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Comments on "White Paper #2: Applying Genomics to Clinical Problems - Therapeutics"

Much of the "disease predisposition, initiation, and/or progression" discussed in this white paper would need to be studied in pediatric populations.

Most chronic disease problems associated with genetic predisposition, such as type 2 diabetes, begin in childhood, as do most single gene disorders.

The issues discussed in this white paper could be argued to be highly relevant to children, yet the concerns are different than with adults. This should be acknowledged in this white paper.

(65) Monday, December 22, 2008 11:15 AM


Incorporating genomics of the clinical trials represents a major research challenge. One important problem is that exposures and outcomes are not defined in a standard way across different clinical trials. Genomics research, by its very nature, requires huge sample sizes. It would be a shame if after spending tens to hundreds of millions of dollars on large scale clinical trials, data cannot be combined because compatibility was not considered ahead of time.

(67) Monday, December 22, 2008 11:48 PM


I really like the way this section is written. However, I wonder why it is targeted to therapeutics. With a little minor tweaking it could be made to include prevention and therapy. It would be a far better document in my opinion if written to include both aspects. If one prevents then one does not need to treat!! Both are medical intervention strategies and both approaches would be best identified in this section. I know White Paper 1 name implies a prevention approach but it really does not in my opinion!

(72) Sunday, December 28, 2008 3:41 PM


How does a system biology approach assist in understanding redundaces in humans. In other words, what molecular mechanisms counterbalance genetic alterations? How does this effect disease onset and natural history?

(76) Tuesday, December 30, 2008 2:36 PM


The questions raised in this White Paper are exactly on target. The Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh is structured to address these questions by approaching complex chronic inflammatory diseases of the liver, pancreas and intestine (IBD) using reverse engineering and mathematical modeling approaches. Perhaps illustrating the answers to many of these questions using chronic inflammatory GI diseases as models will provide a spring-board into revolutionary new disciplines....

(82) Thursday, January 1, 2009 7:04 AM


Advances in validating hypotheses with regard to mechanisms of disease or response to therapy are often made by testing lab-based questions in well-managed biological specimen repositories. For example, the MACS study for HIV or COG for childhood malignancy. The ability to generate and orchestrate meaningful data repositories must be facillitated if genetics-based approaches are going to be used in therapeutic evaluation. How can the NIH be a reource for this need, as opposed to supporting single investigators? Could blood samples, gene expression profiles, or immortalized lymphocytes be maintained in such a way that new questions could be asked by independnet investigators? This is an infrastructire gap, an obstacle to getting full value from clinical research, and an opportunity to include providers of healthcare in the research process. How many valuable patient samples have been wasted because there was no central way to bank genetic samples/data and to correlate this data with responses and outcomes? Why not have a national outcomes research center? or simply a national expression profiling center that can provide data to investigators, and the community at large? The data would be better standardized, and the results accessable. I am sure that a large user-friendly reource center would be utilized by investigatros and serve as a transformative force in how therapeutic outcomes are correlated to primary genetic data over the course of treatment. Only the NIH could fill this need.

(83) Friday, January 2, 2009 3:43 PM


I was struck by the dicotomy of professional inclusion between number 4 and 6. Whereas 4 seeks to find ways to collaborate, to partner, and to bring diverse disciplines together - which I completely agree with and support - number 6 speaks only to "physicians". This is likely an oversite and "unconscious", however, it speaks volumes. Even use of the word "clinicians" would be more inclusive but "clinicians" often does not include the important work of genetic counselors, behavioral scientists, social workers, psychologists, educators, etc who have a significant role to play in "translating" genetic/genomics research into practice and for the public. There is vast and important work to be done in all the areas touched on in this document - we need not only "all hands on deck" but also the diversity of philosophies and scientific thinking of the many.

(86) Saturday, January 3, 2009 2:10 PM


These questions seem very much pure research oriented. Until the sixth group of questions the concept of how to translate this to the patients and especially the clinicians is not addressed. Even in that section, nowhere are on-line resources or resources built into EHRs even mentioned. No matter how much pure research is done and how beautiful it is, if we cannot get the information to the clinicians and the patients in useful form it is worthless from a health care perspective. We need to start doing the research in how this will work in clinical practice as soon as possible, even if we have to create simulations to do so.

