Let s Standardize Reporting of Clinical Trial Results! A Patient Advocate s Perspective

Transcription

1 Let s Standardize Reprting f Clinical Trial Results! A Patient Advcate s Perspective An Opprtunity t Imprve Public Understanding and Trust in Clinical Research, while Making Analysis by Experts Mre Efficient Reprting bias represents a majr prblem in the assessment f health care interventins. 1 we submit that the lack f standards n what needs t be reprted and hw it is frmatted cntributes t reprting bias, misunderstanding, and lss f trust in clinical research. Here Pick a clinical abstract at randm and yu may get a feel fr hw challenging it can be t extract the key infrmatin and its significance: Infrmatin is rganized in a randm rder, and selected by the authrs Here we prpse the use f required elements and a tabular frmat fr reprting n trials fr interventins against cancers and perhaps ther life-threatening cnditins which we expect culd be cmplementary t the Natinal Institutes f Health gal t expand the Clinical Trials Registry and Results Database. 2 Infrmatin is rganized lgically as determined by peer review Scientists may argue that the intended audience fr clinical research is nt the patient cmmunity r the public at large that clinical abstracts are infrmal summaries (cnversatins) by and fr scientists and that structured reprting wuld be burdensme. We remind that by definitin clinical research requires patient participatin invlves individuals wh take substantial risks 1 Natalie McGauran, et; Reprting bias in medical research - a narrative review ; Trials. 2010; 11: April NIH: Expansin f the Clinical Trials Registry and Results Data Bank

2 when participating in drug trials; and that imprving patient utcmes is the cre bjective f clinical research. We nte als that there are many hidden csts, inefficiencies, and missed pprtunities assciated with free-frm clinical reprting, including a substantial invitatin fr biased reprting by what is left ut, ver-emphasized, r lst in the clutter. Ethical clinical research shuld cntribute t generalizable knwledge and imprve human health. The dedicatin f patients wh take the risks t participate in clinical research is dishnred when their data remain secret. - Alastair J.J. Wd, M.D 3 Here we are cmpelled t add t Dr. Wd s cmment that patients are shrt-changed in mre subtle ways when the data is bscured r biased, even if unintentinally by hw it is presented r interpreted by the varius stakehlders. The media tending t reprt in ways that attract readers, r the drug spnsrs tending t reprt in ways that attract investrs, r the investigatrs tending t reprt in ways that will supprt their hypthesis r enhances the significance f their wrk. This is nt t suggest that evil intent r deliberate calculatins t deceive are guiding the actins f investigatrs r drug spnsrs, wh truly play vital rles in clinical research. Mst patients when initially diagnsed with a cancer have little r n medical backgrund r training in drug assessments r scientific methd. Nr d we ften have access t the full text f reprts published in medical jurnals. Hwever, the abstracts describing this research are widely available n the Internet r indirectly reprted thrugh press releases, which have a very pr track recrd fr bjective reprting. 4 The review f clinical reprts is a cmplex task that requires extensive training and skill. Hwever, many patients facing life-threatening disease, r their lved nes, having an urgent need t knw will ften d their best t uncver what the studies suggest r seem t prve in rder t make mre infrmed clinical decisins. Faced with media-brn misinfrmatin and cnflicting interpretatins even amng prfessinals, the public may lse trust in the clinical research prcess. Lacking standards fr reprting, patient and physician analysis will be based ften n incmplete infrmatin. The beliefs f patients will be based n happenstance acquired frm untrained parents, an influential friend, the claims made in shck media, a best-selling bk r ppular website which makes the gal f infrmed medical decisin-making mre challenging than it needs t be. Amid the chatic reprting standards we have bserved that ne reprt can be, unwisely, cnsidered equivalent t any ther. That is, patients may trust specific clinical trial reprts t much r t little, r embrace them t selectively based n what we want t be true, r based n the faith we have in certain individuals r institutins r we may unwisely mistrust any study funded by a drug cmpany r the gvernment. T help t address the cnfusin and its assciated csts (bias, misinfrmatin, and mistrust amng them), we ask if a structured frmat culd be required fr clinical reprts submitted t the medical jurnals with a fcus n the elements f clinical research that are key t assessment f any drug by the FDA fr marketing apprval. Nting that ne need nt have a deep understanding f the bilgy f the disease, r the mechanisms f a drug t appreciate which studies prvide strng r weak evidence f meaningful clinical benefit if the key findings are reprted cnsistently, and backgrund infrmatin is prvided abut each f the key elements. In Table 1 which fllws, we prvide ur draft prpsal: a Tabular frmat with required utcme Elements in Lgic Lcatins (TELL). In Table 2, we prpse reader-friendly but cncise explanatins f TELL elements fr the public and the media. Each shuld be cnsidered starting pints r suggestins frm an interested third party: patients! T jurnal editrs wh may wrry abut the space requirements f a TELL-like frmat and the assciated csts, we nte that imprving the clarity and bjectivity f clinical reprting seems an excellent tradeff. Further, free-frm abstracts might still be used by jurnals if the abstract r full paper includes a link t a TELL. The full text f the published paper culd then prvide the technical illustratins and in-depth backgrund fr scientists, n the bilgy f the diseases and mechanisms f actins, which wuld cntinue t nurture prductive cnversatins and supprt cntinuing prgress against human disease. Advantages f Standard Reprting in a TELL-like frmat: Enhance the ability f the scientific cmmunity t efficiently filter and weigh reprts, and cmpare results acrss different studies and jurnals. 3 Wd, Alastair J.J. Prgress and Deficiencies in the Registratin f Clinical Trials N Engl J Med : Daniel M. Ck et al; Reprting Science and Cnflicts f Interest in the Lay Press PLS ONE. 2007; 2(12): e

