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05/14/2018

Ethical Considerations in the Manufacture, Sale and Distribution of Genome Editing Technologies

by Jeremy Sugarman MD MPH,MA, Supriya Shivakumar PhD, Martha Rook PhD, Jeanne F. Loring PhD, Christoph Rehmann-Sutter PhD, Jochen Taupitz PhD, Jutta Reinhard-Rupp PhD, Steven Hildemann MD PhD

New genome editing technologies are playing an increased role in an array of advanced research and development efforts in the life sciences. In tandem, there has been broad recognition of the need to address the ethical issues associated with the use of these genome editing tools. Although many uses of genome editing technologies do not raise novel ethical concerns, some have rightly attracted considerable attention, especially regarding the possibility of manipulating the human germline (Baltimore et al. 2015; Lanphier et al. 2015). Such concerns have prompted a substantial body of scholarship and high-profile efforts to address these ethics and policy matters (Bonas 2017; German Ethics Council 2016; La Barbera 2014; National Academies of Sciences, Engineering and Medicine, Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations 2017; National Akademie der Wissenschenschaften Leopoldina 2015; Ormond et al. 2017; Reich et al. 2015). While the outcomes of these deliberations offer useful high-level advice, there has been little discussion of the critical ethical issues involved with the practical processes of manufacture, sale and distribution of genome editing technology products that enable this research. Here, we describe these issues and practices being developed and implemented to address them.

Our discussion builds upon the recent experience of Merck KGaA, Darmstadt Germany, a multinational corporation that operates as MilliporeSigma and EMD Serono in the United States and Canada, which is actively involved in discovering, developing, producing, selling and using genome editing tools and technologies.To develop approaches to anticipate and manage the ethical issues emerging in its work the company consulted with its existing Bioethics Advisory Panel (MBAP) that includes an international panel of external experts in bioethics and senior corporate leaders.

 

 

There is an array of products involving gene editing, but only some raise novel ethical concerns during manufacture.  For instance, although the manufacture of basic tools (e.g., chemically synthesized CRISPR guide RNA sequences, CRISPR targeting sequences in a viral format, and libraries for screening and reagents) for scientists engaged in basic research do not raise ethical concerns, these can arise in the customized production of genome-edited cell lines mainly used by drug developers as models for novel drug target screening and validation of mechanisms of action for known genes.

Many of the cell lines currently in use were derived prior to the advent of genome editing technologies, so the possibility of manipulating these cells in such a way was not typically captured in consent processes for the biomaterials used to derive them. However, due to the widespread use of some of these cell lines, and the detailed experimental information that has been gathered about them, these can be the cell lines of choice for experimentation. This poses an ethical question for researchers and suppliers that is redolent of the issues faced regarding the provenance of human embryonic stem cell lines regarding whether it is appropriate to use genome editing in these cell lines.  Therefore, it is important to consider the provenance of the cell lines or biospecimens used by a company to develop a product. Crucial questions regarding provenance include whether consent was obtained at all, and, if consent was obtained, whether it specified research use, and specifically mentioned genome editing and commercial use and/or distribution.  Ifa good-faith effort to protect the rights of the donor can be established based on available evidence such as consent records, the failure of the consent documents to satisfy current consent standards should not necessarily preclude the use of those cell lines on moral grounds (Sugarman and Siegel 2008a; Sugarman and Siegel 2008b).

Accordingly, it is essential that companies manufacturing products involving gene editing technologies examine the provenance of biological materials used in manufacturing to ensure that such uses are ethically acceptable in accord with current guidance, including the recently revised guidance from the International Society for Stem Cell Research (International Society for Stem Cell Research 2016). As appropriate, some uses may require developing new consent agreements for donors of biological materials.  Putting these approaches into practice will require developing formal checkpoints in the product development process requires for assessing consent and documenting it.  Here, companies may benefit from seeking bioethics expertise, either internally or externally. In addition, as experience is garnered with conducting such reviews, consideration may need to be given to developing internationals standards that are tailored to the unique setting of genome editing technologies. Doing so might best involve a multi-stakeholder process involving representatives from industry, academia, bioethics, regulatory authorities and the public. However, this will only be possible and meaningful if companies are able and willing to share information about the nature of provenance assessments in the manufacturing process.

Given that researchers and institutions are primarily responsible for the appropriate end-uses of genome editing products, companies selling these products arguably have an ethical obligation to ensure that purchasers are positioned to conduct ethically sound research. Mechanisms for doing so include ensuring that products are sold to legitimate research organizations and that purchasers agree to the terms and conditions of sale that demarcate a range of ethically acceptable practices.

One safeguard to help ensure that items are sold to legitimate research organizations that is employed involves screening of all new customers. Elements of the screening process include: confirming that orders will be shipped to the laboratory that will be using the supplies; verifying that an appropriate business is located at a new account’s shipping address; ensuring the authenticity of new account holders through credit checks; and verifying that the customer’s statement of intended use matches the company’s type of industry.

Terms and Conditions of sale should specify that the products are intended primarily for laboratory research and are not considered drugs or medical devices.  The specific intended use of the genome editing reagents determines the license that is required. Use of genome editing reagents for research requires a “Licensed Research Use” (LRU) license, which describes the limitations for the use of the product and is often referred to as a “label license”. The label license is the main means to restrict the use of the genome editing reagents to align with the supplier’s standards and purchases would only be dispatched with a label license that outlines the licensed use of the material.

