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Diagnostics and Therapeutics White Paper (PDF - 170KB)

Created on April 14, 2011

9 Submitted Comments on Diagnostics and Therapeutics

Part 1: 1. While infectious diseases were mentioned once or twice in this paper, Infectious diseases are an area where classically either drugs are studied in children much later than in adults, or the drugs are used off-label in children. This can lead to significant problems, particularly in young children ? for example, gray baby syndrome with chloramphenicol use in neonates. 2. This paper as well as other papers seemed very US/resource-rich country and technology-centric. It is critically important to develop diagnostics and therapeutics for children in resource-limited settings, where the bulk of many diseases occur. HIV and tuberculosis are good examples of diseases for which there hundreds of thousands of children becoming infected each year but such children reside in resource-limited settings and hence many of the more advanced technologies such as PCR may not be able to be applied due to technologic complexity and expense. Hence, development of point-of-care diagnostics for HIV and TB in children that can be used at the health center level in resource-limited settings are critical to saving children?s lives in these countries. There is often no financial incentive to companies to develop such technologies and it is a neglected area. 3. Similar comments relate to drug development for children; in the US, ?pediatric? formulation is often interpreted as development of a liquid formulation. This is inadequate for resource-limited countries where storage and temperature is a problem. Again using HIV and TB as examples, innovative (and palatable) drug preparations for young children that are not liquid and can be stored under higher temperature conditions will be critical (for example, could a dissolvable ?film? preparation (like for breath savers) for HIV drugs be made for young infants). Additionally, preparations with longer half-lives to allow once daily or ideally once weekly or monthly administration of drugs that need to be given for long periods or may need to be given for life (like TB) for children or adolescents is important, particularly when it comes to adherence issues. 4. Pharmacogenetics is important but needs to be able to be used in resource limited settings and not just resource rich countries. For example, the anti-HIV drug efavirenz is highly effective and a preferred anti-HIV drug, but appropriate dosing for children under 3 years has not been able to be defined -- recent studies show significant differences i

Submitted by Lynne Mofenson on April 25, 2011 at 10:52 AM

Part 2: 5. The study of biomarkers in different populations, including in resource-limited countries, is critical but not mentioned. For example, normal CD4 counts may differ in Asian and African populations than in white US populations (eg, levels are lower). The presence of ?ethnic neutropenia? has complicated clinical trials, where we are defining toxicities based on norms in U.S. white children while norms in African children for neutrophil count is significantly lower. This results in having children in trials having to discontinue medication in the study for ?toxicity? that is really normal for African children. Because of variation between geographic regions, the #1 accomplishment on page 12 should be establishment of normal values for pediatric immunologic and biomarker tests in a global context. 6. Neurodevelopmental disorder section dealt only with prematurity, which while important, is not the only etiology of neurodevelopmental problems. HIV in particular (and other congenital infections) is associated with significant neurodevelopmental problems. It seemed that this section dealt with only one of many causes of neurodevelopmental problems. 7. A significant issue in evaluating neurodevelopmental problems in resource-limited countries is the lack of well-defined neurodevelopmental tests for such settings with appropriate norms. The available tests are focused on norms in primarily white children in resource-rich countries. There is a critical need for development of appropriate tests for children in other settings. 8. In utero exposure to drugs may be a cause of disease in children (and adults). The classic example is diethylstilbestrol (DES) but there are significant concerns regarding other drugs, such as antiretroviral drugs. Additionally, such adverse effects may be related to nutritional status of the mother or other co-infections/co-morbidities, and hence may be different in resource-limited than resource-rich countries. For example, antiretroviral drugs in particular are necessary to give during pregnancy to treat the mother and prevent transmission to her infant but there is only limited data on long-term effects and what data there are, are from resource-rich countries. Hence, there is a need for an emphasis on need for long-term follow-up of infants born to mothers who receive drugs during pregnancy, and this needs to include resource-limited settings for diseases that are more common there (like HIV and TB).

Submitted by Lynne Mofenson on April 25, 2011 at 10:53 AM

While I agree that "Therapies for diseases and conditions of interest to NICHD have largely arisen from migrating therapies for adult conditions to younger populations.", there have been other exceptions that those mentioned (e.g., vaccines). I refer to attempts to develop therapies with agents that are particularly relevant to neonates - namely lactoferrin, and specifically Talactoferrin (a recombinant human lactoferrfin of Agennix Incorporated in Houston, TX). Utilizing such entities clearly focuses investigations on issues relevant to neonates and away from the adult population. NICHD could help to support this trend by "adjusting" its criteria when evaluating applications from academia and in particular from Small Business for grant support. For example, one of the first questions asked when projects in this area are evaluated is about the SAFETY of the proposed treatment in neonates; The issue of safety before application in neonates inevitably begs the question and forces that the initial testing is done in adult humans... Hence, while the White Paper recognizes that "...enterprise comprised of the public and private sectors encourages the biopharma industry to follow this "adults first" paradigm via support and incentives", and that "This approach is flawed,...), the document should consider in more practical terms how this issues should be addressed. Developing guidelines on what would testing should/needs to be done for satisfactory evaluation of safety in neonates (as different from those for adult population) would be a useful first step...

