EORTC position on the place for transparency in the clinical trials regulation

Transcription

1 EORTC position on the place for transparency in the clinical trials regulation EORTC fully supports the need to increase transparency of clinical trials. Appropriate transparency within the clinical trials regulation would: 1. inform the general public, patients and scientists about the results of clinical research being done in the EU and increase the confidence of the general public in clinical research; 2. provide feed-back on trial results regardless of whether these are positive, negative, or inconclusive, or if the clinical trial could not be completed (providing the main reasons for this), and provide the scientific community with essential background information to foster the next generation of clinical trials; 3. enable independent re-evaluation of the results of pivotal clinical trials or any other clinical trial requiring such independent re-evaluation. The clinical trials regulation proposal released by the European Commission suggests that a public summary of trial results should be made one year after the end of the clinical trial. Clinical trial protocol or the statistical analysis plan and their updates are made public through the EU database during initial authorization of the clinical trial or resulting from the approval of amendment. The ENVI report proposed by the rapporteur Mrs. G. Willmott and amendments proposed by other MEPs also suggest making either lay summary of results, ICH E3 format report with line listings of patient data or full raw data of all clinical trials publicly available. It is important to understand that not all of these proposed formats would be conducive to the achievement of the specified aims. The table below provides a comparative overview of the three proposed formats (summary report, ICH E3 report or full row data set of a clinical trial) to assess whether these formats fit the purposes of the clinical trials regulation. The appropriateness of each of the public formats is considered separately.

2 Is the proposed format appropriate to fit the purpose*? Type of data / possible use Summary of results ICH E3 report Volume of information < 100 pages several hundred pages Learning about trial output when made public (patients, scientists ) Background information for the next trial Reproducing published trial results Yes, missing lay summary Yes, sometimes too little information Not possible Cumbersome Not as easy, cumbersome, too much information If attempted, it would not be reliable Performing additional analysis Not possible If attempted, it would not be reliable Is format globally useful for the defined purpose(s)? Purpose 1 Purpose 2 Purpose 3 *see three purposes defined on Page 1 YES PARTIALY PARTIALY Raw data Example of one trial of 550 patients: forms, data items Not possible without re-analysis Cumbersome (requires reanalysis) Possible, but data should be available in the right format Possible, needs good methodology, data should be available in the right format YES Risk assessment of the public release of the information. Type of data / risks Summary of ICH E3 report Raw data results Can patients potentially be No Yes Yes identified? Will the use be in compliance with the scope of patients consent? Yes Not necessarily (no control) Possible misuse by public What is the risk of misuse of data from the patients perspective Misunderstanding of results Extrapolation of results & different conclusion (unreliable) Low High High Not necessarily (no control) Inappropriate methodology & unreliable conclusions

3 From the above tables, it clearly appears that although the summary of trial results in the current format does not provide sufficient information and does not include a lay summary, the ICH E3 report provides large amounts of data in a cumbersome format with the potential risk of jeopardizing patient confidentiality and producing (by unidentified users) unreliable or inconclusive results. Therefore, to inform the general public and scientific community about clinical trial results in a way that minimizes the risk of data misuse, the EORTC would like to propose compromise amendments (see below). The below amendments clarify the format of the clinical trial report, which should be more than just the summary of results, but not to the extent as seen in the ICH E3 format. To enable independent re-evaluation of the results of pivotal clinical trials or any other clinical trial requiring such independent re-evaluation, sharing of raw data is necessary. However, the precise modalities and mechanisms of such data sharing should be assessed carefully with all stakeholders, including EMA. It should be considered to include within these modalities, among others, the need to request the access to the data with an explanation on who will access the data, why and how data will be used. These delicate modalities should not be set within the regulation (as proposed within the ENVI amendment 150). ENVI 150: (37a) Within two years after the adoption of this Regulation, the Commission should submit the European Parliament an evaluation of the management of raw data, and the feasibility of introducing an open access for independent scientists to raw data from all clinical trials. Compromise amendements Compromise amendement 1 (Replaces ENVI 21) Article 2 paragraph 2 point 30 a (new) Transversal amendment clinical trial report instead of summary of results ; concerns ENVI: 469 on article 29, 2a(new), article 34.3 (see compromise amendment 2), article 34.5, (30a) Clinical trial report : a report containing the full protocol and any annexes or subsequent modifications and dates thereof, lay summary of a clinical trial, a statistical analysis plan and the summary of results. Justification: not all clinical trials will support a drug registration dossier. Many trials aim to gain further knowledge about treatments or to improve treatment strategy. There is no need for these trials to produce a report in the ICH E3 format which contains a lot of potentially identifiable patient data (which cannot be made public in compliance to the current EU data protection legal framework) and brings no added value as compared to other possible formats. Clinical trials report should be publically available,

