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Health Literacy as an Ethical Imperative in Clinical Trials

The workshop’s first session featured two keynote speakers who provided an overview of health literacy as an ethical imperative in clinical trials. Barbara E. Bierer, professor of medicine and faculty co-director of the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT Center), offered her perspective on why health literacy matters. Deborah Collyar, founder and president of Patient Advocates in Research (PAIR), then discussed how health literacy helps patients make decisions. The two presentations were followed by a discussion with the audience, moderated by Lawrence G. Smith, founding dean of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and physician-in-chief at Northwell Health.

WHY HEALTH LITERACY MATTERS

Barbara E. Bierer, Professor of Medicine and Faculty Director, Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard

Bierer opened her keynote address by noting that her presentation on why health literacy matters in clinical trials represents the work of about 50 people, and she emphasized that she is “only one spokesperson” for the larger group. The MRCT Center, she noted, is a research and policy center that focuses on “conduct, oversight, ethics, and regulatory environment for clinical trials with the purpose of improving [their] integrity, safety, and rigor.” The MRCT Center pursues this work with academic credibility

and as an independent convener, she added. The MRCT Center facilitates its research and policy efforts by engaging a range of diverse stakeholders involved in clinical research. According to Bierer, those stakeholders include pharmaceutical companies, contract research organizations, academicians, patients, patient advocates, regulatory folks, and others. “We work to create actionable, ethical, and practical solutions,” she said, “and the MRCT Center works to deliver practical tools and resources that individuals can use.”

Bierer noted that the MRCT Center has been focusing on improving health literacy in clinical trials for about 1.5 years, but that the idea actually started several years before that, when the MRCT Center was focused on returning individual and aggregate summary results to participants. “It’s an unmet need,” she said, “and participants really would like to get the results of their clinical trials participation and almost never do.” The MRCT Center team had analyzed the clinical research pathway, noting multiple opportunities for the implementation of health literacy practices ranging from “access and information in advance of anyone getting sick to the end of the clinical trial when [investigators] communicate [the participants’] individual and summary results.”

Health-Literate Practices to Address Disparities and Increase Participant Trust

Bierer set the stage by highlighting that the MRCT Center team hoped to improve the diversity of participants in their trials with health literacy best practices (i.e., sharing information in ways that support understanding and autonomous action). She added, “clinical trials in the U.S. lack appropriate diverse representation and we don’t know the role of health literacy in reinforcing that inequity.” She added that the ethical foundation of clinical research is voluntary and informed consent: anyone who considers entering and then participating in a clinical trial deserves to understand the trial; its goals, risks, burdens, and potential benefits; and the alternatives to participation. Bierer also identified some of the groups who need to “be around the table” when it comes to developing health-literate practices for clinical trials:

• Funders
• Sponsors
• Investigators and study teams
• Individuals representing the Institutional Review Boards (IRBs)
• Potential clinical trial participants
• Families and caregivers of potential participants

All of these groups could collaborate to create health-literate study materials. Bierer added that such a collaboration could increase trust in the system among participants, their caregivers, and their families. When Bierer began working on the health literacy in clinical research project at the MRCT Center, about 50 people volunteered to participate. Bierer explained that the volunteers adopted a “multidimensional” definition of health literacy:

Bierer added that the workshop audience may be more than familiar with the concept that health literacy represents two-sided communication, but it is worth repeating:

Beyond two groups of individuals communicating, there is also a systems problem, she said. Collectively, “we don’t invest in making health-literate communications, training, and education.” She added that the workshop audience had a high level of health literacy expertise, which was often not the case for investigators and research personnel. “Why is that?” she asked, adding:

Bierer noted that equitable access to research is also deeply important. She added that she remained skeptical about the degree to which investigators and their institutions have embraced the health literacy concept, and whether IRBs consider it their responsibility to “provide oversight to health-literate communications.” There are also resourcing implications,

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¹ “Visualization” as referred to in this presentation refers to graphics, images, and clear design strategies to enhance written and verbal content. “Navigation” refers to an individual’s ability to move through a given health care/research system or process.

she added, including time, money, and people, all of which need to be invested into the process of implementing health-literate practices in clinical trials. She continued,

Health Literacy in the Clinical Trial Life Cycle

Bierer said that at the MRCT Center, they think that

Finally, Bierer said, being attentive to health literacy from the beginning supports communication and information sharing at the end of the trial. “You know your target audience by this point,” and would be able to communicate appropriately, she said.