Submitted by Karel Petrak on May 31, 2011 at 1:08 PM

The Society for Women's Health Research (SWHR) appreciates the opportunity to provide comments to NICHD's Vision process. SWHR strongly encourages the Workgroup on Diagnostics and Therapeutics to recommend investigation and reporting of sex-based differences in all new NICHD research. The benefits and risks of new technologies and therapeutics, as both become more personalized, will require that sex be uniformly recorded in any database undergoing analysis, and that sex-based analyses be conducted and reported to gain a greater understanding of sex and gender differences in disease susceptibility, response to drugs or the way drugs may differ in various populations.

As there are clear sex differences that are known in the absorption, distribution, metabolism, and excretion rates in men and women (Savvy Women Patient, 2006) , new NICHD research needs to factor in and respond to these differences. Research in vaccine development has noted that women mount higher antibody responses following both seasonal flu and H1N1 vaccination (Klein, et all 2010). This research strongly suggests that women could get the same benefit and experience fewer side effects if given a smaller dose than men. Other studies have revealed similar sex differences in response to vaccines for yellow fever virus, measles, mumps and rubella, hepatitis A and B viruses and herpes simplex virus. Vaccines that have shown great promise for women have gone on to not be approved due to combined male/female response rates masking the clear benefit that women in the study experienced.

Such clinical results are building a compelling evidence base supporting sex specific doses and schedules for all drugs, devices, and therapeutics. As the thought leaders in research on sex differences, it is SWHR's hope that NICHD will be cognizant of sex as a variable, and add to the science and advance medicine by reporting where sex differences do and do not exist.

Submitted by Leslie Stevens on June 9, 2011 at 4:58 PM

The purpose of this NICHD Diagnostics and Therapeutics White Paper is to identify goals and objectives related to identifying opportunities for improved diagnosis and treatment of children and individuals with developmental and neurological disorders. The section on neurorehabilitation is predominantly focused on change in underlying structures and increased understanding of basic science. Another research area of importance is the impact of neurological disorders on the individual, their families, or communities. While focusing on the "problem" from the perspective of the physiologic and biologic structures is useful for some research, it would be helpful to consider the impact of the environment on functional performance. As well, the white paper would be strengthened if it included a discussion of how societal factors influence the daily life and recovery of persons with disabilities.

The discussion on measurement, focused primarily at the level of measurement of biological processes or impairments, is extremely important and timely. Although the report acknowledges the use of patient-reported outcomes, further elucidation about how these are related to the biological processes targeted by diagnostic strategies or therapeutic interventions would be beneficial. The report mentions the use of item response theory (IRT) in connection with the use of patient-reported outcomes (PROs), presumably in relationship to the work of the PROMIS Network. Yet whether PROs can, or should, be expected to be sensitive to physiologic or structural changes or aid in diagnosis is not clear. More likely the kinds of outcomes produced by therapeutic changes in neurological structures would be assessed with observations of performance. IRT could be important in addressing issues of rater severity/leniency, which influence outcome measures based on clinical observations. Rater severity is seldom discussed in rehabilitation literature but can have significant effects on patient measures.

Also, we urgently need to develop appropriate and accurate risk adjustment models. While patient-reported and functional performance outcomes is acknowledged in the paper, this topic could be expanded to include a discussion on how such results will account for differences in patient severity when interventions are transitioned into real-world contexts. Current case-mix and risk-adjustment methods have been designed to account for differences in mortality rather than morbidity.

