Publication of Clinical Research PDF

Publication of Clinical Research Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Complex interactions in relationship between industry and an investigator Rutherford: J Vasc Surg, Volume 31(...

Publication of Clinical Research Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Complex interactions in relationship between industry and an investigator Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076 Higher Percentage with financial ties correlated with increased support from authors. Fluconazole looks great compared to amphotericin B because amphotericin is a bad control. Meta analysis compares the means of a bunch of studies to the hazard ratio. 1 = no hazard ratio compared to control. Lines shifting to the right = most Beneficial to the control and to the left = not beneficial to the control. Industry supported studies had hazard ratio greater than 1, therefore financial assistance makes an impact in research.  Potential problems with industry-supported clinical research  Financial conflict of interest  Data collection, analysis, and  Nondisclosure agreements control of data: data  The research contract monitoring committee  Development of research  Data analysis protocols  Interim data release  Comparative groups:  Presentation and publication inclusion and exclusion of data criteria  Adverse events  Blinding and randomization  Negative trials  End points  Delays in publication  Cost considerations  Multiple publications  Institutional Review Board  Publication committees approval Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  Financial conflict of interest  After publication of the first study of the efficacy of TPA, it was reported that several investigators owned stock in the sponsoring company.  As a result, the AMA recommended that investigator should not hold stock or stock options in the sponsoring company or be an officer of the company  a company may offer stock after completion of the research, in recognition of contributions to the development or testing of a device or drug, as long as it is not by prior tacit agreement  Nondisclosure agreements  protect the company against the investigators divulging proprietary information and thereby devaluing the product  frequently do not address the investigators nor give them appropriate credit or reward for innovative ideas or advice Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  The research contract  contract to perform an industry study may be complex  must have a lawyer to protect rights and integrity of investigator  clauses dealing with publication rights, confidentiality, intellectual property, access to data, and conflict resolution, in particular, should be carefully reviewed to ensure patient safety through prompt access to data and to guard the scientific freedom of the investigator. Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Case study of an unfavorable arrangement The Olivieri case at the Hospital for Sick Children in Toronto illustrates the complexity of this problem. The following paragraph was included in the contract of a drug study : Contract provides that all information whether written or not, obtained or generated by you during the term of the LA-02 Contract and for a period of three years hereafter, shall be and remain secret and confidential and shall not be disclosed in any manner to any third party except with the prior written consent of Apotex. Please be aware that Apotex will take all possible steps to ensure that these obligations of confidentiality are met and will vigorously pursue all legal remedies in the event that there is any breach of these obligations. —Excerpt from a letter dated May 24, 1996, from Dr Michael Spino, vice president of Scientific Affairs, Apotex Research Inc, to Dr Nancy Olivieri.  During the study of the drug deferiprone for the treatment of iron overload in patients with thalassemia major, Dr Olivieri became concerned that the drug lost effectiveness with long-term use and suspected that it might worsen hepatic fibrosis. When these safety concerns were reported to the hospital's research ethics board, she was instructed to change the wording of the informed consent. When informed of the change, Apotex terminated the drug trial in Toronto. When it was determined that the data of others reflected similar observations, Dr Olivieri and her colleagues, in the face of threatened legal action from Apotex, published the controversial findings in the New England Journal of Medicine. This study raised important issues within the scientific community related to contracts with companies that are signed by an individual researcher, and the researcher's hospital research institute, hospital administration, hospital institution review boards, and university. It also illustrates the importance of institutional policies and procedures that define the responsibilities for scrutinizing a contract. Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Case study of an exemplary relationship Citing a publication on the economic analysis of low-dose heparin versus the low-molecular-weight heparin enoxaparin (Etchells, Arch Intern Med 1999;159:1221). Under the heading of “funding” the following statement was made: Unrestricted funding for this analysis was provided in part by Rhone-Poulenc-Rorer (Quebec, Quebec), the manufacturer of enoxaparin. The terms of the contract with the company were determined at the outset after we proposed the study design and methods, including measurement, modeling, and analytical strategies. We retained the rights to control entirely the methods and conclusions throughout the study and to publish or otherwise disseminate the results of the study and their conclusions regardless of outcome. The company received a copy of the report and manuscript before publication but was specifically precluded from influencing us at any stage after the contract was signed.  This type of contract is the only acceptable one and is uncommon Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  Development of research protocols  investigator has the ethical responsibility to ensure that the design and execution of the study protect the patient's rights  investigator has a responsibility as a scientist to see it properly designed so as to produce meaningful data to answer the question posed by the trial  investigators should not simply accept a sponsor-drafted protocol but should take an active role in the design of the trial  examples of issues: lacks objective enough end points, too favorable exclusion and inclusion criteria, lacks appropriate controls, uses historical controls, does not account for treatment crossovers or does not analyze their impact on outcome judged solely on an intent to treat basis, has too short a follow up, or fails to include a cost analysis and quality-of-life assessment) Company's underlying goal may only be to prove “safety and efficacy” to take the quickest route to gaining regulatory approval, rather than to compare the treatment with current competitive approaches Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  Comparative groups: inclusion and exclusion criteria  include only favorable groups in study  Blinding and randomization  must define mechanism of randomization  must be double blinded  End points  choice of end points of a trial is critical  end point must constitute evidence of efficacy of treatment  stopping point must be defined  end point must be realistic  Cost considerations  beware of attempts to restrict costs or not permit sufficient patients for appropriate power or sufficient follow up – company may have limited resources for proper study  COI over payments, IRB should get the contract and has recommendations for avoiding COI. Disclose support in consent; Support of research office for study costs is appropriate Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  Institutional Review Board approval IRB must ensure that the study design is scientifically valid  must approve the ethics of the study to ensure that patients are properly enlisted, receive appropriate informed consent, have a low risk-benefit ratio if enrolled in the study, and are not subjected to unnecessary procedures  must be sure that the financial arrangements are appropriate  IRB must receive reports to monitor the study as it progresses  To safeguard patient care, the investigator must have reports from the data- monitoring committee to communicate safety of to the IRB regularly  Data collection, analysis, control of data: data monitoring committee  If the company controls the data and does not provide frequent reports, including complications, investigators may not be able to fulfill their ethical and moral obligation to the patients and their responsibilities to the IRB  Interim evaluation of the data is important to detect unexpected complication, low accrual rates, protocol violations, incomplete follow-up, and other problems to ensure safety (analysis of a trial is a dynamic process) data-monitoring committee is optimum method to protect patients' interests; must not leak data or patterns of enrollment will be affected Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.)  Data analysis  very frequently company only releases summarized analysis of the data to investigators for meeting abstract presentation or manuscript preparation; these investigators cannot review the raw data or perform or check statistical analyses and respond to reviewers or discussants- this often leads to problems  the FDA often approves a drug prior to publication of the manuscript demonstrating efficacy because the raw data is unavailable to the investigators to respond to reviewers. Licensing takes priority over science!  Interim data release  may have conflicting effects: may be too rosy, boosting expectations early, may be more pessimistic later and company may withhold permission to present at meetings.  Has implications for company stock price, usually only abstracted data is made available to scientists Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research- presentation and publication of data Adverse events  Reports of serious adverse events should be circulated immediately by the company to all investigators, who notify patients, institution, and IRB.  Negative trials  there is a tendency not to submit negative results for publication  it is difficult to get negative trials published in good journals.  