Existing Tools to Improve Health Literacy in Clinical Trials

Bierer highlighted some of the work the MRCT Center had done that focused on access, education, and developing patient-facing materials and resources.

Participant Brochures

Harvard Catalyst has developed 25 brochures for potential clinical trial participants, in 15 languages, which “are all health literate and all reviewed by IRBs and have gone through health-literate sorts of revisions by [patient advocacy] professionals.”² She added that, in order to ensure the translated issues would work well, they collaborated with people who were based in the countries in which the brochures would be distributed. Bierer invited the workshop to review the brochures and make suggestions for improvements or for other brochures to be developed.³

Plain-Language Dictionaries

She also highlighted an existing plain-language dictionary, which was not developed by the MRCT Center but by UnitedHealth Group.⁴ “UnitedHealth Group has done a brilliant job of making a 17,000-word dictionary available—and it’s translated into Spanish and Portuguese. There is no need to reinvent the wheel.” She added that the MRCT Center has begun to invest in developing a suite of terms that are used almost exclusively in clinical trial contexts to supplement existing efforts. In addition to plain language, Bierer noted that numeracy is “incredibly important,” adding, “it’s not just visuals that are easy to understand, like a pie chart.” She added that it included clarifying the relative risk and absolute risk when talking with a clinical trials participant.

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² For more information about Harvard Catalyst, see https://www.catalyst.harvard.edu (accessed August 6, 2019).

³ To read more about the process of developing brochures and other educational materials for research participants, see www.cambridge.org/core/services/aop-cambridge-core/content/view/55A05866C8E3EF81181A311D9382FAEC/S205986611800016Xa.pdf/development_of_a_plainlanguage_library_of_educational_resources_for_research_participants.pdf (accessed October 16, 2019).

⁴ For more information about UnitedHealth Group’s Just Plain Clear^® Glossary, see www.justplainclear.com/en (accessed August 6, 2019).

Health-Literate, Patient-Facing, Patient-Centered Materials

Bierer showed the audience several examples of older consent forms, with dense amounts of small text. She pointed to Merck and Health Literacy Media as leaders in the field of developing patient information materials that are clear and useful. She added that she has seen a rising appreciation of patient participation, of how patient engagement can make clinical trials more patient-centric, and of how patient voices in developing clinical trials matter. She continued, “If you work with the community and use their language, by default you are more likely to be health literate in your communications.”

Potential Systems Changes to Improve Health Literacy in Clinical Trials

Bierer emphasized that health literacy is a responsibility of the entire system, and it is not up to the communicator or patient alone. She added that there is a need for both corporate and individual commitments to communication and patient engagement throughout the process. “Trials are engineered to deliver results,” she said, “and they should be engineered to deliver results that are important to participants, patients, their loved ones, and to society—not because it’s the investigator’s favorite question.”

The process of incorporating health literacy into clinical trials requires dissection, analysis, and reengineering, Bierer said, and that goes beyond simply having plain-language terms, but rather toward their use and meaning in the culture in which they will be used. Bierer suggested that there should be more focus on design, numeracy, visualization, and education and training for all individuals involved in clinical trials. She also named a few factors going forward that would improve the use of health literacy practices in clinical trials:

• A commitment to provide resources required by relevant stakeholders
• Use of tools and resources to decrease the perceived burden of clear communication
• Iterative quality improvement of all materials
• Incentive structures to reward the right behaviors

Regarding the last point, Bierer pointed out that any researchers who start a clinical trial will then add that accomplishment to their curriculum vitae (CV). If a trial is not finished, the participants are put at risk without the possibility of benefit, Bierer said, and the investigator is not prohibited from keeping the clinical trial as an accomplishment on their CV.

