Antonia Panayi, BSc, MSc, PhD, ISMPP CMPPTM, Slavka Baronikova, BSc, MSc, PhD, ISMPP CMPPTM,
Shire International GmbH
Over the last few years, requirements for clinical trial transparency and data reporting have become more extensive to help patients and health care practitioners (HCPs) better understand the drugs they are taking or prescribing in clinical trials, with a focus on increasing trust and confidence in regulatory decisions on medicines. Publication professionals within sponsor companies must keep abreast of the changes to transparency laws and regulations, as it has direct implications for their everyday work.
Evolving EMA Regulations
The European Medicines Agency (EMA) has set a new standard for transparency in public health and pharmaceutical research by issuing a Clinical Trial Regulation (EU no 536/2014),1 which entered into force on June 16, 2014. EU 536/2014 will ensure the rules for conducting clinical trials are identical throughout the European Union (EU), and it will provide more transparency on all trial-related information generated during the life cycle of a clinical trial. The novelty of this regulation is that it will include investigational medicinal products regardless of whether they have a marketing authorization. And as of 2018, sponsors are also obliged to make publicly available a summary of results and a lay-person summary within one year of the end of the trial. An EU portal and database are currently being developed for this purpose, and will be the single entry-point for submission of data and information relating to clinical trials required by this regulation.2 However, until the Clinical Trial Register comes into force, the publicly accessible part of the EU clinical trials website3 (EudraCT) remains as the repository for this information.
EMA’s EU 536/2014 is the next leap after EMA’s Policy 0070, which is active as of October 20, 2016. Policy 0070 (in the first phase of implementation) allows the EMA to disclose clinical data documents, including clinical study reports (CSRs) and protocols, submitted to the agency as part of a centralized Marketing Authorization Application (MAA), article 58* procedure, line extension or new indication, regardless of where the study was conducted.† These clinical data documents are publicly available via https://clinicaldata.ema.europa.eu.
To comply with European legislation on personal data protection,4 clinical reports must be anonymized to prevent patients and professionals who participated in clinical trials from being identified. As part of the process, the EMA is also publishing the applicant’s anonymization report, which describes the anonymization methods used and their impact on data utility. In addition, companies must justify the redaction of any commercially confidential information (CCI). Although the agency considers that, in general, clinical data cannot be considered CCI, there are limited circumstances where study reports may be redacted for CCI.
Release of Individual Patient Data
Importantly, a second phase of EMA Policy 0070 will focus on sharing Individual Patient Data (IPD), although a robust plan has not been released as yet.5 This initiative is in parallel with the recent data sharing statement that requires: (1) as of July 1, 2018, manuscripts submitted to International Committee of Medical Journal Editors (ICMJE) journals that report the results of clinical trials must contain a data sharing statement; (2) clinical trials enrolling participants on or after January 1, 2019, to include a data sharing plan in the trial’s registration.6 The article highlights that these initial requirements do not mandate data sharing, but investigators should be aware that editors may take into consideration data sharing statements when making editorial decisions.
Meanwhile, many companies have established their own individual patient data sharing processes that enable qualified researchers to pursue scientific analyses from clinical trials for approved medications in Europe and the US. Some companies have their own portals, such as Pfizer,7 Merck,8 and Shire,9 whereas others are part of centralized scientific review boards, for example, ClinicalStudyDataRequest.com.10 But, a centralized and practical approach from the EMA with input from other key stakeholders, including editors, independent researchers, and sponsors, would incorporate the various perspectives, which could provide benefits to all.
US NIH Final Rule
In the US, the National Institutes of Health (NIH) is also implementing further transparency initiatives with the “Final Rule”11 issued in September 2016.
In a Final Rule special report published in the New England Journal of Medicine,12 Zarin and colleagues from the NIH indicated that ClinicalTrials.gov currently has more than 224,000 study records, but only 23,000 display results. They outlined that the details provided in the Final Rule should help increase accountability amongst investigators and sponsors, and improve compliance for reporting.
