EFTA00603134.pdf

Opinion VIEWPOINT What Happens When Underperforming Big Ideas in Research Become Entrenched? Mkhaell J. Joyner, MD For several decades now the biomedical researchcom- mats. As of April 20I6, the Centers for Medicare & Med- Laboratory of Human munity has pursued a narrative positing that a combi- icaid Services had paid $34 billion in financial incentives Integrative Physiology nation of ever-deeper knowledge of subcellular biol- to service providers for implementing electronic health and Department of ogy. especially genetics. coupled with information record (EHR) systems.' EHRs are an important aspect Anesthesiology. Mayo Clinic, Rochester, technology will lead to transformative improvements in of this narrative because they are thought to provide Minnesota. healthcareand humanhealth.In this Viewpoint. we pro- the structural underpinnings of precision medicine. It vide evidence for the extraordinary dominance of this has been suggested by some that some combination of Nigel Paneth. MD. narrative in biomedical funding and journal publica- these 8 big ideas will yield substantial cost savings for MPH Departments of tions; discuss several prominent themes embedded in health care. Epidemiology and the narrative to show that this approach has largely Expectations that a few DNA variantsexplain most Biostatistics and failed: and propose a wholesale reevaluation of the way common diseases have faded as the genetic architec- Pediatrics and Human forward in biomedical research. ture of most diseases has proved to be formidably corn- Development. College of Human Medicine. plex. Apparently. hundredsor even tensof thousandsof Michigan State Primacy of the Narrative genetic variants are involved in each common disease. UnNersay. In 2016 approximately $15 billion of the $26 billion of ex- The functionof thesevariants isdifficult todecipher.Very East Lansing. tramural research funding sponsored by the National In- few genes havefound undisputed rolesin preventiveef- stitutes of Health (NIH) could be linked to some version forts or pharrnacogenetic testing. JohnP.A.loannklis. MD.D5c of search terms that include gene, genome, stem cells, Continued enthusiasm for gene therapy ignores StanfordPrevention or regenerative medicine.' These topics have also in- what is known from classic single-gene disorders such Research Center. creasedgeometrically intheir representationarnangpub- as sickle cell anemia. The complex biological processes Department of khed articles. Between 1974 and 2014 the annual num- set in motion by a single amino acid substitution that Medone arelMeta. Research Innovation berof published articles indexed inPubMed increased by leads to painful crises, stroke, and other complications Center at Stanford. 410%(from 234 613to1196 110). butthoseidentifiedwith are not predictable from the genomic defect. but only StanfordUniversny. genome increased by 2127% (2705 to 60246). Be- by appreciating thecomplexity of biological systems at Stanford. California. tween 1994 and 2014. the annual number of articles in- the level of tissues and organs. Sixty years after the dis- dexed in PubMed increased by 175% (from 435 376 to covery of the genetic defect, no targeted therapy has 1196 110), but articles identified with gene therapy or stem emerged for sickle cell anemia. cell increased by 874% (2635 to 25 662)and752%(3452 The complex and adaptive nature of most tumors to29 196).Apparentty alarge number of scientists either thwarts the optimistic projections for molecularly tar- believe in the potential of these topics or feel compelled geted therapy for cancer. A randomized trial of to work on them, recognizing that these topics consti- targeted therapy based on molecular profiling for ad- tute a major locus of important science. financial sup- vanced cancers from diverse anatomical locations port, recognition, and prospects for a successful career. showed no improvement in progression-free sur- vival.5 The NCI-Molecular Analysis for Therapy Choice Exploring Some Key Examples (NCI-MATCH) trial links patients withcancertodrugstar- In 1999. Collins' envisioned a genetic revolution in medi- geted against their cancer DNA mutations. So far, just cine facilitated by the Human Genome Project and de- 2.5% of screened patients have been assigned to a trial scribed 6 major themes: (I) commondiseases will beex- intervention group. Even though this fraction should plained largely by a few DNA variants with strong increase as the number of trial treatment groups is in- associations to disease. (2) this knowledge