(91) Tuesday, January 6, 2009 9:37 AM


I think that we are at critical intersection of genomics and clinical medicine and many of the points outlined in this white paper are right on target in planning for the future and optimizing the successes that have been garnered to date. While complex traits are slowly being mapped and will eventually have an important impact on the populations health, the field that is most exciting at the intersection of these two fields right now is human Mendelian developmental disorders. The mapping of disease genes and understanding of the basic molecular and cellular mechanisms involved in their pathogenesis has led to startling breakthroughs and the realization that we can now begin to think of biochemical therapeutics for such disorders as Marfan syndrome, Tuberous Sclerosis, Fragile X syndrome and others.
Developing initiatives that would encourage pooling of patient cohorts to power studies identifying modifiers for these Mendelian traits through National and International collaborations and common clinical and sample databanks would help propel this research to a new level and identify both important counseling markers and therapeutic targets. Mechanisms that encourage the interaction of academic clinicians with basic scientists working in areas related to specific diagnoses should be the standard for PPGs and other large funding mechanisms.
We are on the cusp of developing active therapeutics for behavioral and cognitive deficiencies that would never have been dreamed of 10 years ago. Developing the infrastructure to help support this ground breaking research and to catalyze the rate at which these breakthroughs are achieved should be a priority for the future.

(94) Wednesday, January 7, 2009 4:13 PM


2. Developing clinically usable gene-pathway-drug resources should be a very, very high priority. Clinical geneticists are increasingly availed of new errors in gene dosage in unique or rare disease patients who will never be the subject of clinical trials. We can potentially provide them (and their insurers) value beyond the identification of the genetic defect, i.e., treatment options informed by biological knowledge of the pathways affected by their particular genotype that, coupled with compatible clinical features that fall within the scope of drug indications, could provide a basis for informed drug selection and application. This should target FDA-approved drugs in the beginning, then orphan drugs. Environmental toxin exposure avoidance can be added to this. This approach will turn out to be applicable to less rare diseases as well.
At this time, I believe the relative impact of nutritional modifications in this context will be too small to be relevant.

(100) Wednesday, January 7, 2009 7:58 PM


Q1 First bullet. Alternatively, given evidence that gene pathways are significantly more complex than previously appreciated, will a major gene approach impair identification of potential treatments for both Mendelian disorders and complex disease that might be found using other approaches?
Q4 First bullet. What is meant by an "unconventional" academic discipline? Also, the players are defined as academics and industry. Without engagement of a broader range of health care providers (e.g. VA, private not-for-profit systems capable of participating in research such as Kaiser, Mayo, Intermountain) many opportunities will be unrealized. Involvement of systems such as these will be particularly critical in addressing the issues raised in Q6 as academia has been singualarly unsuccessful in addressing educational shortcomings in practicing physicians.
Q5 Arguably the most successful model testing therapeutic interventions is the Children's Oncology Group. Also, there is an emerging model funded through the National Coordinating Center (HRSA) to develop a network for studying outcomes and treatment of inborn errors of metabolism. This suggests the potential for NHGRI to partner with other governmental groups outside of NIH to promote this type of cooperative approach.
One of the other issues not mentioned is the inherent difficulty of translating clinical trial results into practice--specifically the recognition that real world implementation frequently doesn't show the benefit seen in a tightly controlled trial, for a multitude of reasons. I think Q5 needs to include questions about the role of so-called real world clinical trials including how these should be designed and funded, when real world trials are appropriate, how are outcomes data collected and shared, who coordinates analysis and follow-up.
Q6 overlaps a number of issues raised in the 'Applying Genomics-Diagnostics, Preventive Medicine' white paper. I've commented on that previously and will not repeat here, other than to say some resources need to be devoted to new ways to educate at the point of care (so-called just-in-time education).

(105) Thursday, January 8, 2009 10:25 AM


This discussion misses several points - most cases of disease are not the consequence of simple mendelian inheritance; age of onset for most cases of disease can be modified by reductions in exposure (obesity, smoking, etc) and most treatments involve responding to somatic rather than germinal events.

(111) Monday, January 12, 2009 10:55 AM


These are well posed questions. There is still a sense of a dichotomy between rare, high penetrance genetic variation and common low penetrance variation. It's not clear whether this is real in human populations, or just a simplification. In terms of defining genetic disease risk, this needs to be addressed. It may be less relevant for identification of new therapeutic targets.

Are genetic/genomic research programs too basic, insufficiently associated with translational research to follow? For example, is it necessary to identify all genetic factors of disease when only about 10% of the protein-coding repertoire is accessible to classical small molecular chemistry?

(112) Monday, January 12, 2009 3:34 PM


Gene profiling has had its best use in breast cancer. The results are decidedly mixed. There are now multiple gene signatures being marketed and patients are paying out of pocket for them. In my opinion they add little, over and above the free Adjuvant! online tool. A huge clinical trial is being conducted by ECOG to test one of these prospectively. Are we going to launch a trial for each genetic event that shows a decent correlation to survival?
In my opinion the only genetic tools of worth will tell patients that they do not need therapy, or that they will benefit from one therapy more than others.

(113) Monday, January 12, 2009 4:10 PM


This set of questions is more objectively worded and structured in a way that is easier to follow - suggest similar structure for the first paper.

In terms of content, comprehensive and interesting questions are raised.

Agree that prevention needs more emphasis here.

(129) Wednesday, January 28, 2009 11:20 AM


We suggest that question 6 on education initiatives necessary for maximizing progress be further expanded to address the need to develop resources such as a catalog of signatures for different disease processes. Standards are also needed across these trials so that the data can be pooled across trials for more robust analysis.

In addition the expansion of question 6, these additional questions should be asked:

What further clinical/epidemiology resources and strategies are needed for the discovery and validation of gene variants (including gene-gene and gene-environment interactions) as determinants of human disease?

What biologic mechanisms contribute to the racial and ethnic disparities in disease incidence and mortality?

(134) Thursday, January 29, 2009 9:05 AM


Overall: This process of open comment shows NHGRIýs commitment to community engagement. We suggest that NHGRI make the conversation accessible to more people by using plainer language where possible (e.g., where technical language is not required).

Overall: What are the benefits of targeted therapeutics relative to costs?

Question 2 and 4 : What is the role of the private sector in comparison to or in partnership with NIH? What is the role of NIH in terms of coordinating efforts and creating incentives for collaboration (national and international)? Recognizing the overlap between the three papers, weýd advocate for a more integrated approach. In doing so, the idea of ýbuilding a bigger sandbox with incentives for all to play in fairly,ý could be addressed as opposed to alone in the third paper.

Question 5: Involving public health professionals or utilizing the approaches and lessons learned in this field will assist in efforts to educate patients and physicians.

Question 6: What is the impact of variations in therapeutic response that correlate with existing socially defined groups? How can negative impacts, such as stigma, be avoided?

Question 6: The questions as they are currently written do not portray neutrality. Rather than asking about social and behavioral practices or biases that limit acceptance, we recommend asking how research can be conducted, therapeutics marketed, therapies prescribed by providers so as to reduce the limited acceptance and utilization by patients. Rather than asking about how to ýshapeý expectation questions could ask, 'What are the expectations?' or ýWhat created these expectations?ý

(138) Thursday, January 29, 2009 7:16 PM


Regarding question 3, "What are the critical gaps in infrastructure?":

Regarding infrastructure required to conduct large-scale research studies (see bullet point 1), there are ethical questions to be considered related to recruitment of patient populations from large health care systems: First, will certain patient populations be targeted for inclusion in genetics research studies because their clinical data are easily available as part of large health care system databases (e.g., Indian Health Service (IHS), Medicaid/Medicare, Veteran's Administration (VA) hospitals, Kaiser-Permanente)? How would targeting of these patient populations relate to the ethical principle of justice in the distribution of burdens and benefits of human subjects research? If large health systems such as the IHS, the VA, Mayo, Kaiser-Permanente, etc. do become key sources of participants for clinical trials, how can the boundaries between health care and research be kept clear? Furthermore, how can researchers ensure that patients who are recruited for studies by their own health care providers do not feel coerced to participate?

