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Translational Science, DNA Commercialization, and Informed Consent: The Need for Specific Terminology, Insights from a Review of H3Africa Projects

In the past decade, there has been an acceleration in genomic research, its applications, and its translation into healthcare products and services for the benefit of public health. These advances are critical to realizing the potential of genomic research for facilitating improved health and disease prevention, diagnosis, and treatment. Despite its tremendous opportunities, the dynamic and increasingly global landscape of genomic research commercialization has been accompanied by a variety of ethical challenges and concerns. The potential for unauthorized use of DNA samples from African people to develop a DNA chip amplifies discussion on the meanings, implications, and impacts of commercialization, benefit sharing, and appropriate consent in genomic research. Leadership of the Human Heredity and Health in Africa (H3Africa) Consortium convened a panel of experts to review research ethics practices employed in H3Africa Consortium projects and make recommendations regarding commercialization. Eighteen investigators submitted documents for projects involving data sharing and use of genetic information. A total of 39 informed consent documents associated with the 18 projects were reviewed. All 18 projects specified that samples would be used in future research. Less than half of the projects included language noting that samples could be used in drug or product development, that DNA samples would not be sold, and that profits would not be shared with participants. Four projects referred to commercialization. Analysis of information included in consent documents contributed to the development of a Commercialization Typology. The Typology identifies factors to consider regarding acceptability of particular instances of commercialization. DNA samples for translational research in product development require a transparent commercialization framework to inform the consent process.


Introduction
Over the past decade, there has been an acceleration in genomic research, its applications, and its translation into healthcare products and services for the benefit of public health. These advances are critical to realizing the potential of genomic research for facilitating improved health and disease prevention, diagnosis, and treatment. DNA microarray chips, which contain thousands of DNA sequences, increase researchers' capacity to identify gene sequences associated with particular diseases and to develop pharmaceuticals. The creation of DNA chips require samples from large numbers of individuals and populations. An important goal of scientists is to expand representation of diverse populations in creating DNA chips to enhance the potential for scientific advances and public health improvement. Achieving this objective has implications for the collection and use of DNA samples from populations in low-and middle-income countries (LMICs). Thus, despite its tremendous opportunities, the dynamic and increasingly global landscape of genomic research commercialization has been accompanied by a variety of ethical challenges and concerns [1][2][3][4][5].
Recent reports of alleged unauthorized use of DNA samples from hundreds of African people to develop a DNA chip [6] have reignited discourse on the meanings, implications, and impacts of commercialization, benefit sharing, and appropriate consent in genomic research. These reports have also amplified attention to protocols and procedures for consenting participants into largescale global projects that are likely to generate commercial resources or products. The term "commercialization" is open to different interpretations, leading to potential divergence in understandings when the term appears in a consent form. In particular cultural contexts, the concept of commercialization may be inseparable from the idea of money changing hands suggesting that samples are bought and sold. This illustrates the important role that perception plays in someone's understanding of reality. At one extreme, the very idea of commercialization may produce a negative reaction, as when it is considered to involve making profits, likely at the expense of others, where the loss may be not only financial but possibly damaging to a group's self-identity. Hence, it may be associated with the concept of exploitation. There are examples of situations where this has occurred historically [7,8]. At the other end of the spectrum, commercialization may be a necessary means toward a public good. Drugs and vaccines, for example, require investment in research and clinical trials. Commercialization could be one way of distributing benefits. Questions about fairness in the distribution of benefits remain. In between these 2 ends of the spectrum, there are contested areas over the distribution of benefits [9][10][11]. The potential for exploitation exists in the area of benefit sharing and reciprocity. For example, commercialization of DNA chips by pharmaceutical companies to produce medicines may result in these products only being available in wealthier countries rather than LMICs. Additionally, investigators who collect samples from donors in LMICs may have concerns about giving them to companies from industrialized nations because they are unsure if they will be able to benefit professionally in this transaction. Scientists from LIMCs may not have the scientific infrastructure or capacity to develop applications from DNA chips.
The Human Heredity and Health in Africa (H3Africa) Initiative, established in 2012, facilitates research into diseases on the African continent and develops infrastructure, resources, training, and ethical guidelines to support a sustainable African research enterprise. Because of the vast amount of genetic diversity in African populations, H3Africa provides an unparalleled research resource for the benefit of people in Africa and across the globe. Data sharing is a guiding principle for H3Africa, and the translation of research findings to commercial products and resources is consistent with its mission.
There is a growing literature on applications of informed consent processes for genomic research implemented in African settings [12][13][14][15][16][17][18][19][20][21], including establishment of and governance for biobanks [22][23][24][25][26][27][28][29]. The H3Africa Guideline for Informed Consent (https:// h3africa.org/) describes challenges surrounding the implementation of consent for genomic research, highlighting concerns about literacy skills, decisional authority to provide consent, and variability in national policies that may impact implementation of informed consent for genomic research. The H3Africa Guideline for Informed Consent suggests that broad consent, in which potential participants give permission to share stored genetic material with other investigators for future unspecified research, is preferred for genomic research in African settings. While broad consent reduces complexities associated with tiered consent, in which potential participants are offered choices about storing, using, and sharing specimens and data, challenges remain. There are concerns that it may reduce the ability of participants to indicate particular choices, especially in population groups whose autonomy may already be compromised by some form of vulnerability [30][31][32][33]. A recent report commissioned by the African Academy of Sciences and the African Union Development Agency suggests that a tiered approach to informed consent may be preferable in African settings [34]. Regardless of whether broad consent or tiered consent approaches are used, clarity and comprehension are key factors for achieving the potential translational benefits of DNA commercialization. DOI: 10.1159/000521371 Methods Driven by a commitment to transparency and accountability, the H3Africa Administrative Coordinating Center (https:// h3africa.org/) convened a panel of experts (R.C., P.M., and C.D.M.R.) to review research ethics practices employed in the H3Africa Consortium projects and make recommendations for improvements with regard to commercialization. The panel was asked, in consultation with members of the H3Africa Consortium, to review policies for data and biospecimen access and H3Africa consent forms and determine how projects have implemented informed consent procedures for studies involving biobanking and sharing data and/or biospecimens.
The H3Africa Administrative Coordinating Center (https:// h3africa.org/) asked H3Africa investigators to submit informed consent documents for their projects. Eighteen investigators submitted documents for projects involving data sharing and use of genetic information (Table 1). Qualitative analysis was employed to identify language included in consent forms on data sharing and data use.
We developed a Commercialization Typology to frame the findings and recommendations. Communications with Consortium members provided context for the entire project, particularly the interpretation of findings from the consent review process. Careful examination of H3A Guidelines and policies pertaining to data and biospecimen access was a critical element of our work (http://biorepository.h3africa.org). Our review of consent forms and other research documents submitted by the subset of 18 investigators for H3Africa projects represents the heart of the report we prepared, "H3Africa Report on Commercialization and Informed Consent," available on H3Africa's website (https://h3africa.org/). Our report focused on ethical questions concerning commercialization of data and/or biospecimens. While there are many legal issues raised by commercialization, these were beyond the scope of our report.