will lead to creased, even if effectiveness is demonstrated, the rar- Corresponding improved diagnosis, (3) such knowledge will also drive ity of the targeted mutations means that this approach Author: John P. A. preventive medicine, (4) pharrnacogenomics will im- will help only a minority of patients with cancer" loannidis. MD. DSc. provetherapeutic decision making; (5)genetherapy will The prospects of effective treatment based onstem StanfordPrevention treat multiple diseases; and (6) a substantial increase in cells have been challenged in comprehensive reviews of Research Center. Department of novel targets for drug development and therapy will en- the available trials. For instance, incongestive heart fail- Me6cine and sue. These 6 ideas have more recently been branded as ure. improvements in cardiac function have been ob- Meta-Research personalized or precision medicine.; Similarly, there is served only in industry-sponsored studies, and a posi- Innovation Center at Stanford. Stanford the increasing interest in and expectation that stemcell tive relationship has been noted between effect sizeand OnNersay.1265 Welch therapy—a sevenththeme—can treatcommondiseases.3 the number of experimentaldesign flaws.' To itscredit, Rd. Medical School To avoid the misconception that big ideas are all the International Society for Stem Cell Research has is- Office 13Iclg. Room related to biological sciences, an eighth theme is the sued "anti-hype" guidelines that Itilighlight the respon- X306, Stanford. CA 94305 (power! emphasis in the narrative on the clinical and research sibility of all groups communicating stem cell science @stanford edu). value of converting medical records to electronic for- and medicine—scientists. clinicians, industry. science AMA October 4.2016 Volume 316. Number 13 1355 CopyrigM 2016 American Medical Association. All rights reserved. Downloaded From: by a Royal Society of Medicine - Library User on 02/19/2.017 EFTA00603134  Opinion Viewpoint communicators, and media—to present accurate, balanced reports ing, more complex measurements, and more sophisticated instru- of progress and setbacks" 8 mentation. The second is to reevaluate and reset the current focus. The financial and clinical benefits predicted from shifting to Public funders such as NIH should expand the funding for ba- EHRs have also largely failed to materialize because of difficulties in sic, "blue sky" science for which it is impossible to set. predict, and interoperability. poor quality, and accuracy of the collected infor- promise specific deliverables. In so doing, NIH should fund many mation; cost overruns associated with installation and operation of more high-risk. unconventional ideas insteadof supporting the same EHRs at many institutions; and ongoing privacy and security con- familiar highly funded research fronts. However, novel funding cerns that further increase operational costs. These features make mechanisms like NIH Pioneer Awards are currently only a tiny frac- the use of EHRs for research into the origins of disease, as pro- tion of the total budget. posed in the Precision Medicine Initiative, highly problematic. No When NIH funds translational or preclinical research with spe- clearly specified targets for either improved outcomes or reduced cific deliverables promised (as in the case of personalized medicine. costs have been developed to assess the performance efficiency of and stem cell therapy), independent assessors should regularly ap- EHRs. Although it is difficult to argue for a return to paper records, praise whether these deliverables were achieved and, if so. at what any claim of future transformation of the medical record should cost, and with what effect. Assessors must be objective. indepen- include well-defined accountability and review mechanisms. Oth- dent of thefunding source. and havenoprofessional stake in whether erwise, the health care system may become hostage, wasting a particular line of research is deemphasized. The deliverable crite- increasing resources to continuously upgrade electronic technol- rion should include public health benefit achieved by these initia- ogy without really helping patients. tives (ie, measurable reductions in mortality and morbidity). Criteria None of these popular topics has had any measurable effect on such as number of publications. citations, prizes, and recognition are population mortality, morbidity. or life expectancy in the United irrelevant as these are simply self-rewarding artifacts of the system. States. The improvements of the past decades