Bierer closed her talk with the news that the MRCT Center is developing a website dedicated to health literacy resources for clinical trials, and she invited the workshop audience to collaborate with her team.⁵

HEALTH LITERACY HELPS PATIENTS MAKE DECISIONS: A PATIENT PERSPECTIVE⁶

Deborah Collyar, Founder and President, Patient Advocates in Research

Collyar opened her keynote by offering a “real-world approach” from a patient perspective on what it is like to be involved in clinical trials. Collyar noted that she hoped the workshop would present opportunities to accelerate the availability of information to people at the time they need it, throughout diagnosis, treatments, and clinical trial considerations, and with clinical trial results summaries.

In the “U.S. disease crisis system,” Collyar said, explaining that she thinks the term is more appropriate than “health care system,” each individual is relabeled as a “patient” as soon as they are diagnosed with a medical condition or illness, and the more serious it is, the more acute the difference becomes. From a patient perspective, she continued, “it’s like being catapulted onto a different planet without a roadmap, dictionary, or any type of survival training. You feel totally alone and ill-equipped for what you’re about to hear.”

She added that it is important to know that when someone is diagnosed with an illness or disease, their body often puts them into a physiological, traumatic, stress state that causes both physical and emotional symptoms⁷:

She added that this is why she and her colleagues always tell people to bring another person with them or record their conversation, so they can listen to it alone or with loved ones later and try to process the information. “The more we can help [patients] in that situation, the better,” she said,

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⁵ See https://mrctcenter.org/health-literacy (accessed October 21, 2019).

⁶ This section is based on the presentation by Deborah Collyar, and her statements are not endorsed or verified by the National Academies of Sciences, Engineering, and Medicine.

⁷ See www.medlineplus.gov/stress.html (accessed October 16, 2019), www.apa.org/helpcenter/stress-body (accessed October 16, 2019), and https://store.samhsa.gov/system/files/sma13-4775.pdf (accessed October 16, 2019) for more information about traumatic stress.

“and the more we can help health care providers in that situation, the better.” She added that this would not include distributing medical literature to patients, because it is not helpful—even when the shock wears off, there are too many terms that people do not understand.

Another point that is very important, Collyar continued, is that when someone is finally diagnosed with their final illness or condition, “they have probably gone through many different medical providers and many subspecialties, and may have received diagnoses that were not correct. They may even have been treated for an illness or a condition they did not have. That happens too often.” There are plenty of ways to breed mistrust among oncology patients, she continued. Collyar emphasized that she believes there are myriad opportunities to engage and inform patients about clinical research and clinical trials throughout their diagnosis and treatment experience. But common problems that add to the mistrust of the medical community include medical professionals that

• misdiagnose patients,
• treat patients as data repositories,
• fail to consider what is in it for the patient, and
• fail to consider the significant costs for patients and their families.

She elaborated on her last point regarding costs:

Collyar noted that she has heard of patients being “blamed” for a lack of interest in clinical trials because only 3–5 percent of patients enroll in clinical trials, but studies show that people are interested in clinical research (Anderson et al., 2018; Applied Clinical Trials, 2007; DasMahapatra et al., 2017). Patients are often willing to consider clinical trials as part of their treatment decision-making process, but “very few of them actually go to a doctor who does clinical trials. That’s a large part of the problem.”

The other part of the problem with clinical trial enrollment and retention, Collyar added, is both the limited participant eligibility for clinical

trials, and the number of patients interested in participating compared with the clinical trials that currently exist: there is not a clinical trial to suit the needs of every single patient. If we truly mean to engage and center patients, she said, then “we actually have to start thinking differently about the way we conduct clinical research.”

Words Matter

Collyar emphasized how overwhelming medical information after a diagnosis can be. She noted that while experiencing shock from a serious diagnosis, patients are often also exposed to unfamiliar medical terms and concepts in a short period of time. This common occurrence, Collyar explained, prompted her to develop material for PAIR called “Words Matter,” which highlights terms that are commonly used but may have different meanings outside of clinical settings (see Table 2-1). She asked the audience to consider whether a “negative test” result would be considered good or bad from the patient’s perspective. “If you take a pregnancy test, and you want to get pregnant, is [a negative test] good or bad? If you don’t want to get pregnant, is [a negative test] good or bad? We have to think about that.” Collyar added that there are several terms commonly used in medical settings that do not always mean what patients think they do. “We need to stop saying ‘cure’ until it does mean ‘oh, good, I’m never going to have to worry about this disease again.’”