Regarding question 5, "What are the opportunities and obstacles regarding human clinical trials?," specifically bullet point 3, ýShould it be a requirement that every trial will include the collection, storage and potential distribution of patient samples in order to further elucidate disease mechanisms and the molecular basis for variation in therapeutic response?ý:

This question in bullet point 3 implies that patient samples might be stored in specimen/data banks. Repositories of specimens and data are also advocated for in other comments on this white paper (see comments 83 and 94). There are a number of important ethical questions related to the "collection, storage, and potential distribution of patient samples": How can access to specimens/data in repositories be adequately regulated? How can misuse of specimens/data be prevented? Will specific regulatory requirements of all specimen/data banks be developed by the federal government? If so, what should be included in these federal regulations? How will diverse stakeholders, such as American Indian/Alaska Native communities, be included in the process of developing such regulations? How can patient autonomy and informed consent be respected when specimens/data are shared beyond the original research project? Is ýblanket consentý adequate? Is it truly informed consent when research participants are asked to give their biological specimens for any future use, even though they may not know for what purpose? How can research participants be adequately protected in efforts to maximize the utility of specimens/data?

Human clinical trials and specimen/data banks not only pose ethical issues related to individual research participants, but also for specific groups, particularly American Indian/Alaska Native tribes. Related questions: If a repository contains specimens which are identifiable by American Indian/Alaska Native tribe, then what are the potential harms/risks for the tribe as a group (e.g., stigmatization)? What are the potential benefits for the tribe as a group? How can potential harms be minimized and potential benefits be maximized for American Indian/Alaska Native tribes as groups? Should informed consent for specimen use be obtained from American Indian/Alaska Native tribes as groups? If so, what would be the procedure for obtaining group consent? Is "blanket consent" adequate or should American Indian/Alaska Native tribes be asked to provide informed consent for each specific use of tribally-identified specimens? How can American Indian/Alaska Native tribes be involved in national-level discussions about policies/procedures/regulations related to specimen banks and genetics research more broadly? How can policies/procedures/regulations for specimen banks be modified to incorporate the perspectives of American Indian/Alaska Native communities? A good model is the Alaska Native Specimen Bank, which is regulated by a committee that includes representatives from Alaska Native communities, and is housed by the Anchorage branch of the Centers for Disease Control.

(149) Friday, January 30, 2009 1:26 PM


One of the major issue is that genomic finding remains to be a patter recognition for those who use this tool. This may even apply for clinical trialist. There is a major gap between those who could understand genomic findings and who conducts hypothesis oriented wet bench research. Unless there is a major effort to improve this gap, it will be difficult to come up with biologically meaningful way to use the genomic findings in the clinic.

(159) Sunday, February 8, 2009 6:35 PM


It is surprising to not see the inclusion of Clinical Translational Science network/initiative within the questions as it is a potential avenue to use with therapeutics. Under Question 3, consent for tissue sampling of all tumors needs to be addressed as we are currently constrained by not having enough tissue samples for genome testing for all races and ethnicities. Question 5 is less developed and it is unclear if it is only addressing rare disorder trials, or trials in general as many clinical trials now have a genetic component.

(166) Thursday, February 12, 2009 1:31 PM


RE question 3, infrastructure:
it would be very useful if NHGRI were to assemble a centralized collection of 1,000
healthy adult control samples of defined ethnicity that could be tested centrally for specific variants identified in patients by academic investigators, who could submit a specific variant for testing in the control population. This would aid in the distinction between neutral and pathogenic variants, and would be cost effective
compared with the current need for individual investigators to collect
control samples for each patient study.