in these outcomes, After several decades of substantial investment, the fundamental which have been substantial but are now stalling. have largely question is whether these big ideas have improved quality of life and reflected improvement in nonmedical aspects of everyday life and life expectancy. by how much, for how many. and for whom. These the operation of broad-based public health and classic prevention are public dollars that should benefit the many, not the few. efforts. such as curtailing smoking, that are undervalued as out- Mechanisms should be in place to sunset underperforming ini- moded and old-fashioned by the narrative. The anticipation that tiatives.In the current environment, scientists are pigeonholed in a improvements in medical care and outcomes derived from big narrowdiscipline and are penalized by study sections if they exit their ideas will reduce costs also seems unlikely given the high costs of specific niche. There should be incentives for scientists to acknowl• applying targeted therapeutic interventions to small numbers of edge that their research focus should be abandoned and help them people based on complex and expensive technologies, as well as switch to another potentially more fruitful research area. the inevitable overdiagnosis and overtreatment that follows from Another key question is whether NIH is best suited to fund more intensive monitoring. Similarly, EHRs may increase health all kinds of research that have specific deliverables. In some cases. care costs due to their ability to enhance revenue capture and as a private entrepreneurs may be most suited to develop new drug tar- result of unanticipated security and upgrade expenses. What his- gets, new drugs. new tests, and new technologies. Financial suc- torical precedent is there that adoption of vast new oversophisti- cess in the market is a strongand sufficient incentive. Public funders cated technology reduces costs? Eventually. what is the definition may need to focus more on blue sky science and on late evaluation of success and over what time frame? research, to evaluate without conflicts the drugs and other tech- nologies developed by entrepreneurs. A Need for Reevaluation NIH deinvestment inpreclinical research promises that clearly do When claims about high- profile, dominant "big ideas" are viewed not deliver will allow morefundingtobedirected toward work of clear against their mediocre benefits, it seems that 2 basic courses of ac- public health importanceand for imaginative biomedical researchthat tion are available. The first is to continue with calls for more fund- is truly innovative and not constrained by current narratives. ARTICLE INFORMATION 2. Collins FS. Shattuck lecture—medical and 6. National Institutes of Health. NCI.Mdecular Published Online: July 28. 2016. societal consequences of the Human Genome Analysis for Therapy Choice (NU-MATCH) trial. dc.:10.1001flama.2016.11076. Prclect. N Engl./ Afe0.1999.341(1):28-37. http://wwwcanc er.goviabout.cancer/treatment 3. Joyner Ml. Paneth N. Seven questcris for /clinical.triabinci.supportedfnci.match. Accessed Conflict of Interest Disdosura: Al authors have July22. 2016. completed and submitted the ICMJE Form for personalized medicine../Ama.2015.314(10):999. Disclosure of Potential Conflicts of Interest. IOCO. 7. Nowbar AN. Mielevicat M. Karavassilis M, et al. Dr loannidis reports support from an unrestricted 4. Centers for Melcare & Medicaid Services. Data Discrepancies in autologais bone marrow stem cell gift from Sue and Bob 011onnel. No other and program reports. hoptifvnviv.cms.gov trials and enhancement of ejection fraction disclosure were reported. fregtiations-and.gtadance/legelation (DAMASCENE). BM/ 2014:348:g2688. fehrincentiveprograms/dataandrepons.html. 8. ISSCR releases updated giadelnes for stem cell REFERENCES Accessed July 22.20/6. research and clinical translation [press release). 1. National Instimes of Health. Estimates of 5. Le TcurneauC Deiced JP. Gni-calves A.et al. Skokie, IL: International Society for Stem Cel funding for various research. condition, and disease Molecularly targeted therapy based on tumour Research; May 12. 2016. categories. https,fireport nth.govkategoncal molecular profiling versus conventional therapy for ,spending.aspx.Accessei July 21. 2016. advanced cancer (SHIVA). Loncet Oncoi. 2015:16 (13).1324.1334. 1356 JAMA October 4.2016 Volume 316. Number 13 fi CopyrigM 2016 American Medical Association. AO rights reserved. Downloaded From: by a Royal Society of Medicine - Library User on 02/19/2017 EFTA00603135