TABLE 2-1 Words Matter: Differences in Medical/Scientific Terms Among Medical Professionals Compared with the General Public

SOURCE: Adapted from a presentation by Deborah Collyar at the workshop Health Literacy in Clinical Trials: Practice and Impact on April 11, 2019.

“Patients want better treatment, not just more treatment,” said Collyar. Part of better treatment is having answers and plans tailored specifically for them, not just other patients, she added. For example, she said:

Another promising area of treatment is immunotherapies for cancer patients. There is great promise in immunotherapies, Collyar said, but only a minority of cancer patients are helped by them. “We need to set expectations correctly and properly for everyone so we don’t oversell or overhype it. A lot of tumors don’t respond to immunotherapy.” It can be a layer of treatment for cancer patients, she continued, but patients also need realistic expectations. For example, she said, fewer patients experience adverse side effects or adverse events (AEs) from immunotherapy than from chemotherapy (Baxi et al., 2018; Marshall et al., 2018; Puzanov et al., 2017). However, she continued, when patients do experience immunotherapy AEs, “they are horrible.”

Duration of response is another concept that can confuse patients and participants in clinical trials. “When someone hears that they have had a complete response from their cancer treatment, they think they are done. They don’t know it’s defined as a 3-month or 6-month period in the clinical trial. We have to do a better job of explaining what those terms actually mean.”

Collyar noted that she served as co-chair on the Cancer and Leukemia Group B’s Committee on Advocacy, Research Communications, Ethics, and Disparities (CARE) from 1998 through 2010, and helped them create better clinical trials with better results, especially for patients. “Feasibility is a big part,” she added. As patient advocates, “we not only help with that, we also help sponsors understand how to identify and solve some of the issues that patients have, not just for the scientific compound itself.” Collyar has also been involved in developing recruitment plans with regulators and IRBs, helping explain to patient communities what clinical research is and why they might want to consider it. CARE was one of the first groups that advocated for providing participants in clinical trials with their results, doing so in the late 1990s. To emphasize the point that clinical trials need to center on the patient’s perspective, she asked the workshop to say which of the following two statements should be used:

• The patient failed the treatment.
• The treatment failed the patient.

She urged the workshop to avoid using the first option, to avoid blaming patients for the failure of a treatment. “This is more than a semantic exercise,” Collyar emphasized. She added, “We have to rethink the way that we approach medicine and clinical trials if we want to make an impact on how patients feel about them.”

What Patients Want to Know About Clinical Trials

Collyar pointed out that a primary concern for patients is about the feeling of total isolation, postdiagnosis. Medical professionals can help patients understand that they are not alone, that there are others who share their diagnosis, and that there is precedent for participating in clinical research and even what the results of that research have been thus far. Collyar added that clinical researchers and medical professionals should constantly consider questions a patient might ask or help them consider those questions because “ongoing communication is key” (see Box 2-1 for sample questions).

Patients also want to hear about the results of the study they participated in and contributed to. On the topic of plain-language summaries, Collyar expressed excitement about a relatively new regulation from the European Medicines Agency (EMA) that requires the results of each clinical trial carried out in the European Union (EU) to be made publicly available.⁸ Though

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⁸ Clinical Trial Regulation EU No. 536/2014 requires consistent rules for conducting clinical trials throughout the EU and that information on the authorization, conduct, and results of each trial be made publicly available. For more information on the regulation, see https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation (accessed August 29, 2019).

the EMA also uses the term “lay summaries,” Collyar noted that she prefers “plain-language summaries,” because none of the definitions of “lay” identify it as being nonmedical, and several of them are derogatory. She continued, “there is no reason we can’t call it a public trial result summary,” adding that the plain-language element of the summaries is just one part of health literacy. Collyar explained that plain-language summaries represent an opportunity to influence the field and improve the patient experience at large.

Another important concept to consider is the option to switch treatments (also called a crossover) in a clinical trial, Collyar said. This is an important consideration because if a patient is assigned to one arm of a randomized study and their cancer comes back, they could switch to the other arm of the study, ideally without jeopardizing the generalizability or statistical significance of its results. Collyar added that a white paper was published in 2016 describing how to report results in trials that involved treatment switching (Green Park Collaborative, 2016).

What Clinical Trials Should Really Be About

Collyar said crossover designs are just one example of clinical researchers rethinking clinical trial design. She added that the trials should be designed and conducted with clinical use in mind, considering “how patients would actually use this drug.” Although patient-reported outcomes (PROs) started as a means of reporting AEs, Collyar said, they encompass much more than that and should be utilized to reflect more of the patient’s experience in the trial. Collyar added that the U.S. Food and Drug Administration (FDA) and other regulatory agencies have been very receptive to using PROs in the approval process.

Collyar observed that, because of shorter FDA approval cycles for clinical research, there are many more questions left unanswered. Collyar urged clinical researchers to focus on finding ways to answer those questions, even after drugs are commercially available. Lingering questions include the following:

• What are the long-term effects of the drug?
• What kind of regimens are best for the drug?
• Which populations does the drug work in?
• Which subtypes of disease benefit the most from the drug?

Collyar added that patients should also be informed about risk evaluation and mitigation strategies (REMS), and how they can allow drugs to have shorter approval cycles, while reducing the risk of AEs.⁹

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⁹ FDA can require drug manufacturers to develop REMS for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. For more information about REMS, see https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems (accessed August 29, 2019).

Closing her presentation, Collyar asked the workshop to remember what patients, clinical research participants, and health care providers need as four Cs: clear communication of content and context.

DISCUSSION

Including Primary Care Providers

Smith opened the panel discussion by noting that, in his experience as a primary care physician (PCP), PCPs are often shut out of their patients’ entire clinical trial process. He explained that patients had booked appointments to treat symptoms that were actually AEs from a trial, but as their PCP, he was unaware the patients were enrolled in trials at all. At best, this can cause confusion within a PCP’s office, and, at worst, it causes medical complications or mistreatment. He wondered why there were not handouts given to trial participants to share with their PCPs and how to encourage specialists who enroll participants to communicate with PCPs about their patients participating in clinical trials.

Bierer replied that she thought this was a great point, and part of a prior MRCT Center return-of-results project (in which she and Collyar were involved) addressed the disconnect between investigator and health care provider. She noted that early and constant communication to the provider is important, with the participant’s consent, especially because trial results take significant time to become available. Because of this, investigators can have trouble identifying and contacting the participants after the study, she added, at a time when many participants have returned to the care of their PCP. And if investigators cannot contact their participants with results, there is only a slim chance they will be able to contact the participants’ PCP unless communication had already been established. Improving multiparty communication deserves “significant study, dissection, analysis, and the establishment of whether there are tools we can make available now,” she said.

Bierer noted that some trials are now conducted in communities with PCPs as investigators. On the one hand, this keeps PCPs connected to their patients’ experiences; on the other hand, it raises a set of ethical issues. However, Bierer said, “we need a system where there is both communication and knowledge.”

Collyar agreed and added that most patients want their doctor to know that they are participating in a clinical trial, and most want to continue to see the PCP they have built a relationship with over a course of years. She noted, “We have to make sure that information is available in both directions.”

Engaging Stakeholders During Clinical Research

Terry C. Davis from the Louisiana State University Health Sciences Center in Shreveport asked the panelists about their takeaways regarding stakeholder engagement. As the co-chair of a stakeholder engagement group on a particular clinical research project, she asked, “what is the best way to involve stakeholders, and how often?”

Collyar noted that investigators seem to think about “the patient” as a single person, when in fact “there is an entire spectrum, of ages, experiences, cultures, and issues” among patients. “My dream,” she added, “is that we actually are able to use clinical trial results in a way that makes our new trials better (including adaptive clinical trial design), so that we’re raising the bar on better designs and helping to build better results and impacts for patient communities as new drugs are developed.”

Bierer added that not enough is known about stakeholder engagement, particularly in trial design. She noted a few questions she thought should be answered:

• How many patients should be consulted on trial design?
• How many focus groups would you need to conduct?
• Is the focus group diverse enough?

She added that materials are often reviewed by trial participants but only initially, and then the iterative process stops, although she believes it could be continually improved and tailored.

