Statistical Analysis Plan in Clinical Trial Registries

Recently, a question comes up when I search the clinicaltrialregistry.eu – the EU clinical trial registry website – the counterpart of clinicaltrials.gov in US. Should the clinical trial registries include the statistical analysis plan (for primary and secondary efficacy endpoints)? The statistical analysis plan could include the statistical methods for primary and secondary endpoints, missing data handling, stopping rule for early termination of the study, justification for sample size estimation, and so on.

For clinicaltrials.gov in US, Protocol Registration Data Element Definitions for Interventional and Observational Studies requires the inclusion of some details about statistical analyses:

Detailed Description Definition:

Extended description of the protocol, including more technical information (as compared to the Brief Summary), if desired. Do not include the entire protocol; do not duplicate information recorded in other data elements, such as Eligibility Criteria or outcome measures. Limit: 32,000 characters. 
For Patient Registries: Also describe the applicable registry procedures and other quality factors (for example, third party certification, on-site audit). In particular, summarize any procedures implemented as part of the patient registry, including, but not limited to the following: 

• Quality assurance plan that addresses data validation and registry procedures, including any plans for site monitoring and auditing.

• Data checks to compare data entered into the registry against predefined rules for range or consistency with other data fields in the registry.

• Source data verification to assess the accuracy, completeness, or representativeness of registry data by comparing the data to external data sources (for example, medical records, paper or electronic case report forms, or interactive voice response systems).

• Data dictionary that contains detailed descriptions of each variable used by the registry, including the source of the variable, coding information if used (for example, World Health Organization Drug Dictionary, MedDRA), and normal ranges if relevant.

• Standard Operating Procedures to address registry operations and analysis activities, such as patient recruitment, data collection, data management, data analysis, reporting for adverse events, and change management.

• Sample size assessment to specify the number of participants or participant years necessary to demonstrate an effect.

• Plan for missing data to address situations where variables are reported as missing, unavailable, non-reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results.

• Statistical analysis plan describing the analytical principles and statistical techniques to be employed in order to address the primary and secondary objectives, as specified in the study protocol or plan. 

In EU, the clinicatrialregistry.eu is mainly based on the EudraCT database. As part of the clinical trial application (similar to IND in US), the sponsor needs to provide the clinical trial protocol information to be entered into EudraCT database.

In the guidance “Detailed guidance on the European clinical trials database (EUDRACT Database)”, it asks for the information regarding the clinical trial design, but there is no mention of the statistical analysis plan.

As a matter of fact, all clinical trial registries across different countries are supposed to meet the requirements by International Clinical Trials Registry Platform (ICTRP) from World Health Organization. In the list of elements for WHO Trial Registration Data Set , there is no mention of statistical analysis plan as part of the registration elements.

No matter what, there seems to be different understanding about the details of the clinical trial to be posted in clinical trial registries. Some companies posted very detail information including how the clinical trial data would be analyzed. Other companies were very restraint and posted as little information as possible.

In terms of the elements regarding the statistical analyses, there are actual more studies in clinicaltrialregistry.eu with some details than studies in clinicaltrials.gov even though the requirement regarding the inclusion of the statistical analysis plan is mentioned in clinicaltrials.gov, not in clinicaltrialregistry.eu. For example, in a study “A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib”, a lot of details about the statistical analyses are provided in the clinicaltrialregistry.eu.

When I try to see if the interim analysis and its corresponding boundary method are mentioned in clinicaltrialregistry.eu, I can clearly see the inconsistencies across different trial sponsors.

Here are some studies that the interim analysis and boundary method are mentioned.

• Postoperative Ileus reduction by NicOtine gum CHewIng after Operation: a pilot cohort study
• A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib
• A Phase III, International, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Clinical Worsening Study of UT-15C in Subjects with Pulmonary Arterial Hypertension Receiving Background Oral Monotherapy

Here are some studies that the interim analysis is mentioned, but the boundary method is not.

• A multicenter, double-blind, placebo-controlled Phase 3 study assessing the safety and efficacy of selexipag on morbidity and mortality in patients with pulmonary arterial hypertension
• A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects with Advanced Solid Tumors (KEYNOTE 158)
• AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension
• LUME-Meso: Double blind, randomised, multicentre, phase II/III study of nintedanib in combination with pemetrexed / cisplatin followed by continuing nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin followed by continuing placebo monotherapy for the treatment of patients with unresectable malignant pleural mesothelioma
• A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi- Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction (HFrEF) - VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA)