EFTA00603134.pdf

Opinion VIEWPOINT Mkhaell J. Joyner, MD Laboratory of Human Integrative Physiology and Department of Anesthesiology. Mayo Clinic, Rochester, Minnesota. Nigel Paneth. MD. MPH Departments of Epidemiology and Biostatistics and Pediatrics and Human Development. College of Human Medicine. Michigan State UnNersay. East Lansing. JohnP.A.loannklis. MD. D5c Stanford Prevention Research Center. Department of Medone arelMeta. Research Innovation Center at Stanford. Stanford Universny. Stanford. California. Corresponding Author: John P. A. loannidis. MD. DSc. Stanford Prevention Research Center. Department of Me6cine and Meta-Research Innovation Center at Stanford. Stanford OnNersay.1265 Welch Rd. Medical School Office 13Iclg. Room X306, Stanford. CA 94305 (power! @stanford edu). What Happens When Underperforming Big Ideas in Research Become Entrenched? For several decades now the biomedical researchcom- munity has pursued a narrative positing that a combi- nation of ever-deeper knowledge of subcellular biol- ogy. especially genetics. coupled with information technology will lead to transformative improvements in healthcareand hu man health. In this Viewpoint. we pro- vide evidence for the extraordinary dominance of this narrative in biomedical funding and journal publica- tions; discuss several prominent themes embedded in the narrative to show that this approach has largely failed: and propose a wholesale reevaluation of the way forward in biomedical research. Primacy of the Narrative In 2016 approxi mately $15 billion of the $26 billion of ex- tramural research funding sponsored by the National In- stitutes of Health (NIH) could be linked to some version of search terms that include gene, genome, stem cells, or regenerative medicine.' These topics have also in- creasedgeometrically intheir representationarnang pub- khed articles. Between 1974 and 2014 the annual num- berof published articles indexed inPubMed increased by 410%(from 234 613to1 196 110). butthoseidentifiedwith genome increased by 2127% (2705 to 60246). Be- tween 1994 and 2014. the annual number of articles in- dexed in PubMed increased by 175% (from 435 376 to 1 196 110), but articles identified with gene therapy or stem cell increased by 874% (2635 to 25 662)and752%(3452 to29 196).Apparentty alarge number of scientists either believe in the potential of these topics or feel compelled to work on them, recognizing that these topics consti- tute a major locus of important science. financial sup- port, recognition, and prospects for a successful career. Exploring Some Key Examples In 1999. Collins' envisioned a genetic revolution in medi- cine facilitated by the Human Genome Project and de- scribed 6 major themes: (I) commondiseases will beex- plained largely by a few DNA variants with strong associations to disease. (2) this knowledge will lead to improved diagnosis, (3) such knowledge will also drive preventive medicine, (4) pharrnacogenomics will im- provetherapeutic decision making; (5)genetherapy will treat multiple diseases; and (6) a substantial increase in novel targets for drug development and therapy will en- sue. These 6 ideas have more recently been branded as personalized or precision medicine.; Similarly, there is the increasing interest in and expectation that stemcell therapy—a sevenththeme—can treatcommondiseases.3 To avoid the misconception that big ideas are all related to biological sciences, an eighth theme is the emphasis in the narrative on the clinical and research value of converting medical records to electronic for- mats. As of April 20I6, the Centers for Medicare & Med- icaid Services had paid $34 billion in financial incentives to service providers for implementing electronic health record (EHR) systems.' EHRs are an important aspect of this narrative because they are thought to provide the structural underpinnings of precision medicine. It has been suggested by some that some combination of these 8 big ideas will yield substantial cost savings for health care. Expectations that a few DNA variantsexplain most common diseases have faded as the genetic architec- ture of most diseases has proved to be formidably corn- plex. Apparently. hundredsor even tensof thousandsof genetic variants are involved in each common disease. The functionof thesevariants isdifficult todecipher. Very few genes havefound undisputed rolesin preventiveef- forts or pharrnacogenetic testing. Continued enthusiasm for gene therapy ignores what is known from classic single-gene disorders such as sickle cell anemia. The complex biological processes set in motion by a single amino acid substitution that leads to painful crises, stroke, and other complications are not predictable from the genomic defect. but only by appreciating thecomplexity of biological systems at the level of tissues and organs. Sixty years after the dis- covery of the genetic defect, no targeted therapy has emerged for sickle cell anemia. The complex and adaptive nature of most tumors thwarts the optimistic projections for molecularly tar- geted therapy for cancer. A randomized trial of targeted therapy based on molecular profiling for ad- vanced cancers from diverse anatomical locations showed no improvement in progression-free sur- vival.5 The NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) trial links patients withcancertodrugstar- geted against their cancer DNA mutations. So far, just 2.5% of screened patients have been assigned to a trial intervention group. Even though this fraction should increase as the number of trial treatment groups is in- creased, even if effectiveness is demonstrated, the rar- ity of the targeted mutations means that this approach will help only a minority of patients with cancer" The prospects of effective treatment based on stem cells have been challenged in comprehensive reviews of the available trials. For instance, in congestive heart fail- ure. improvements in cardiac function have been ob- served only in industry-sponsored studies, and a posi- tive relationship has been noted between effect sizeand the number of experimentaldesign flaws.' To itscredit, the International Society for Stem Cell Research has is- sued "anti-hype" guidelines that Itilighlight the respon- sibility of all groups communicating stem cell science and medicine—scientists. clinicians, industry. science Downloaded From: AMA October 4.2016 Volume 316. Number 13 1355 CopyrigM 2016 American Medical Association. All rights reserved. by a Royal Society of Medicine - Library User on 02/19/2.017 EFTA00603134 Opinion Viewpoint communicators, and media—to present accurate, balanced reports of progress and setbacks "8 The financial and clinical benefits predicted from shifting to EHRs have also largely failed to materialize because of difficulties in