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Correspondence to: P Wicks pwicks@patientslikeme.com

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Correspondence to: P Wicks pwicks@patientslikeme.com
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  CLINICAL TRIALS Subjectsnomore:whathappenswhentrialparticipantsrealize they hold the power? OPEN ACCESS Patients will hold us all accountable in new and necessary ways PaulWicks vicepresidentofinnovation  ,TimothyVaughan directorofdatascience  ,JamesHeywood cofounder and chairman  PatientsLikeMe, Cambridge, MA 02141, USA The social contract of the randomized controlled trial isimbalanced: patients adhere to arduous protocols, arerandomized to placebo, and are blinded to their health status.Although most participants (>90%) would like a lay summaryof results, 1 only a minority (<10%) receive one, 2 with theremainder left with the option of paying around $30 (£18; €22)toreadtheresultsoncethestudyispublishedinapeerreviewed journal. 3 Suchimbalancesmayhavecontributedtoanemergingmovement, enabled online by “patient powered researchnetworks,” 4 in which participants have begun systematically tounblind themselves, pool their data, parse literature, conductstatistical analyses, and post their findings online.In2007,patientswithamyotrophiclateralsclerosis(ALS)usedGoogle to translate an Italian conference abstract suggestingthatlithiumcarbonatemightslowtheirillness. 5 Inapublicationtitled “Lithium delays progression of ALS” 16 patients treatedwith lithium (all of whom survived 15 months) were comparedwith 28 control patients (a third of whom did not survive thetrial). 6 Within six months of the abstract’s publication 160patients reported obtaining lithium off-label and tracked theirprogression using Google Spreadsheets and the validated ALSfunctional rating scale (ALSFRS-R). 7 A patient in Brazil and acaregiver in the United States initiated this patient led study,raising the question of where ethical oversight lay. 8 9 Our patient network, PatientsLikeMe, already allowed entry of ALSFRS-R scores but added tracking of lithium bloodconcentrations, data entry reminders, and monitoring by nursesto curate reported side effects. We presented data indicatingthat lithium was ineffective within nine months of therandomized controlled trial 10 then published longer termfollow-up data with more sophisticated analyses in an openaccess  Nature Biotechnology  paper, which included the entirede-identified dataset as supplementary material. 11 Fourrandomizedcontrolledtrialssubsequentlyreplicatedournegativefindings. 12 Shortlythereafterrandomizedcontrolledtrialsoftwonewdrugswere under way: of NP001, manufactured by Neuraltus (in aphase II trial) and Biogen’s dexpramipexole (phase III).Participants in these trials shared data while formally enrolledunder protocols in which they were meant to be blinded andunaware of their ALSFRS-R score. They charted their ownprogress, seized on known side effects such as neutropenia inanattempttounblindthemselves,andusedrudimentarystatisticstoanalyzetheefficacyofbothdrugs.AroundathirdofthetotalNP001groupand10%ofUSdexpramipexolepatientsrecordeddataonline.Athirdexperimentalgroupwasformedwhensomepatients read the patents on NP001 and inferred that theindustrialcleanersodiumchloritemightbetheactiveingredient.Some patients who could not enroll in the trial started ingestingindustrial sodium chlorite orally or intravenously. 13 Althoughwehaddataonfewerparticipantsthanforthelithiumtrial,wesharedouranalysisofallthreegroupsthroughFigshareon the eve of the unblinding of the dexpramipexole trial. 14 Withimportantcaveats,weestimatedthatdexpramipexolewasbelowthecuspofprovidingaclinicallysignificantbenefit 15 andNP001 just above it, but with confidence intervals that were too wideto draw a reliable conclusion (figure). Alarmingly, patientsingesting off-label sodium chlorite progressed worse thanexpected (figure). Biogen’s dexpramipexole trial reported noeffect, 16 and funding is awaited for a phase III trial of NP001.WhenALSUntangledusedourdatatowarnagainstthepotentialdangers of sodium chlorite, its off-label use diminished. 17 Correspondence to: P Wicks pwicks@patientslikeme.com No commercial reuse: See rights and reprints http://www.bmj.com/permissionsSubscribe:http://www.bmj.com/subscribe BMJ   2014;348:g368 doi: 10.1136/bmj.g368 (Published 28 January 2014) Page 1 of 2 Observations OBSERVATIONS  EstimatesofeffectsizeforselectedALStreatments.Eachlinerepresentstheprobabilitydistributionoftheeffectsize;a high, narrow peak indicates that the effect size is moreprecisely estimated (generally because of larger samplesize). More effective treatments will be centered towardthe left 14 The concept of “scientific altruism” may be being trumped by“maximizeyourchanceofsurvival.”Forbetterorworse,digitaltools enable greater self knowledge and rapid dissemination.The consequence is that scientific design, informed consent,and ethical oversight can be short circuited by patient led“disobedience.”Somedrugcompanieswillchoosetosharetheirclinical trial data (as AllTrials suggests), but even if they don’tthe data can become available if participants choose to sharetheir data themselves, something that will only be enhanced bypatient access to electronic medical records. Today membersof PatientsLikeMe report tracking their outcomes in over 400randomized trials. Patients increasingly realize that