8
Key Themes, Challenges, and Opportunities

Over the course of the workshop, participants noted many potential uses of biomarkers, recognizing both their promise and limitations. Discussion of and reaction to the committee’s report coalesced around a few important topics, including

  • The structure and usefulness of the biomarker evaluation framework;

  • The value of biomarkers and surrogate endpoints;

  • Considerations in the food and nutrition settings; and

  • Communication of information to consumers and medical professionals.

BIOMARKER EVALUATION FRAMEWORK

Many speakers noted the importance of a biomarker evaluation framework across product areas. For example, Andrew Shao said that an absence of an accepted framework has limited the amount of research conducted on the role of diet and nutrition in health promotion and disease prevention: “We anticipate that a formal biomarker evaluation process will add clarity to product development, as companies that choose to invest in research will have a better understanding a priori that the research will have broader acceptability and applicability to public health recommendations.” Stephen Williams said that the pharmaceutical industry wants a consistent, transparent biomarker evaluation framework that



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8 Key Themes, Challenges, and Opportunities Over the course of the workshop, participants noted many potential uses of biomarkers, recognizing both their promise and limitations. Dis - cussion of and reaction to the committee’s report coalesced around a few important topics, including • The structure and usefulness of the biomarker evaluation framework; • The value of biomarkers and surrogate endpoints; • Considerations in the food and nutrition settings; and • Communication of information to consumers and medical professionals. BIOMARkER EVALuATION FRAMEWORk Many speakers noted the importance of a biomarker evaluation framework across product areas. For example, Andrew Shao said that an absence of an accepted framework has limited the amount of research conducted on the role of diet and nutrition in health promotion and dis - ease prevention: “We anticipate that a formal biomarker evaluation pro - cess will add clarity to product development, as companies that choose to invest in research will have a better understanding a priori that the research will have broader acceptability and applicability to public health recommendations.” Stephen Williams said that the pharmaceutical indus- try wants a consistent, transparent biomarker evaluation framework that 

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 BIOMARKER AND SURROGATE ENDPOINT EVALUATION would enable drug companies and regulators to decide what level of evidence may be required for a particular biomarker application, and acknowledged some aspects of the committee’s recommended frame- work were steps in the right direction. Jack Zakowski agreed with the committee’s biomarker evaluation framework, especially the focus on the interdependence of the three steps of the framework, and Guy Johnson noted that the framework was comprehensive. While there was general agreement on the need for a biomarker evaluation framework, several speakers expressed differing opinions on specific aspects of the frame- work and its implications. James Mayne and Dr. Williams were concerned that the report did not specify criteria that should be applied to biomarkers at each step of the evaluation framework. “I eagerly tore through the document … look- ing for the actual elements of the decision framework, by what criteria would decisions be made in the regulatory space,” said Dr. Mayne. “That was not provided, at least not in the detail I was looking for.” John R. Ball noted that the committee didn’t view their recommendations as the last word in biomarker evaluation but as a fulfillment of their charge to develop a framework for biomarker evaluation across the Food and Drug Administration (FDA) regulatory spectrum. He added that although the Center for Food Safety and Applied Nutrition’s (CFSAN’s) work would be simplified if the Institute of Medicine (IOM) committee had developed a five-item checklist of criteria that every biomarker used in a health claim had to fulfill, the committee found this notion unrealistic. Given limited understanding of chronic disease and the biological significance of existing biomarkers, the committee concluded that evaluation must be conducted by expert panels on a case-by-case basis, Dr. Ball said. For further discussion of the committee’s evaluation framework and related recommendations, see Chapter 3 of its report (IOM, 2010). The effect of the biomarker evaluation framework on innovation gen- erated additional discussion. By employing a rigorous biomarker evalu - ation framework, there were concerns that this may unintentionally dis - courage research in the area of biomarkers. However, many speakers noted that the biomarker evaluation framework will not have a chilling effect on biomarker research and development. Thomas Fleming suggested that a lack of clarity, both from the regulatory and scientific perspective, on biomarker evaluation standards is much more likely to inhibit innovation. Implementation of Recommendation 3 of the report could help FDA to bring scientific and regulatory clarity to biomarker evaluation across the FDA’s centers and regulated product categories. David DeMets added that the inappropriate use of a biomarker would have negative effects on innovation. Dr. Mayne said that the report clearly stated that the frame - work is not intended for biomarkers used in the discovery space: “I think