(172) Tuesday, February 17, 2009 6:42 PM


On behalf of the American Society of Gene Therapy, I applaud the planning work groups efforts to use the power of genomics to identify and direct therapies for genetic disorders. I was very impressed with the emphasis on both common and rare disorders as well as single gene and complex disorders. The emphasis on using genomics tools for both diagnostics (paper 1) and therapeutics (paper 2) is a major strength of the Institute.
On behalf of the ASGT I suggest that the second paper be extended to explicitly include gene therapy. Gene therapy has shown remarkable progress over the last 5 years. Over 1000 patients have received gene therapy for malignancies, and in the cases of certain p53 tumors, where mutant p53 genes are causing the tumor, and B-cell malignancies, gene therapy has resulted in cures/remissions. For single gene disorders, gene therapy has been used successfully to cure hereditary blindness and immune deficiency in dozens of patients. Just around the corner are inborn errors of metabolism, which have been successfully treated in at least 12 different animal models.
Against this record of thousands of gene therapy patients, treated and/or cured without incident, are 6 adverse events due to gene therapy: Jesse Gelsinger and 5 patients with X-SCID who got leukemia. Of the 5 X-SCID patients, 4 were successfully treated and continue to be cured of their immune deficiency with no detectable leukemic cells. This unparalleled record of safety cannot be matched in any other nascent field, and is the strongest reason to move forward with gene therapy as part of the long term plan.
For every therapeutic target identified by genomics, there should be both a drug and a genetic target. For some disorders, the drug may be better, or gene therapy involving an siRNA. For other disorders gene addition may be superior. It is most likely that the most effective therapies with be developed from options provided by both small molecules and gene transfer. The ASGT membership urges NHGRI to include support of gene therapy as part of the therapeutics initiatives.
In practical terms, Gene Therapy is a good field for NHGRI to support. Although the translational activities are restricted to individual diseases, the same gene transfer technology can be used to treat both blindness and cancer, immune deficiencies and inborn errors. With this "disease oriented" approach, Gene Therapy support and leadership is divided among many institutes, with no one institute claiming to be the champion for this field. Just as Chemical Genomics cuts across many therapeutic outcomes, gene Therapy covers the same areas. If NHGRI were to assume a leadership role in gene therapy, it would be a great benefit to the field and would promote cooperation among the "disease oriented" institutes.

(175) Thursday, February 19, 2009 2:32 PM


I would like to see gene therapies included in the roadmap. Critical to these potential treatments are advances in understanding the regulation of gene expression.

(177) Monday, February 23, 2009 6:01 PM


Paper 2, section 5 discusses strategies for maximizing the benefit of clinical trials. Collecting samples for future work is clearly a good strategy but raises the issue of getting follow up data on participants. If samples are not anonymized, investigators face a daunting task of tracking down subjects in the event that a future discovery uncovers a risk related to a gene that they have identified in their subjects. Yet if subjects are anonymized, investigators are unable to link later genetic discoveries made by using the samples to outcomes in their study population.

(188) Tuesday, February 24, 2009 5:38 PM


Additional questions to consider:

Would it make sense to follow pathways, gene families, and other molecular phenotypes, rather than clinical phenotypes, or organ systems to understand disease pathogenesis and prognosis?
Can we capture best practices for assay development for high throughput screening? Can we develop training methods for improving the commoditization of these assays?

Should drugs that have not been brought all the way through product development for orphan drugs also be revived and retested? What can be learned from FDA-approved drugs that are currently being used in an off-label fashion? What about therapies approved outside the US?

How do we learn of libraries available worldwide, and what is in those libraries? How can we expand the usefulness of libraries? Can public-private partnerships help increase access?
How can researchers harness the potential of patient populations self-organizing through social networks and other mediums?

How can industry partner with disease advocacy organizations, which have proven their unique ability to facilitate cohort development, disease characterization, biobanking, longitudinal studies, etc?
Should there be a cohesive, focused effort to discover therapies for rare conditions?

Is the regulatory environment sufficient for clinical trials for rare genetic disorders? Do we need new requirements for R01 basic science that would enable it to be forward looking, considering a potential future role of FDA (e.g. IND submission to FDA)? Could FDA be engaged much earlier in the process, possibly by developing a review program specific for rare diseases?
Should there be a mentoring or partnership program between genetic/genomic experts and industry when developing trials? Would putting the capacity of information technology to work in a long tail manner to aggregate both clinical trials and the participants be effective in achieving maximal impact of clinical trials?
How will we design an informed consent process that facilitates patient engagement in research design and that is flexible regarding potential additional uses of contributed samples?

What role do disease specific organizations have in educating patients about therapeutic advances? How can their educational resources be brought to serve the larger community?
What mechanisms exist or could be developed to collect clinical data post-marketing to continue learning about diseases, treatments, and changes in natural history with new therapies?

(193) Friday, February 27, 2009 4:45 PM


Thank you for the opportunity to comment on your long-range planning process.