companies are not likely to want to report negative trials  failure to publish negative results may result in the continuation of harmful patient treatment, unnecessary duplication of studies, and failure to release important scientific data;  failure to publish negative data subverts the ethical principle of honesty in publishing research data.  In some instances, the contract between the investigator and the company may appear to give the company the right to block publication but informed consent is a contract as well and states something to the effect: “the patient has agreed to participate in an activity with risk and has the right to be assured that the results of the study will be transmitted to the scientific community in a timely fashion.” Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076  Potential problems with industry-supported clinical research (cont.) Delays in publication  Although the company may encourage early publication of favorable results, conflict may result if the results are not favorable to the company  patients were assured of prompt disclosure of the results of a trial if there is a clear difference between groups either way  Investigators should be certain that a publication committee is established before the start of the study and that provision for prompt publication of the results is assured in the research contract they sign  The research contract should specify that the company can only delay publication for a reasonable time, ordinarily, 90 days, to allow them to review the manuscript and complete application for patent submission  Multiple publications  multiple publications of the same longitudinal data may have different starting points, obfuscating the data  Publication committees  early establishment of a publications committee from among the principal investigators chaired by one of them is the optimum for ensuring publication. Rutherford: J Vasc Surg, Volume 31(5).May 2000.1066-1076 COI=conflict of interest  TYPES OF SCIENTIFIC MISCONDUCT IN CLINICAL TRIALS FROM SELF-REPORTS OF CLINICAL TRIAL EXPERTS Overinterpretation of "significant" findings in small trials Selective reporting based on p values Selective reporting of outcomes in the abstract Subgroup analyses done without interaction tests Negative or detrimental studies not published Putting undue stress on results from subgroup analyses Inappropriate subgroup analyses Selective reporting of (1) subgroups, (2) outcomes, (3) time points Selective reporting of positive results or omission of adverse events data Failure to report results or long delays in reporting Post hoc analysis not admitted Giving incomplete information about analyses with nonsignificant results Analysis conducted by the sponsor of the trial Coultas D. Proceedings of the American Thoracic Society. 4(2):194-8, 2007  Publication standards  Editorial oversight, through publication standards and independent investigations is a key method for controlling misconduct in the interpretation and communication of research results.  Recognizing the need for quality improvement of clinical trial reports, two groups published proposals in the mid-1990s for improved and more structured reporting of clinical trial results.  Subsequently, these guidelines were consolidated into Consolidated Standards of Reporting Trials (CONSORT) in 1996, and updated in 2001; these are available online at www.consort- statement.org.  The current CONSORT statement consists of a 22-item checklist and a diagram template for patient flow Coultas D. Proceedings of the American Thoracic Society. 4(2):194-8, 2007  Methods to limit ethical misconduct in the interpretation and communication of clinical trial results. Coultas D. Proceedings of the American Thoracic Society. 4(2):194-8, 2007  CONSORT E-CHECKLIST Paper Section* Item Description Title and abstract 1 How participants were allocated to interventions (e.g., "random allocation," "randomized," or "randomly assigned") Introduction Background 2 Scientific background and explanation of rationale Methods Participants 3 Eligibility criteria for participants and the settings and locations where the data were collected Interventions 4 Precise details of the interventions intended for each group and how and when they were actually administered Objectives 5 Specific objectives and hypotheses Outcomes 6 Clearly defined primary and secondary outcome measures and, when applicable, any methods used to enhance the quality of measurements (e.g., multiple observations, training of assessors) Sample size 7 How sample size was determined and, when applicable, explanation of any interim analyses and stopping rules Randomization–sequence generation 8 Method used to generate the random allocation sequence, including details of any restrictions (e.g., blocking, stratification) Randomization– allocation, concealment 9 Method used to implement the random allocation sequence (e.g., numbered containers or central telephone), clarifying whether the sequence was concealed until interventions were assigned Randomization– implementation 10 Who generated the allocation sequence, who enrolled participants, and who assigned participants to their groups Blinding (masking) 11 Whether or not participants, those administering the interventions, and those assessing the outcomes were blinded to group assignment; when relevant, how the success of blinding was evaluated Statistical methods 12 Statistical methods used to compare groups for primary outcome(s); methods for additional analyses, such as subgroup analyses and adjusted analyses Coultas D. Proceedings of the American Thoracic Society. 