interoperability. poor quality, and accuracy of the collected infor- mation; cost overruns associated with installation and operation of EHRs at many institutions; and ongoing privacy and security con- cerns that further increase operational costs. These features make the use of EHRs for research into the origins of disease, as pro- posed in the Precision Medicine Initiative, highly problematic. No clearly specified targets for either improved outcomes or reduced costs have been developed to assess the performance efficiency of EHRs. Although it is difficult to argue for a return to paper records, any claim of future transformation of the medical record should include well-defined accountability and review mechanisms. Oth- erwise, the health care system may become hostage, wasting increasing resources to continuously upgrade electronic technol- ogy without really helping patients. None of these popular topics has had any measurable effect on population mortality, morbidity. or life expectancy in the United States. The improvements of the past decades in these outcomes, which have been substantial but are now stalling. have largely reflected improvement in nonmedical aspects of everyday life and the operation of broad-based public health and classic prevention efforts. such as curtailing smoking, that are undervalued as out- moded and old-fashioned by the narrative. The anticipation that improvements in medical care and outcomes derived from big ideas will reduce costs also seems unlikely given the high costs of applying targeted therapeutic interventions to small numbers of people based on complex and expensive technologies, as well as the inevitable overdiagnosis and overtreatment that follows from more intensive monitoring. Similarly, EHRs may increase health care costs due to their ability to enhance revenue capture and as a result of unanticipated security and upgrade expenses. What his- torical precedent is there that adoption of vast new oversophisti- cated technology reduces costs? Eventually. what is the definition of success and over what time frame? A Need for Reevaluation When claims about high- profile, dominant "big ideas" are viewed against their mediocre benefits, it seems that 2 basic courses of ac- tion are available. The first is to continue with calls for more fund- ARTICLE INFORMATION Published Online: July 28. 2016. dc.:10.1001flama.2016.11076. Conflict of Interest Disdosura: Al authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr loannidis reports support from an unrestricted gift from Sue and Bob 011onnel. No other disclosure were reported. REFERENCES 1. National Instimes of Health. Estimates of funding for various research. condition, and disease categories. https,fireport nth.govkategoncal ,spending.aspx.Accessei July 21. 2016. ing, more complex measurements, and more sophisticated instru- mentation. The second is to reevaluate and reset the current focus. Public funders such as NIH should expand the funding for ba- sic, "blue sky" science for which it is impossible to set. predict, and promise specific deliverables. In so doing, NIH should fund many more high-risk. unconventional ideas insteadof supporting the same familiar highly funded research fronts. However, novel funding mechanisms like NIH Pioneer Awards are currently only a tiny frac- tion of the total budget. When NIH funds translational or preclinical research with spe- cific deliverables promised (as in the case of personalized medicine. and stem cell therapy), independent assessors should regularly ap- praise whether these deliverables were achieved and, if so. at what cost, and with what effect. Assessors must be objective. indepen- dent of thefunding source. and havenoprofessional stake in whether a particular line of research is deemphasized. The deliverable crite- rion should include public health benefit achieved by these initia- tives (ie, measurable reductions in mortality and morbidity). Criteria such as number of publications. citations, prizes, and recognition are irrelevant as these are simply self-rewarding artifacts of the system. After several decades of substantial investment, the fundamental question is whether these big ideas have improved quality of life and life expectancy. by how much, for how many. and for whom. These are public dollars that should benefit the many, not the few. Mechanisms should be in place to sunset underperforming ini- tiatives. In the current environment, scientists are pigeonholed in a narrowdiscipline and are penalized by study sections if they exit their specific niche. There should be incentives for scientists to acknowl• edge that their research focus should be abandoned and help them switch to another potentially more fruitful research area. Another key question is whether NIH is best suited to fund all kinds of research that have specific deliverables. In some cases. private entrepreneurs may be most suited to develop new drug tar- gets, new drugs. new tests, and new technologies. Financial suc- cess in the market is a strong and sufficient incentive. Public funders may need to focus more on blue sky science and on late evaluation research, to evaluate without conflicts the drugs and other tech- nologies developed by entrepreneurs. NIH deinvestment in preclinical research promises that clearly do not deliver will allow morefundingtobedirected toward work of clear public health importanceand for imaginative biomedical researchthat is truly innovative and not constrained by current narratives. 2. Collins FS. Shattuck lecture—medical and societal consequences of the Human Genome Prclect. N Engl./ Afe0.1999.341(1):28-37. 3. Joyner Ml. Paneth N. Seven questcris for personalized medicine../Ama.2015.314(10):999. IOCO. 4. Centers for Melcare & Medicaid Services. Data and program reports. hoptifvnviv.cms.gov fregtiations-and.gtadance/legelation fehrincentiveprograms/dataandrepons.html. Accessed July 22.20/6. 5. Le Tcurneau C Deiced JP. Gni-calves A. et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA). Loncet Oncoi. 2015:16 (13).1324.1334. 6. National Institutes of Health. NCI.Mdecular Analysis for Therapy Choice (NU-MATCH) trial. http://wwwcanc er.goviabout.cancer/treatment /clinical.triabinci.supportedfnci.match. Accessed July22. 2016. 7. Nowbar AN. Mielevicat M. Karavassilis M, et al. Discrepancies in autologais bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE). BM/ 2014:348:g2688. 8. ISSCR releases updated giadelnes for stem cell research and clinical translation [press release). Skokie, IL: International Society for Stem Cel Research; May 12. 2016. 1356 JAMA October 4.2016 Downloaded From: Volume 316. Number 13 fi CopyrigM 2016 American Medical Association. AO rights reserved. by a Royal Society of Medicine - Library User on 02/19/2017 EFTA00603135