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 KEY THEMES, CHALLENGES, AND OPPORTUNITIES the committee made it clear that those areas are omitted so as not to con- strain innovation and not to preconfer how or which biomarkers might be advanced.” See also pages 100–102 and 116–121 of the committee’s report (IOM, 2010). One of the aspects of the biomarker evaluation framework that received substantial discussion was the third step of the biomarker evaluation framework, utilization. Several speakers questioned the placement of the utilization step after analytical validation and qualification. For example, Dr. Johnson said that for biomarkers used to support health claims, the context of use is very specifically defined in terms of the food vehicle, its target audience, and the setting in which it is consumed. It would there- fore be difficult to separate biomarker utilization as applied to food from qualification, he said. Dr. Williams asserted that the specific context for biomarker use must be defined at the outset of evaluation. “If you have not defined [the context of use] then you don’t know what the value of success would be, or the value of the truth, if the biomarker actually does what you think it does. And you don’t know what the consequence of error would be … if it fails to do so,” Dr. Williams said. These determina - tions drive tolerance to risk: “If the truth is extremely valuable and failure is inconsequential, then your tolerance for variation of all kinds is pretty good, and you don’t require much evidence,” he said. “But if there is not much value to the truth and there are terrible consequences to errors, then you are going to require a lot of information about precision of that biomarker and lot of evidence that actually it is going to do what you say it is.” Therefore, he said “if you haven’t defined the [biomarker’s] purpose first, then I don’t think you can define how good is good enough, and that’s what validation and qualification are about.” Maria Lopes-Virella said that the committee recognized that there must be a rationale for embarking on the evaluation of a biomarker, which can, in some sense, be seen as utilization, which is the reason the frame- work was depicted as circular. In organizing the evaluation framework, the committee placed analytical validation, qualification, and utilization in order of the decisions that would be made, understanding that the biomarker evaluation process would be initiated on the basis of an initial motivation or context of use. The committee reasoned that only after passing the first two thresholds—validation and qualification—should decisions be made about whether or not to use a biomarker. However, if a biomarker cannot be reproducibly measured, or is otherwise analytically invalid, there is no point in evaluating it further, said Dr. Ball. He added that the evaluation framework is not a series of disjointed steps, but rather an integrated process. Further explanation of the committee’s rationale for the order of evaluation framework steps can be found on pages 119–120 of its report (IOM, 2010).

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0 BIOMARKER AND SURROGATE ENDPOINT EVALUATION Dr. Ball said that the Center for Drug Evaluation and Research’s (CDER’s) concept of qualification differs from the committee’s because it includes consideration of a biomarker’s context of use. “I think conceptu - ally, because of the way CDER started with an integrated kind of approach [to biomarker evaluation], both industry and FDA conceptualize the pro - cess as integrated,” he said. Alternatively, the committee conceptualizes the evaluation process as stepwise but always informed by context. The order of the three steps also has a functional rationale, Allan Jaffe noted: existing analytical validation data “can be put together in a fairly facile way” before determining whether the biomarker can be used in a particular context. Dr. Jaffe said that defining a narrow context of use for a biomarker from the outset may limit its potential applications. Instead, “we start to investigate biomarkers, [conducting] the analytic valida- tion first. We then look … at disease entities that have large numbers of individuals [who] we can study to develop some sort of relationship to outcomes, and then we’ll look at other contexts of use.” THE VALuE OF BIOMARkERS AND SuRROgATE ENDPOINTS Throughout the discussion forum, speakers provided their perspec - tives on the value of biomarkers, especially those used as surrogate end - points. Kathleen Ellwood noted that reliance on long-term clinical trials is not always feasible, and that the FDA requested the IOM to undertake this study to address the absence of an agreed-upon, systematic, and transparent process for qualifying surrogate endpoints. Several speakers from the food and nutrition industries said that they rely on biomarkers and surrogate endpoints to conduct trials on nutritional interventions, because it is too costly or logistically challenging to conduct trials with clinical endpoints. These speakers also highlighted the importance of observational studies of the impacts of foods on clinical outcomes in the bodies of evidence supporting claims on foods. In the drug development setting, Dr. Williams noted that surrogate endpoint or efficient clinical endpoint availability was associated with more therapies, as compared to diseases that lacked surrogate endpoints, according to a recent review. Other stakeholders expressed concerns about the use of surrogate endpoints. Michael Lauer disagreed with the committee’s statement that “biomarkers can enable faster, more efficient clinical trials for life-saving and health promoting interventions,” and noted that perhaps the oppo- site of this statement is true. Dr. Lauer said that it is impossible to avoid clinical endpoint clinical trials to assess the effect of interventions. Dr. Fleming noted that validated surrogate endpoints are extremely rare; however, he added that there are many other uses of biomarkers that are critically important, including the diagnosis and prognosis of disease,