Submitted by Trudy Mallinson, PhD, OTR/L, NZROT on June 9, 2011 at 9:20 PM

On behalf of the Coalition for Pediatric Medical Research, a group that consists of more than 20 of our nation's leading children's hospitals, I am writing to offer the following comment as to the value of novel consortia to advance research in the area of rehabilitation of neurological disability. One of the most effective mechanisms for ensuring enhanced collaboration and sharing of data and resources has been the networked research consortia. Examples of successful networks include the Children's Oncology Group, the Pediatric Heart Network, and the Comprehensive Cancer Centers. Because of this success, NICHD and NIH more broadly should seek ways to better use this resource. The Coalition for Pediatric Medical Research strongly supports creation of a networked consortia focused on pediatric research across the board including basic and translational science. Such infrastructure is greatly needed to overcome longstanding funding challenges in pediatric biomedical research, challenges that will not likely dissipate anytime soon given the fiscal challenges facing the NIH and the nation at large. Infrastructure should include both cutting edge technologies to support bioninformatics, data warehouses, tissue and specimen banks and other shared services necessary to conduct 21st century science, as well as human capital so the field is able to attract and retain early-career researchers. By supporting such infrastructure, NICHD will help ensure the field is well-positioned for the future and better able to compete for R01 and other opportunities. In summary, we recommend that NICHD expand on this recommendation and explore the use of networked consortia more broadly.

Submitted on behalf of the Coalition for Pediatric Medical Research by Drs. Arnold Strauss, Cincinnati Children's; David Williams, Boston Children's, and William Hay University of Colorado.

Submitted by Arnold Strauss on June 10, 2011 at 8:45 AM

I notice that there a few brief references to the cost and/or value of diagnostics. However, I think that the economics of diagnostics and therapeutics would benefit from rigorous attention, epsecially in the context of health care reform and the long run challenges facing our health care system. I am suer there woudl be many health economists who woud be willing to provide this perspective if asked to.

Submitted by David Meltzer on June 10, 2011 at 2:49 PM

We would also suggest that clarification is needed for the statement, "More children born between 32 and 36 weeks gestation suffer neurodevelopmental disorders than those born at very low birth weight." It is questioned whether the phrase "more children" is simply based on the greater number of children born at 32-36 weeks as compared to low birth weight, or is the percentage in fact higher in the 32-26 week group?

Further, the notion to develop a databank with biostatistical support that would include all laboratory, clinical, imaging, and follow-up data for all children in the study is supported. We suggest the NICHD seek to create of a databank of imaging results from "normal" children. We also recommend additional study of the equipment used for imaging as it was approved in most cases for adults, but questions still exist about the quality of the equipment relative to children. NICHD should consider devising a plan to address privacy issues for children who are part of any study. Finally, SOT questions whether the current predictivity for preterm birth is considered adequate or should NICHD consider improving the predictability with additional research?

In terms of the section entitled, Therapeutic Development, it is believed that the Society could offer a good deal of expertise on the subject of safety assessment. In addition, SOT could assist the NICHD in identifying the scientific gaps that need to be filled in order to allow them to inform their approach to safety assessment concerning new therapies and those under development.

Submitted by Martha Guest on June 10, 2011 at 5:05 PM

This impressive white paper mentions the crucial area of translational work, but fails to identify key topics that help move technological breakthroughs at the bench to patients. The following are some important example questions not included in the paper:
* What are the incentives to adopt a new technology in clinical practice given the set of insurance arrangement that exist? What features of the new technology are most likely to lend itself to adoption by insurers, doctors, and patients? What are the barriers to adoption?
* What effect will the dissemination of a new technology have on other behaviors by patients? For instance, will the use of a new anti-asthmatic drug lead to asthmatic kids engaging in behaviors that increase the likelihood of an asthma attack?
* Which patients are most likely to adopt a new technology? Which patients are most likely to adhere to therapy? (Answers to questions such as these often explain why results seen in randomized trials often do not translate to real world clinical setting; answers also help identify ways to improve adoption and adherence).
* At given prices, would the dissemination of a new technology improve net social welfare? If not, at what price would it do so?
* What are the long run consequences for health (broadly considered) and for other outcomes (again broadly considered) of a given new technology?
There are other areas of study in this multi-disciplinary area, that are as important in understanding the role of new diagnostic and therapeutic technologies. Translational work amounts to research in the economics of health and health care and a set of statistical and econometric tools well suited to the analysis of observational data. Regarding training, the white paper fails to identify deficits in econometric training, and in particular in the sophisticated analysis of observational data. Because the resources simply do not exist to run a randomized trial for every important question, clinical medicine necessarily relies on observational studies to provide answers to a wide variety of questions. It is a crucial task to train physicians to become sophisticated consumers and econometrics, as a discipline, has exactly the aim of trying to understand when causal relationships can be inferred from statistical correlations and when they can not. This area is underdeveloped in medical schools, and is an area where great advances might be made with relatively small investments.

Submitted by Jay Bhattacharya on June 10, 2011 at 10:26 PM

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Last Reviewed: 06/04/2012