Education and the Informed Consent Process

Michael McKee from the University of Michigan Medical School noted that the deaf and hard-of-hearing communities and, more broadly, people with disabilities, are all at a disadvantage with regard to accessing information available to the mainstream population. Accordingly, he posed two questions to the panelists:

1. Could you highlight or provide some examples of what has worked in your communities on the educational part before you delve into the consent process?
2. Could you share some examples of different methods of informed consent education—audio, visual, written—that have worked and which approaches might be ideal to use?

Bierer responded first by noting that her experience in this area was anecdotal and not endorsed by any employer or university. If you are ask-

ing how to do informed consent well, she said, it is important to appreciate that developing informed consent documents is a serious process. She added that participants may understand one part of an informed consent document initially, and, as the trial proceeds or their participation proceeds, they may recognize the significance of another part of it. As an investigator, she said, “I see it as an ongoing responsibility” to maintain open communication with any participant, to allow any question to be raised at any time in the trial. One important part of the initial informed consent process, for Bierer, is annotating the original document, pulling out what needs to be said, what needs to be asked about the end of each paragraph, and thinking through, in advance, what reflections a participant would need to give in a “teach-back” setting to document comprehension. Once that information is collected, investigators can develop a script to engage with participants about the subject.

Bierer noted that a principle oversight responsibility of IRBs is to monitor and review consent processes, conversations, and documents, although she has seen few consent interactions actually monitored by an IRB professional. She also noted that McKee’s question brought up the broader issue of the inclusion of marginalized communities in clinical research. Some of those groups that tend to be excluded are people with disabilities, she said, as well as rural communities and Native American communities.

Bierer added that cultural competence should be prioritized among researchers, including having adequate translation and interpretation services, and developing culturally appropriate educational materials.

Collyar noted that therapeutic misconception is also a hurdle when it comes to informed consent. Patients do not see the informed consent process in the same way the research community does, she said, and patients do not necessarily understand the difference between participating in a clinical trial and choosing a treatment that is already available. She also noted that the way this issue has been approached has been unsuccessful—the “misconception” is actually in the research world, because, for the patient, it is actually their treatment.

Patient Safety and Health Literacy in Clinical Trials

Jay Duhig from AbbVie Inc. asked how to help people understand the difference between research and treatment. He cited an issue among some trial participants: clinical research documents instruct participants to tell their study doctor if they experience a certain side effect. Duhig explained that no matter how “health literate” the material is those participants understand that if they report that specific side effect, their treatment will be discontinued. In some cases, participants believe that their treatment from the trial is their best chance for managing their disease, which means that they will not always report a serious side effect if they think it means they will lose the treatment altogether. Duhig continued, “how do we address that from a patient standpoint?”

Addressing therapeutic misconception is a major issue, Collyar agreed. She hears frequently that patients go to their study doctors and “put their best foot forward,” describing certain symptoms or side effects they might be experiencing. She added that this is another important reason for having a trusted family member or friend accompany the patient to doctor visits, because they can help create a clearer picture for the study team.

Collyar admitted she was unsure about how to solve the issue, but emphasized that clear communication and expectations were paramount, because patients’ understanding that their safety is the highest priority can help frame the way they think about clinical research. She also reiterated how PROs become more important to help resolve these kinds of issues.

Bierer agreed with Collyar and said she thinks setting expectations with participants is often difficult. She wondered if exploring anonymous reporting in a different way might be useful, adding that some patients already use social media in ways that affect their inclusion, exclusion, and/or retention in trials.

The Role of Support Groups in Patient Decision Making

Linda Harris from the U.S. Department of Health and Human Services’ Office of Disease Prevention and Health Promotion posed the final question of the panel. “I wanted you to talk about the role of support groups in helping patients make decisions about their clinical trial experience,” she said. “Are they friends of those of us who are advocates of health literacy? Could they be recruited to be more helpful?”

Collyar said she thought they could be useful and certainly could be recruited to be more helpful. She noted that the AIDS movement in the early 1990s taught many patients to organize and become activists for their own health. While companies may not allow support groups because of potential bias, Collyar said, patients are talking anyway. “Why not have some

control over the discussion that is already there to make sure it’s accurate and useful and constructive?” She added that it could debunk some of the urban legends, like “don’t tell your doctor about your side effects or you’ll be taken off treatment.” Collyar said, “That’s real in the patient world; many think that.”

REFERENCES

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