The Final Rule further clarifies and expands the reporting requirements of the Food and Drug Administration Act of 2007 (FDAAA).13 The additional registration and summary information required by the Final Rule, and associated effective dates, are listed below:
- Full protocol and statistical analysis plan (SAP), and more frequent updates to posted data
- Registration information: study start date on or after January 18, 2017
- Results information: primary Completion Date on or after January 18, 2017
- Unapproved, unlicensed, and uncleared products
- Different types of adverse event information
- Checklist with structured criteria for evaluating whether a study is an “applicable clinical trial” (ACT) and who is responsible for submitting
- ACTs are any interventional studies, other than phase 1, initiated on or after January 18, 2017
These expanded requirements are the minimum needed to meet the legal obligations of the Final Rule, but sponsors can surpass these requirements by including trials that are not covered by the law, or by including more detailed information than requested, or by uploading information ahead of any strictly enforced deadlines. Figure 1 below shows key elements of the Final Rule, Policy 0070, and EU 536/2014.
Figure 1. Key Elements of the Final Rule, Policy 0070, and EU no. 536/2014.
Adapted from the EMA website http://www.ema.europa.eu/ema/?curl=pages/special_topics/general/general_content_000555.jsp. Last accessed May 25, 2017.
The ClinicalTrials.gov data entry system, known as the Protocol registration and Results System (PRS), was ready to support all regulatory submission requirements from the rule’s effective date January 18, 2017. The first results summaries will be available as of January 18, 2018.
Importantly, there are potential legal consequences for non-compliance, including civil monetary penalties, imprisonment, or substantial fines for individuals and organizations, and a ‘name and shame’ list on ClinicalTrials.gov.
Impact on Medical Publications
So, what does this mean for publication professionals? Study sponsors will need to review their systems, processes, and procedures to ensure complete and timely clinical trial reporting. Also, coordination will be needed among various stakeholders, including Publications, Biostatistics, Clinical/Medical Development, and Data Transparency groups, across geographical regions to ensure consistent content across different forums, without compromising the timeliness of publications.
How do all these changes influence scientific publications?
- Scientific manuscripts should continue to interpret the clinical data and describe the disclosed trial data in the context of the clinical development program and unmet need for the specific medicine within the therapy area.
- Primary manuscripts of eligible clinical studies should ideally be publicly available at the same time as CSRs are disclosed on clinical trial public registries, and should be linked via study/National Clinical Trial (NCT)/EudraCT number.
- There still remains confirmation from the ICMJE that the summary of trial results will not be considered pre-publication. We expect that the ICMJE and journal editors will provide feedback in the coming months.
In summary, this unprecedented level of public access to reports from clinical trials will benefit patients, healthcare professionals, academia/researchers, and industry. Providing a more comprehensive list of data will enable study sponsors to determine the need for new trials. Through the sharing of results, drug developers can learn from failed initiatives, which could minimize the risks to patients, lead to further innovations in clinical trial design and, ultimately, allow quicker access to medicines for patients. Furthermore, data sharing might facilitate the independent analysis of data by researchers after a medicine has been approved.
*Article 58 allows the EMA’s Committee for Medicinal Products for Human Use (CHMP) to give opinions, in cooperation with the WHO, on medicinal products for human use that are intended exclusively for markets outside of the European Union (EU). For all positive opinions adopted under Article 58, the Agency prepares and publishes a European public assessment report (EPAR), which reflects the scientific conclusions reached at the end of the evaluation process.
†For marketing authorization, line extensions, and extension of indication applications, clinical data documents are posted 60 days after the European commission decision and following the EPAR publication. For article 58 applications, it is within 150 days after the CHMP opinion. For withdrawn applications, within 150 days after receipt of the withdrawal letter.
- https://ec.europa.eu/health/human-use/clinical-trials/regulation_en#ct4 Last accessed 24 April 2017
- http://www.ema.europa.eu/ema/?curl=pages/special_topics/general/general_content_000555.jsp Last accessed 24 April 2017
- https://www.clinicaltrialsregister.eu/ctr-search/search Last accessed 24 April 2017
- http://ec.europa.eu/justice/data-protection/ Last accessed 24 April 2017
- http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000556.jsp Last accessed 24 April 2017
- Taichman DB, Sahni P, Pinborg A et al. Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors. Ann Intern Med 2017 doi:10.7326/M17-1028
- http://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests Last accessed 12 May 2017
- https://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf Last accessed 12 May 2017
- http://www.shiretrials.com/ Last accessed 12 May 2017
- https://clinicalstudydatarequest.com/ Last accessed 24 April 2017
- https://prsinfo.clinicaltrials.gov/ Last accessed 24 April 2017
- Zarin DA, Tse T, Williams RJ. Trial Reporting in ClinicalTrials.gov. The Final Rule. N Engl J Med 2016; 375:1998-2004
- https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/foodanddrugadministrationamendmentsactof2007/default.htm Last accessed 24 April 2017