Results
A total of 39 informed consent documents associated with the subset of 18 H3Africa projects were reviewed: 27 Adult Consent Forms, 8 Child Assent Forms, and 4 Information Sheets ( Table 2). All 18 projects specified that samples would be used in future research. Seven (38.8%) of the 18 projects suggested that the samples could be used to develop drugs or other products (Table 3). In describing future use of samples, 4 (22.2%) of the 18 projects referred to commercialization ( Table 3). The term "commercialization" was not defined in the documents when it was used. Six (33.3%) of the 18 projects said explicitly that DNA samples would not be sold, and 6 (33.3%) indicated that profits would not be shared with the participants ( Table 4).
Analysis of the H3Africa consent documents contributed to our development of a Commercialization Typol- ogy to clarify possible meanings of commercialization and to identify associated issues of concern. An obvious starting point might be that the word "commercialization" conjures up an image of buying and selling. While selling may be a mode of commercialization in the pathways from research to product development, there are others to be considered, such as investment. Moreover, attitudes toward commercialization may depend on what exactly is commercialized: for example, how different bodily tissues (e.g., blood) are regarded as having more or less importance. Also, the identity of the different parties involved, and the balance of power between them, may affect how we regard commercial transactions.   The vertical columns in the typology describe different modes of commercialization. What type of commercial engagement is proposed? A potential monopoly of ownership of the results of research? Or a situation in which a commercial company is offering to invest in infrastructure for research or future health care, for example, by financing laboratories or treatment facilities? A partnership is an arrangement between parties whereby they agree to cooperate to advance their mutual interests, sharing in both responsibilities (e.g., contributing something of value) and benefits. This is achieved by constructing a trust-based agreement "to share the benefits of research in meaningful ways and ensure …incentives are aligned so that we can succeed together" [35]. A preparatory period of transparency and consultation about what is important to the different parties is a prerequisite.
The horizontal columns illustrate various modifiers of potential commercial engagement. For example, what type of company is involved? Not all companies are thought to have good reputations, whether justifiably or not, in particular cases. Another question concerns consequences in the longer term. Who will the end users be of any resulting product: the source population and/or others? What are potential harms or benefits that may accrue to the source population? Is there a benefit-sharing plan in place? Infrastructure to support scientific translation of DNA samples and data for population health is a theme that cuts across all of these questions in the Commercialization Typology; therefore it was not included as a separate component. Similarly, some themes, such as intellectual property and conflicts of interest, are also relevant across all questions raised in the Commercialization Typology and have not been included as separate items.
Although the typology does not weigh different factors, there are some guiding principles to take into consideration about priorities. First, while this typology could be used in different settings, there is a need to ensure that any instance of commercialization does not conflict with overarching aims (in our case, those of H3Africa). Second, specific consent to commercialize (or not) is widely acknowledged to override other considerations. Difficulties arise when such consent is either silent on commercialization issues, e.g., in legacy collections, or insufficiently clear. These situations will require deliberations and actions relevant to each case. The typology we present thus has implications for the design of consent forms going forward, in terms of the need for specificity, and this point informs our recommendations.

Conclusion
The commercialization typology highlights the complex range of meanings associated with "commerce." Rather than a polarity, issues surrounding commercialization fall along a continuum between exploitation and shared benefit. Our analysis of the informed consent documents suggest clarity is needed about sharing genetic samples. Less than half of the 18 projects indicated on consent forms that genetic samples would not be sold, and that participants would not share in the profits from drug or product development. Moreover, only 4 of the 18 projects used the term "commercialization." Our recommendations are as follows: 1. Standardized language for concepts such as selling and profiting in relation to commercialization is needed 2. Consent forms need to be explicit about researchers not selling samples and participants not profiting 3. Investigators should refrain from using the term "commercialization" without specificity 4. Community engagement for studies involving the sharing of biospecimens and/or data should include conversation about commercialization 5. Empirical research is needed on perspectives of diverse stakeholders regarding commercialization 6. A global framework is desirable to guide commercialization processes