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1 KEY THEMES, CHALLENGES, AND OPPORTUNITIES informing patient-specific therapeutic strategies, primary endpoints in proof-of-concept studies or screening trials, patient enrichment, and as additional measures of biological activity in phase III clinical trials. CONSIDERATIONS FOR FOOD AND NuTRITION APPLICATIONS Many speakers emphasized the importance of a biomarker evalua- tion framework. However, there was some discussion among speakers that the committee’s framework and associated recommendations would be difficult to implement in a food or nutrition setting. Several stake - holders said that foods are different from other FDA-regulated product areas, and suggested that biomarker evaluations in foods require special consideration. Dr. Shao said that the overall context of biomarker use is different in foods than in drugs. Foods are presumed to be safe, and while that doesn’t mean they’re risk free, he said their risk paradigm is very different from that of a cancer drug. Foods with health claims promote health and are not urgent interventions, he added. The health effects of foods are mod- est as compared with drugs, and they are spread over a heterogeneous population, as compared with patients prescribed a particular drug, Dr. Shao said. As noted in her earlier presentation, Roberta Ness said that the committee’s rationale for recommending that the same degree of scientific rigor be applied across all regulatory settings—including food—resulted from an understanding that foods may not be implicitly free from harm. Dr. Ball added that the committee recognized that drugs are ingested by a small proportion of the population, and their use is guided by physi - cians, whereas foods are ingested by everyone, largely without guidance, and individuals may be less able to interpret both the risks and benefits associated with consuming a particular food. To this point, Dr. Johnson suggested that the public may indeed be exposed to risk through the addition of nutrients such as vitamin D to foods, but that eating larger amounts of individual, unfortified foods, such as strawberries, poses little risk to public health. Douglas Balentine said that the process by which food and nutrition companies identify promising biomarkers is fundamentally different from the way the pharmaceutical industry develops biomarkers. Many food biomarker leads come from epidemiological or observational studies that examine “intake markers” such as beta-carotene or the consumption of certain foods. For example, results of a study of fiber intake and choles - terol levels might suggest that eating whole grains is associated with a reduction in risk of coronary vascular disease and death, and blood samples from this study also suggest that individuals with lower risk have lower values of the biomarker, low-density lipoprotein cholesterol

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2 BIOMARKER AND SURROGATE ENDPOINT EVALUATION (LDL-C). The food industry would like to take this information and use it to pursue studies on foods, or on food fiber in purified form, to look at the effect of fiber on LDL-C, he said. To do so, they need to know if LDL-C is a valid biomarker, and if not, what kind of evidence is needed to support its use as a biomarker to examine foods that claim to offer health benefits. Observational studies drive the identification of clinical endpoints, Dr. Balentine said. Food companies are unlikely to develop a biomarker because to do so would involve proving that the link to the clinical endpoint is valid, he said. If that is the case, there is little need for a biomarker. “We need rigorous science and … appropriate trials that you can do within foods and complex foods,” he stated. “The food industry does all kinds of randomized studies,” Dr. Johnson said, noting that such studies are required by the FDA to support health claims. However, randomized studies of food “cannot be based on a hard clinical endpoint. You cannot randomize people to Cheerios or cornflakes and see who gets heart disease 20 years down the pike,” he said. Thus, he had hoped that the committee would recommend “ways to use surrogate endpoints to inform shorter-term clinical trials that the food industry could do with an endpoint that made sense.” Victor De Gruttola responded that “if you can only do the random- ized study on the biomarker, but not the clinical endpoint, then you are in the world of observational studies.” Such studies show a causal effect on the biomarker, but to conclude that there is a causal impact on the clinical endpoint requires a randomized controlled trial, he said—unless the biomarker has been validated as a surrogate endpoint. If evidence from a controlled trial of foods shows an effect on a biomarker, and epidemiologic evidence suggests that the effect on the biomarker may be correlated with the effect on the clinical endpoint, this information leads to a hypothesis, Dr. Fleming added. “That is where we were with beta-carotene,” he said: the hypothesis was that increasing beta-carotene levels should reduce disease incidence (see also section on beta-carotene qualification in IOM, 2010). This hypothesis turned out to be incorrect, and that determination could only have been made through a randomized controlled trial that studied clinical outcomes. While acknowledging the difficulty of conducting large-scale clinical endpoint trials with foods, Dr. Fleming said that foods can be marketed without such claims, unlike drugs. If you want to make that claim for any product, then reliable evidence for that claim can only be obtained through large-scale clinical or validated surrogate endpoint trials, he said. “There are many different ways foods could be beneficial for public health,” Dr. Fleming said. However, to claim that a food prevents cancer, for example, requires the same kind of reliable evidence as would a drug making the same claim, he asserted.