3 Help spnsrs and clinical investigatrs t make better decisins when designing clinical studies t measure TELL events. Act as a deterrent against intentinal r unintentinal spnsr/investigatr bias and cmmn media-brn misinfrmatin. Discurage reprting f clinical data that has nt yet matured. Help build supprt and imprve public cnfidence in the bjectivity f clinical science, needed t merit public funding f NIH. Prvide a strnger basis fr infrmed cnsent amng patients and their treating physicians when cnsidering clinical trials based n preliminary evidence f efficacy and safety. Fster mre bjective judgments amng financial investrs abut which candidate drugs have the mst ptential, helping t attract needed capital t the mre deserving inventins, while letting the less prmising agents fail faster. By prviding universal templates fr abstracts the authrs may prduce higher quality abstracts mre efficiently. And, as nted, such reprting wuld be cmplementary t the NIH initiative t expand the Clinical Trials Registry and Results Database. The results culd be efficiently prted, frm ne registry t anther if it is first reprted in a structured way. Finally, we have bserved in FDA drug advisry cmmittee reviews that the review is usually based n utcme events and detail abut the study ppulatin (the cntext), as included in TELL belw. Such infrmatin is rarely if ever prprietary in need f prtectin frm public disclsure. Karl Schwartz President, Patients Against Lymphma See TEL Tables 1 and 2 belw.

4 Table 1 Elements N Evaluated / Intent t Treat Ppulatin Clinical circumstance Study Type Primary Clinical Questins Primary Findings Met? Yes/N/Mixed Secndary Clinical Questins TELL Reprt Frmat (prpsed starting pint): Number f participants in the clinical trials - Evaluated / Intent t Treat. We prpse that intent t treat be included in all clinical research abstracts, expressed as: N = Evaluated / ITT Example: Evaluable: N = 300/500 Medical cnditin (and subtypes): Risk: High, medium, lw risk Perfrmance index Prgnstic index Median number f prir therapies (and type) Median age Genetic characteristics if any Phase: Randmized / Single arm Prspective / subset analysis Endpints: Safety Overall respnse rate CR rate, Prgressin Free Survival, Survival Prvide pre-specified gal (relative t histrical cntrl) if a single-arm study As defined in Primary Clinical Questins Expressed as Rate, include Cnfidence range, such as: Evaluated: CR/n (%) (CI range) Intent t Treat: CR/n (%) (CI range) Endpints: Safety Overall respnse rate CR rate, Prgressin Free Survival, Survival Prvide pre-specified gal (relative t histrical cntrl) if a single-arm study Secndary Findings Met? Yes/N/Mixed Fllw-up Administratin As defined in Secndary Clinical Questins Expressed as Rate, include Cnfidence range, such as: Evaluated: CR/n (%) (CI range) Intent t Treat: CR/n (%) (CI range) Median fllw-up: Final r Next: Hw prtcl was scheduled and administered Cycle = x, Number f Cycles, Number f Treatment Days, Treatment Duratin in weeks Rute: Oral, IV, Cntinuus infusin, Subcutaneus) Hw Endpints were measured Summary f hw utcmes were measured, such as: By: Independent / Investigatr Schedule (weekly, mnthly): Type (bld, imaging): Maturatin f Data Safety Results Mrtality Limitatins Cmpleted / Interim? Time t enrllment and analysis? Median time f fllw up: Need fr fllw-up? Expressed as rate with range: By grade (severity): Serius first. Fr Evaluated: SE/n (%) (CI range) Fr ITT if txicities led t drpping ut Death rate: Treatment-related:, Other: On study Off Study Evaluated Intent t Treat Expected rate in this ppulatin: Authrs describe limitatins f the study methds and design such as sample size, r study type t describe level f evidence and if findings are cnsistent with ther studies Discussin Free text area. Authrs might prvide here the implicatins f the findings interpretatins, and backgrund that des nt fit in the clinical results fields.