4 and therefore should not, contain any information that may lead to an identification of individual patients (it should only contain tables and aggregated data). The level of information provided should, however, enable the public to corroborate the presented results. Compromise amendement 2 (Replaces ENVI 51, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 539, 540 & 545) Article 34 paragraph 3 3. Within two years from the end of any clinical trial, the sponsor shall submit through the EU portal the clinical trial report, whether the results are positive, negative, or inconclusive. If the clinical trial has prematurely ended, the information concerning the reasons for this premature end should be submitted. The summary of trial results shall be made in compliance with Annex III a. The summary of trials results should only contain tabulated, aggregated or anonymous data. The Commission shall be empowered to amend this annex by adopting delegation act in accordance with the article 85. Where for scientific reasons it is not possible to include results of all analyses planned in the protocol within two years, an updated clinical trial report shall be submitted as soon as new results are available. In this case, the protocol shall specify when the results are going to be submitted. This clinical trial report submitted via the EU portal should be made public. Justification: Reports of all results should be published: positive or negative. The report should also be made for trials abandoned prematurely for reasons other than safety. Summary of results in this case should explain reasons for the premature end and justification when applicable. Two years is better than one year. Indeed the best way to make trial results public is to publish them in a peer-reviewed journal. It is not appropriate to make results public before even having a reasonable chance to publish them. It is frequently not possible to perform the analysis and to have results published within one year because of objective constraints outside the authority of the sponsor. On the other hand, two years is still a reasonably acceptable time to have results published through the means and for the purposes covered by this regulation. It should also be acceptable that such a clinical trial report is public even for trials with drugs for which marketing authorization has not been granted yet. Reporting for inconclusive and prematurely stopped trials covers also all cases of trials which would be stopped because drug development has been stopped. Elements of the Annex III, when taken together with the protocol and statistical analysis plan, constitute a reasonable compromise between summary of results only and a full report as per ICH E3 standards. ICH E3 report should, instead, be acceptable if produced anyway by some sponsors (to avoid duplication).

5 The amendment to the third paragraph of the text is justified by the fact that some clinical trials contain secondary endpoints that can only be analyzed long time after the end of the trial. Taking the example of cancer clinical trials, the primary endpoint is frequently progression-free survival, but the secondary endpoint is frequently overall survival. Once trials end and all patients finish protocol treatment and protocol follow-up, primary analysis is performed and the trial report is produced. The information on whether patients are still alive will continue to be collected for much longer periods, and the overall survival analysis will only be possible years after the trial ends. Submission of the clinical trial report should be a single submission to the portal; it is up to the portal to make it publically available to the EU database (This database will replace EudraPharm) Compromise amendement 3 (Replaces amendement ENVI 731) Annex IIIa Content of the summary of the results of clinical trials The summary of the results of the clinical trials referred to in Article 2, paragraph 2, 30 a (new) is part of the clinical trial report and shall contain information on the following elements (if not already included in the trial protocol or its appendixes): 1. Trial information: a) Study identification b) Identifiers c) Sponsor details d) Paediatric regulatory details e) Result analysis stage f) General Information about the trial g) Population of trial subjects with actual number of subjects included in the trial 2. Subject disposition: a) Recruitment b) Eligibility c) Pre-assignment Period d) Post Assignment Periods 3. Baseline Characteristics: a) Baseline Characteristics (Required) Age b) Baseline Characteristics (Required) Gender

6 Justification: c) Baseline Characteristics (Optional) Study Specific Characteristic 4. End Points: a) Endpoint definitions b) End Point #1* Statistical Analyses c) End Point #2, Statistical Analyses *Information shall be provided for as many end points as defined in the protocol. 5. Adverse Events: a) Adverse events information b) Adverse event reporting group c) Serious Adverse Events d) Non-serious adverse event 6. More Information: a) Global Substantial Modifications b) Global Interruptions and re-starts c) Limitations & Caveats Proposed list of elements should ensure the general public and scientific community are adequately informed about clinical trial results. Note: The proposed amendments are compatible with amendments ENVI 131, 169, 170, 171, 446 and 447 and should be acceptable without any modification. There are no other amendments which propose making trial results and/or data public and/or transparent.