I agree with previous comments that the language and framing of many of these questions could be modified. For example, use of the term physician could be broadened to include researchers, clinicians, practitioners, service providers, etc., and patients could be broadened in many instances to include consumers and/or the general public. Also, I would particularly encourage reframing of the following question: "What social and behavioral practices or biases will limit acceptance or utilization of novel therapeutic practices? How can these be recognized, manipulated and/or managed in a manner that promotes beneficial health practices?"

Perhaps more fruitful questions include: Once the evidence base is established to ensure the validity and utility of novel therapeutic practices, how can we encourage their acceptance or utilization? What barriers exist to widespread adoption? What knowledge or communication strategies are most effective in dispelling fears, misperceptions or biases?

In addition, rather than questioning how to ýshapeý public expectationýperhaps you could ask "how do we educate the public to ensure accurate and/or realistic expectations?"

One important theme appears to be missing from the discussion of mechanistic underpinnings of disease predisposition, initiation, and/or progression: gene-environment interactions. When considering complex disease genetics in particular, it appears that the complexity underlying the mechanisms and processes must be accounted for. As such, gene-environment interactions must be considered along with the biological, physiological, and behavioral mechanisms that underlie gene variant-disease associations. In particular, behavioral and social factors are important considerations in our conceptualization of the environment, and increasing evidence supports their role in the complex interplay of genes and environments in health outcomes. In addition, many factors influencing health are not static, that is, they affect risk and resilience in a variety of ways throughout the life course (e.g., in utero, during infancy and childhood, during pregnancy, or during old age). It is therefore anticipated that the actions of gene variants and gene-environment interactions may have critical or sensitive periods across the developmental trajectory.

I particularly like the phrasing of this question: "Are existing patient populations (e.g. unified by disease, genotype or response to therapy), patient samples (e.g. DNA, cell lines, surgical specimens) and study results (e.g. genome-wide association studies) being collected in a way that maximizes the potential, efficiency and incentive for sharing?" Facilitating data sharing is a topic of interest to me, and your question succinctly points out that there are multiple components to data sharing (potential, efficiency, and incentive) as well as multiple targets for improving the utility of the data to be shared (pre-data collection to data results, with examples). Nicely conceptualized. I might add a consideration of associated phenotypes (e.g., the inclusion of a variety of demographic, clinical, environmental, psychosocial, etc variables) within datasets to facilitate the incentive for their use across a variety of scientific disciplines and to maximize the ability to ask ever-increasingly nuanced questions.

(200) Friday, February 27, 2009 11:03 PM


Examining the development of new therapeutics based on genomic information is an important component of the overall project and we found that the questions clearly and comprehensively addressed the topic.

(204) Monday, March 2, 2009 2:52 PM


The Association for Molecular Pathology (AMP) is an international medical professional association representing approximately 1,600 physicians, doctoral scientists, and medical technologists who perform laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Since the beginning of our organization we have dedicated ourselves to the development and implementation of molecular diagnostic testing, which includes genetic testing in all its definitions, in a manner consistent with the highest standards established by the Clinical Laboratory Improvement Act (CLIA), the College of American Pathologists (CAP), the American College of Medical Genetics (ACMG), and the United States Food and Drug Administration (FDA). Our members lead and work at the majority of clinical molecular diagnostic laboratories in the United States as well as in laboratories in many other countries. We are frequently involved in the development of novel molecular tests, and in the validation of laboratory developed or commercial assays.

Thank you for the opportunity to comment on the White Papers in Phase 1 of NHGRIýs Long-range Planning project. Our comments are as follows:

White paper 2:
Applying Genomics to Clinical Problems ý Therapeutics
(IS: No comments: my comments were addressed in the reviews already posted promote integration of genetic, genomics, functional pathways, research and clinical disciplines to distill the most powerful data)

Q3. additional questions (Simhan Nagan):
ý How do we weigh in practical factors such as the high costs associated with conducting genome-wide association studies, and the elaborate IT-infrastructural support needed to analyze the computationally intensive data generated.
ý How can processes that streamline ethics committee approvals and obtaining informed consent documents for genome-wide association studies in the global environment of a typical drug trial be established.

(208) Monday, March 2, 2009 2:57 PM




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