5 TABLE 2 Elements N Evaluated / Intent t Treat An easy way t judge the pwer f the study at a glance. Intent t Treat (ITT) Ppulatin (Clinical circumstance) Study Type Primary Clinical Questins Endpints Methds: Prtcl Methds: Assessment Maturatin f utcmes Efficacy and Safety Results Mrtality Limitatins These are prpsed explanatins f TELL elements, which t save space wuld nt be included in published abstracts but culd be available n the Internet fr the public and media. Stands fr the number f participants in a study. It prvides the denminatr - a way t estimate the rate f results in the real wrld. T illustrate by extreme example, imagine hw little cnfidence we can have in a study f tw patients, reprting a 100% respnse rate. A meaningful denminatr is absent frm case reprts and testimnials a reasn such reprts are described as anecdtal which is shrthand fr nt evidence f causality (that the interventin led t the result) r predictive f utcmes fr thers. Study results frm a pre-defined N (r prspectively defined patient sample) prvide mre cnfidence than a numbered determined by chance, circumstances, r investigatr ad hc decisins. The latter culd be determined when the utcme is mst favrable, which undermines the integrity f the result. This number accunts fr all f the participants that enrlled in the study, nt just thse wh cmpleted the prtcl and were available fr evaluatin. When the ITT is greater than the number Evaluated, it calls int questin the integrity f the analysis, and hw well it culd apply t results in the real wrld. Hw scientists and regulatrs interpret the results f a study is dependent n the ppulatin the natural histry f the disease untreated, r treated differently, but als the characteristics f the participants (age, perfrmance, number and type f prir therapies). Did the study ppulatin have lw r high-risk disease? Fr example, respnse rates in the previusly untreated lymphma patients can be mre difficult t interpret than in thse wh have received many prir therapies. Randmized studies prvide the mst bjective basis fr identifying and cmparing risks and benefits, relative t the cntrl therapy typically the standard f care. Endpints describe what is being measured t determine if the interventin prvided meaningful clinical benefit net benefit r harm. Of the measures used in clinical research, Survival is cnsidered the mst reliable as it accunts fr measured and unmeasured effects. Hwever, survival differences cannt always be measured fr cnditins that have a lng clinical curse, especially where ther treatments will cnfund assessment was it imprved by the first r last treatment? Patients will want t knw hw the drug is administered: rally, by IV, by cntinuus infusin, and the duratin f treatment. Ntably, Independent data mnitring is ften used in pivtal phase III trials t guard against biased interpretatins, and t prvide cnsistent evaluatin methds. Even after a study has cmpleted the administratin phase, many mnths r years may be needed t measure the endpints, such as time t prgressin r ther events being measured in the study. (A reasn that validated bimarkers that predict lnger-term utcmes are urgently needed t accelerate prgress.) T reliably calculate the respnse rates in the study ppulatin requires a predefined defined denminatr (N), which is the basis fr estimating the rates fr study drug effects in the general ppulatin. Ntably, case reprts and testimnials, lacking a denminatr (the number f participants), cannt be used t determine if the interventin even caused the utcme, r hw likely the reprted utcme will ccur in thers which is critical t medical decisin making. Mrtality events can be acceptable in a ppulatin with high-risk disease. Reprducibility is the crnerstne f cnfidence in clinical utcmes the bjective assessment f risks and benefits. Size (N) cunts, but having a secnd grup achieve similar findings makes errr (false negatives r psitives) less likely. Discussin Randmized studies prtect against patient selectin bias and prvide a reliable cntrl t cmpare benefits and risks. Experts have nted that the cnclusins f research authrs are prne t bias, which can be cnsidered a cnclusive finding by the general public when published r quted by the press.