information, opportunities to participate in clinical research, and treatment.

So, public attention could be problematic, but it is beneficial for stem cell researchers. Next, the series on communication-related things that stem cell researchers do not do:

The research community is encouraged to engage interactively with the public through responsive outreach and communications and by providing opportunities for public comment and feedback.

Researchers should make efforts to seek timely corrections of inaccurate or misleading public representations of research projects, achievements, or goals.

For the first time ISSCR provides recommendations on how to not hype your research:

… forward-looking statements on inherently uncertain developments, such as predictions on time required until clinical application, the likelihood of product approval, or speculation on the potential economic impact of currently unrealized technologies, must be accurate,circumspect and restrained.

For potentially sensitive or high-profile cases, it is advisable to seek additional comments from independent experts to ensure objectivity and balance.

Clinical trials designed to evaluate safety and/or efficacy should not be described using language that might suggest the primary intent to be the delivery of care, as this may lead to confusion about the risk/benefit profile of study participation (see also Recommendation 3.3.3.1). Communications about ongoing studies should explain that clinical efficacy is not established, and that the results may reveal the intervention to be ineffective or, in some cases, harmful.

Now, I’d like to bring your attention to transparency and results reporting. Trials registration and adverse events reporting are not only signs of transparency (as per Guidelines), but also regulatory requirements.

Preclinical studies—at least those that are aimed at confirming the core principles and hypotheses underwriting a development program— should be reported in full regardless of whether they confirm, disconfirm, or are inconclusive with respect to the hypothesis they are testing. The guidelines recognize that publication may reveal commercially sensitive information and therefore acknowledge that a reasonable delay is permissible to secure appropriate protections of intellectual property. Nevertheless, preclinical studies supporting a trial should be published before the first report of trials.

Recommendation 3.3.7.3: Researchers should promptly publish aggregate results regardless of whether they are positive, negative or inconclusive. Studies should be published in full and according to international reporting guidelines.

Journal editors should accommodate publication of inconclusive and disconfirmatory findings.

Not really happening now… We see publications of negative or inconclusive results very rarely.

My favorite statement on transparency:

Researchers and sponsors should promote open and prompt sharing of ideas, methods, data, and materials.

There is no “open and prompt sharing”! Closed access/ paywalls to publication is prohibiting it. Patents/ IP are prohibiting it. Publishing culture and “fear to be scooped” is prohibiting it.

ISSCR, as did many other organizations in the past, calls for cooperation and collaboration on development of (1) all kind of standards, (2) clinical safety/ outcome registries and (3) public repositories/ banks of stem cell lines:

Recommendation 5.1: Researchers, industry and regulators should work towards developing and implementing standards on design, conduct, interpretation, and reporting of research in stem cell science and medicine.

I’d like to conclude on mechanisms of the Guidelines enforcement:

These ISSCR guidelines should be upheld and enforced through standards of academic, professional, and institutional self-regulation.

I was trying to read new ISSCR 2016 Guidelines very critically and thoroughly. It captures almost all broad and controversial aspects of translational stem cell research in very concise way. Overall, it is a great document – must have on your desk.

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