Basic restrictions in a model LRU agreement required for purchase of CRISPR reagents could include:

  • Prohibitions against (a) any clinical use, including, without limitation, diagnostic and prognostic use; (b) any human, veterinary, or livestock use; (c) commercial use; and (d) reverse-engineering of the product in any way or creating any derivatives or sequence variants.
  • Stipulations that licensed products and any related material are used in compliance with all applicable laws and regulations, including—without limitation— applicable human health and animal welfare laws and regulations.

Nevertheless, despite a supplier’s ethical intent and due diligence, it does not have absolute control of the uses or end products once the genome editing tools are provided. Accordingly, broad deliberation is needed about whether means should be developed to monitor the appropriate use of genome editing tools and if so, the extent to which this responsibility rests with industry, scientific professionals, and/or governmental bodies.

The ease with which genome editing can now be performed raises the specter of rogue actors using the technology for nefarious purposes, as has been imagined as a potential use of gene drives (National Academies of Sciences, Engineering and Medicine 2016). Less sensational but much more likely is the possibility of inadvertent negative effects of genome editing on agricultural crops, insect species or even the human population. If an organism with a potential negative impact is inadvertently or deliberately spread, sequence information specific to the strain is critical to taking efforts to develop suitable tracking tools and prevent potential harm. Indeed, the potential for synthetic biology technologies to be misused for bioterrorism, which is arguably an analogous situation,has spurred the development of bioinformatics tools designed to rapidly identify sequences of concern.

The US National Academy of Sciences, Engineering, and Medicine recently published a report on dual use research of concern in the life sciences (National Academies of Sciences, Engineering and Medicine 2017), which concluded that the governmental polices regulating the dissemination of life sciences information with potential negative impact are fragmented and can only be applied to those conducting research with federal funds. This leaves a large segment of the research community (including industry and do-it-yourself researchers) outside the reach of governmental regulations (Deutsche Forschungsgemeinschaft/ Leopoldina, 2014; German Ethics Council 2014; National Research Council (US) Committee on a New Government-University Partnership for Science and Security 2007).

While the International Gene Synthesis Consortiumscreens for sequences relevant to bioterrorism organisms, CRISPR gRNA sequences are too small to be screened effectively with current technologies. Nevertheless, industry could play an important role in developing appropriate oversight mechanisms. Doing so might reasonably start with convening a supplier industry group that includes academic thought leaders as advisors. The goal of such a group would be to develop a common stance on bioethical responsibility and ways to support the responsible sale of genome editing products.

A Call to Action

Companies that develop and distribute tools for genome editing have a responsibility to construct and implement policies and procedures to protect the integrity of science, to educate their employees to make certain that all research conducted within the company adheres to the highest ethical standards. Given the nature of these issues, finding appropriate ways of incorporating bioethics expertise will be crucial. Doing so might take any number of forms that are used in the corporate sector for obtaining such expertise including internal staffing, ad hoc consultation with external experts, using standing advisory boards (Van Campen et al. 2015), or a hybrid approach (Caplan et al. 2018). Regardless of the particular approach adopted, it is essential that these mechanisms are appropriately structured (Brody et al. 2002).  In addition, given the nature of the ethical issues associated with genome editing, companies should consider developing and engaging inter-industry collaborations to ensure best practices are developed and followed. However, companies alone are unlikely to be able to manage all ethical concerns regarding whether genome editing tools and products are appropriately used and to determine whether a system to monitor uses should be developed and implemented. Nevertheless, they can and should be part of efforts to examine such issues. Similarly, they must be part of the evolving policy discussion of ethically appropriate uses of genome editing if they are going to be comprehensively addressed.


DISCLOSURES

Steve Hildemann – Chief Medical Officer (CMO) and Employee at Merck KGaA in Darmstadt 

Jeanne Loring – Advisor on the Merck KGaA, Darmstadt, Germany Bioethics advisory panel. For this manuscript, I acted as an independent scholar and did not receive payment for my contribution.

Christopher Rehmann-Sutter – In my role as advisor on the Merck KGaA, Darmstadt, Germany Bioethics Advisory Panel, I acted as compensated private consultants. For this manuscript, I acted as independent scholar and did not receive payment for my contribution.

Jutta Reinhard-Rupp – Employee of  Merck KGaA

Martha Rook – Employee of MilliporeSigma (A business of Merck KGaA, Darmstadt, Germany) and  board member of the Alliance for Regenerative Medicine.

Supriya Shivakumar – Employee of MilliporeSigma (A business of Merck KGaA, Darmstadt, Germany) and corporate advisory board member of the RNA  Institute, University of Albany, NY 

Jeremy Sugarman – Member of Merck KGaA’s Bioethics Advisory Panel and Stem Cell Research Oversight Committee for which I receive consulting income; for this manuscript, I acted as an independent scholar and did not receive payment for my contribution.  I am also a member of IQVIA’s  (formerly Quintiles) Ethics Advisory Panel and  receive consulting income.

Jochen Taupitz – Advisor on the Merck KGaA, Darmstadt, Germany Bioethics Advisory Panel. For this manuscript, I acted as independent scholar and did not receive payment for my contribution.

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