they areboth statistically and literally the “power” in trials and we needto build systems that redress the imbalance. If we collectivelydo nothing, a phase III study might be rendered scientificallynullbyacriticalmassofparticipantsmakingintentionalprotocolviolations on PatientsLikeMe, Facebook, or Twitter.This would be a tragic outcome. To prevent that, we proposeforging a new social contract that maximizes both scientificdiscovery and patient autonomy, setting the stage for bettertrialswithmoreengagedparticipants.Togetherwecandeveloprigorousnewmethodstoincludepatientsinselectingtherapies,protocol design, recruitment, feedback, lay summaries,publications, and assessment of value. We are encouraged bythe development of an online “open research exchange” thatallowsresearchersrapidaccesstopatientsforconceptelicitationand psychometric validation during the development of patientreported outcome measures, 18 which are now required by theFDA. 19 We believe that patients may surprise many of us withtheir ability to identify obstacles to trial enrolment, prioritizethe outcomes they truly value, and help us learn what works inthe real world, not just in trials. With the new tools at theirdisposal patients will hold us all accountable in new andnecessary ways. Patients themselves have already laid much of the groundwork; let’s ask them to continue building on thesenew systems together as equals. Competing interests: We have read and understood the BMJ policy ondeclaration of interests and declare PW, TV, and JH are employees ofPatientsLikeMe and own stock or stock options in the company. ThePatientsLikeMeresearchanddevelopmentteamhasreceivedresearchsupport from pharmaceutical companies and private foundations.Provenance and peer review: Not commissioned; not externally peerreviewed. 1 Partridge AH, Winer EP. Sharing study results with trial participants: time for action.  J Clin Oncol   2009;27:838-9.2 Cox K, Moghaddam N, Bird L, Elkan R .  Feedback of trial results to participants: a surveyof clinicians’ and patients’ attitudes and experiences.  Eur J Oncol Nurs   2011;15:124-9.3 ScienceDirect.Payperview.http://info.sciencedirect.com/sciencedirect/buying/individual_ article_purchase_options/ppv.4 Workman TA. Engaging patients in information sharing and data collection: the role ofpatient-powered registries and research networks. US Agency for Healthcare Researchand Quality, 2013.5 Frost JH, Massagli MP, Wicks P, Heywood J .  How the social web supports patientexperimentation with a new therapy: The demand for patient-controlled andpatient-centered informatics.  AMIA Annu Symp Proc   2008:217-21.6 Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, et al. Lithiumdelays progression of amyotrophic lateral sclerosis.  Proc Natl Acad Sci USA 2008;105:2052-7.7 CedarbaumJM,StamblerN,MaltaE,FullerC,HiltD,ThurmondB,etal.TheALSFRS-R:arevisedALSfunctionalratingscalethatincorporatesassessmentsofrespiratoryfunction. J Neurol Sci   1999;169:13-21.8 O’ConnorD.Theapomediatedworld:regulatingresearchwhensocialmediahaschangedresearch.  J Law Med Ethics   2013;41:470–83.9 Vayena E, Tasioulas J. Adapting standards: ethical oversight of participant-led healthresearch.  PLOS Med   2013;10:e1001402.10 WicksP,MassagliM,FrostJ,MacedoH,FelzerK,HeywoodJ . Apatient-ledtrialoflithiumin ALS using the internet.  Amyotroph Lateral Scler   2008;9:S59.11 Wicks P, Vaughan TE, Massagli MP, Heywood J .  Accelerated clinical discovery usingself-reportedpatientdatacollectedonlineandapatient-matchingalgorithm. NatBiotechnol  2011;29:411-4.12 Armon C. Is the lithium-for-ALS genie back in the bottle? Not quite.  Neurology  2010;75:586-7.13 Dokser Marcus A. Frustrated ALS patients concoct their own drug.  Wall St Journal   2012Apr 15. http://online.wsj.com/news/articles/ SB10001424052702304818404577345953943484054.14 Heywood J. Waiting for P<0.05.  Figshare   2012. http://dx.doi.org/10.6084/m9.figshare.9680215 Castrillo-VigueraC,GrassoDL,SimpsonE,ShefnerJ,CudkowiczME.Clinicalsignificancein the change of decline in ALSFRS-R.  Amyotroph Lateral Scler   2010;11:178–80.16 Cudkowicz ME, van den Berg LH, Shefner JM, Mitsoumuto H, Mora JS, Ludolph A, et al.Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis(EMPOWER):arandomised,double-blind,phase3trial. LancetNeurol   2013;12:1059-67.17 ALSUntangled Group. ALSUntangled No 19: Sodium chlorite.  Amyotroph Lateral Scler Frontotemporal Degener   2013;14:236-8.18 Wicks P, Heywood B, Heywood J. Online platform to accelerate patient involvement inopen instrument development.  Qual Life Res   2013;22:1-137.19 Gnanasakthy A, Mordin M, Clark M, DeMuhro C, Fehnel S, Copley-Merriman C .  A reviewof patient-reported outcome labels in the United States: 2006 to 2010.  Value Health  2012;15:437-42. Cite this as:  BMJ   2014;348:g368 This is an Open Access article distributed in accordance with the Creative CommonsAttribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute,remix, adapt, build upon this work non-commercially, and license their derivative workson different terms, provided the srcinal work is properly cited and the use isnon-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/ . No commercial reuse: See rights and reprints http://www.bmj.com/permissionsSubscribe:http://www.bmj.com/subscribe BMJ   2014;348:g368 doi: 10.1136/bmj.g368 (Published 28 January 2014) Page 2 of 2 OBSERVATIONS
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