4(2):194-8, 2007  CONSORT E-CHECKLIST (Cont.) Paper section Ite Description m Results Participant flow 13 Flow of participants through each stage (a diagram is strongly recommended); specifically, for each group report, the numbers of participants randomly assigned, receiving intended treatment, completing the study protocol, and analyzed for the primary outcome. Describe protocol deviations from study as planned, together with reasons. Recruitment 14 Dates defining the periods of recruitment and follow-up Baseline data 15 Baseline demographic and clinical characteristics of each group Numbers analyzed 16 Number of participants (denominator) in each group included in each analysis and whether the analysis was by "intention to treat." State the results in absolute numbers when feasible (e.g., 10/20, not 50%). Outcomes and estimation 17 For each primary and secondary outcome, a summary of results for each group, and the estimated effect size and its precision (e.g., 95% confidence interval) Ancillary analyses 18 Address multiplicity by reporting any other analyses performed, including subgroup analyses and adjusted analyses, indicating those that are prespecified and those that are exploratory Adverse events 19 All important adverse events or side effects in each intervention group Discussion Interpretation 20 Interpretation of the results, taking into account study hypotheses, sources of potential bias or imprecision, and the dangers associated with multiplicity of analyses and outcomes Generalizability 21 Generalizability (external validity) of the trial findings Overall evidence 22 General interpretation of the results in the context of current evidence Coultas D. Proceedings of the American Thoracic Society. 4(2):194-8, 2007  Meta-analysis  The statistical analysis of data from multiple randomized cancer clinical trials  Purposes include:  testing of a null hypothesis about a given treatment in a given cancer  estimation of the treatment effect  exploration of the treatment effect in subsets of patients Fundamental reason for the interest in meta-analyses is that:  most cancer clinical trials are too small, thus the power is too small to detect critically meaningful differences  there is little precision in estimating meaningful differences  there is no value in doing subset analysis  The combination of trials into a single analysis is meant to overcome these difficulties caused by small sample sizes for individual trials  Meta-analysis (cont.)  The importance of meta-analyses lies mainly in exploration, not confirmation  A meta-analysis is a poor substitute for one large, well- conducted trial  The expectation that a meta-analysis will be done does not justify designing studies that are too small to detect realistic differences with adequate power  A well-done meta-analysis  is a good review of existing data  can provide an idea of the possible magnitude of treatment benefit  can generate hypotheses about treatment effects and subsets power  The quality of each trial needs to be taken into account  With very large meta-analyses, keep in mind that not all statistically significant results are clinically meaningful  Meta-analysis principles  All trials must be included – published or not!  Identification of all such trials may be the most difficult part of a meta analysis  Including only trials that were published runs the risk the well known bias toward the publication of positive trials  Cannot arbitrarily select tangentially related published results, throw them together and call them a meta-analysis For meta analysis, cannot select unrelated published results. Results in meta analysis must be relevant to drug for a given Disease.  Meta-analysis principles (cont.)  The raw data from each trial must be retrieved and reanalyzed  This allows a common endpoint to be estimated with standard errors from each trial  Published data are almost never sufficient for this purpose because different studies used different endpoint definitions and possessed different endpoints in the results sections of the manuscripts  Use of raw data allows the employment of a uniform set of inclusion criteria and to update survival results.  This gives the added advantage of providing more mature survival data  Reduces bias that was the result of trials that stopped early in one sided monitoring (A is better than B rather than one is better than the other)  Meta-analysis principles (cont.)  Be very careful about lumping fundamentally different interventions into one meta analysis  Treatment regimens often differ in basic ways that could affect efficacy, such as dose, dose intensity, dose-modifying agents, route or timing of administration  Truly disparate interventions should not be forced into a single measure of treatment benefit  Each trial should be presented in summary form and the overall analysis, if any, should be done by stratifying on the trials, not by collapsing over trials.  Meta-analysis principles (cont.) A measure of the quality of the trials should be incorporated into the analysis  Sensitivity analyses using different weights for each trial, including leaving out some trials altogether, should be performed