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 KEY THEMES, CHALLENGES, AND OPPORTUNITIES Most health claims involve cardiovascular disease because FDA con- siders LDL-C a valid biomarker, Dr. Johnson stated. If there were other biomarkers that were similarly validated, the food industry could use them to make a positive impact on public health, he said. Dr. Lopes-Virella said that it would be more scientifically valid to make a claim stating effect on cholesterol rather than clinical outcome if the data supporting the claim are based on biomarker endpoints. If the claim is not based on clinical endpoints, “don’t say that it reduces heart disease,” she insisted. Some speakers noted that there is a lack of incentives for the food and nutrition industries to conduct rigorous studies to support the biomarker evaluation framework. Furthermore, speakers noted that nutrition-based clinical trials are complicated by a number of circumstances, including individuals in the control arms who inadvertently consume the inter- vention, the complex and highly variable food matrices that can modify nutrient bioavailability, and overall dietary patterns. Dr. Shao said these factors also make running and interpreting trials for foods and supple- ments extremely difficult and complex. Dr. Ball responded that the com - mittee recognized that the food industry lacks the profit margins, financial incentives, and logistics to carry out studies of biomarkers similar to those conducted by the pharmaceutical industry. Because of these disincentives, the committee felt strongly about recommending that the Department of Health and Human Services (HHS) should facilitate a coordinated, department-wide effort to encourage the sharing of data about biomark- ers, he said (see also Chapter 5 of the committee’s report [IOM, 2010]). Dr. Jaffe noted that he understood that there is a lack of clarity of how to operationalize this recommendation, especially in the food settings. However, he added that having a unified framework could help the food and supplement industries by leveraging the biomarker evaluation expe- riences of the drug and device industries. IMPROVINg COMMuNICATION AND uNDERSTANDINg Another theme addressed in the report and raised several times in dis- cussion is the challenge of communicating information about biomarkers— and science in general—to the public. The validity of claims that are made on the basis of biomarkers depends in part upon how they are understood by patients, consumers, and health care workers, Dr. Ball said. However, lack of numeracy among medical professionals, as well as among the general public, presents a major obstacle to consumer understanding and interpretation of claims based on biomarkers, he noted. It is not enough to simply provide numbers, he said; we need to be aware of how people understand the information they receive and how they act in response. Dr. Jaffe added that the place to start making efforts to communicate

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 BIOMARKER AND SURROGATE ENDPOINT EVALUATION such information better at all levels is at medical schools, during intern - ships and residencies, where physicians can be taught to think proba - bilistically. Dr. Zakowski observed that nearly everyone is innumerate in some aspect of their decision making, but that media interest in this report—and in scientific developments in general—represents an oppor- tunity to teach the importance of numeracy. Dr. Khoo added that scientists need to better communicate among themselves regarding the implications of their work. “I think we also need to educate the food science discipline [regarding biomarkers] … because where the food industry is going to have to digest this information is, in many ways, in product development,” she said. For example, there are multiple ways food scientists might approach a surrogate endpoint such as blood pressure. Biologists and medical scientists need to agree among themselves what a biomarker means, rather than present conflicting or confusing information to the public or the media, she said. “I certainly want to support the notion that communication as per- haps the ultimate end product of this work is extremely important,” Dr. Mayne said. He urged that all stakeholders be included in educational efforts involving biomarkers, because “these concepts are not easy for anyone to get their brain around.” He further suggested that a “layered approach” to communicating information about biomarkers could help people understand how it applies to their own choices, and how they can use it to “frame their expectations, whether they are taking a box of cereal off the shelf or whether they are trying to advance a new diagnostic.” Dr. Ball said he was struck by the interest of both the lay and trade press in the report, which he thought reflected the importance of healthy eating to the public. That issue is unlikely to fade, he added, and it ought to be addressed by both regulatory and industry sectors. Dr. Johnson noted that one of the fundamental goals of the Nutrition Labeling and Education Act (NLEA) of 1990 was to provide people with the information they need to select a healthful diet. The food industry has “a tremendous potential to communicate positive, useful, helpful infor- mation,” he said. In addition, he said that food companies understand that claims not based on sound science will backfire. Melissa Musiker said the Grocery Manufacturers Association (GMA) was equally surprised by the degree of media interest in the report. She emphasized that consumers fail to distinguish among the different types of health claims. The GMA puts considerable effort into determining how to make a structure–function claim that is truthful and communicates appropriate information to consumers, she said. Dr. Balentine noted that Unilever would welcome improvements in numeracy that would allow consumers to better distinguish among prod- ucts with health claims. For example, their products contain what they

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 KEY THEMES, CHALLENGES, AND OPPORTUNITIES believe to be an effective dose of plant sterols, based on the results of clinical trials, while other companies put far smaller amounts of sterols in comparable items. Unfortunately, he said, the claims that Unilever is able to make today do not differentiate their product as containing a higher level of this more expensive ingredient. Communication was one of the main topics the committee discussed, according to Dr. Lopes-Virella, and committee members were concerned that their message be clear and not frightening. Most importantly, she said people need to understand that biomarker-based information, like nearly all medical information, conveys probabilities. “Everyone needs to understand there are no absolutes in medicine,” she emphasized.

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