GCP violation and tampering with evidence

Last week, biotech company BioXcel reported positive efficacy results of their investigational product Igalmi in the treatment of Alzheimer's Agitation, but the supposed good news was shadowed by data integrity issues. On the same day, the company revealed allegations that an investigator had failed to adhere to trial protocol and was alleged to have fabricated emails to cover their tracks.

See the article "Missed trial protocols, fabricated emails and failed endpoint mar BioXcel's Alzheimer's agitation readout".

The company filed Form 8-K and revealed the GCP violation issues. Here are the excerpts from the SEC filing: 

          Important Information Regarding TRANQUILITY II Phase 3 Clinical Trial 

In December 2022, the U.S. Food and Drug Administration (“FDA”) conducted an inspection of one of the clinical trial sites in the Phase 3 TRANQUILITY II clinical trial, where the principal investigator enrolled approximately 40% of the subjects participating in the trial. At the conclusion of this inspection, the FDA issued an FDA Form 483 identifying three inspectional observations. These observations related to the principal investigator’s failure to adhere to the informed consent form approved by the Institutional Review Board for a limited number of subjects whose records the FDA reviewed, maintain adequate case histories for certain patients whose records the FDA reviewed, and adhere to the investigational plan in certain instances. For example, the FDA cited the principal investigator’s delay in informing the sponsor’s medical monitor or pharmacovigilance safety vendor of a serious adverse event (“SAE”) for one of the subjects, which report was made to the Company’s vendor outside of the 24 hour time period prescribed by the clinical trial protocol. The principal investigator for this clinical site responded to the FDA observations within the time period requested. The FDA inspection remains open, however, as the FDA has not issued an Establishment Inspection Report. 

In May 2023, it came to the Company’s attention that this same principal investigator in the TRANQUILITY II clinical trial may have fabricated email correspondence purporting to demonstrate that the investigator timely submitted to the Company’s pharmacovigilance safety vendor a report of an SAE from a different subject than the one cited in the FDA Form 483, and purporting to show that the vendor had confirmed receipt. Upon receipt of this information, the Company promptly initiated an investigation and recently received confirmation that the principal investigator fabricated the email correspondence related to the timing of the reporting of this SAE to the Company’s pharmacovigilance vendor to make it appear as though this SAE had been timely reported to the pharmacovigilance vendor as required by the clinical trial protocol. The Company also confirmed that this SAE had been timely entered into the electronic data capture system, even though the SAE had not been separately reported to the Company’s pharmacovigilance safety vendor within the 24 hour timeframe required under the protocol. 

In connection with this ongoing investigation, the Company was made aware that the fabricated email correspondence was provided to the FDA by the principal investigator’s employer during the on-site inspection in December 2022. After unblinding of the data, the Company determined that the SAE that was the subject of this fabricated correspondence between the principal investigator and the Company’s pharmacovigilance vendor occurred in a subject in the placebo arm. This principal investigator has not participated in any other clinical trial sponsored or conducted by the Company. Moreover, the study was designed such that trained study staff other than principal investigators were to conduct assessments of the primary efficacy measure.

In this case, the fabrication of evidence to hide the late reporting of the SAE to the sponsor is far more serious than the late reporting of the SAE itself. The situation is similar to tampering with evidence and obstruction of justice in the criminal law. 

ICH E6 Good Clinical Practice requires the investigational site to report the serious adverse events (SAEs) to the sponsor in a timely manner usually within 24 hours when the site staff become aware of the occurrence of an SAE. Failure to do so will be recorded as a major protocol deviation. 

However, fabricating the evidence to conceal the protocol deviation (late reporting of the SAE) is no longer a GCP compliance issue, it is a scientific misconduct issue. 

Protocol Deviations - How is the Protocol Deviation Data Analyzed and Used?

For any clinical trial, the study protocol is the blueprint of how the clinical trial should be conducted. Clinical study protocols must be conducted according to the International Council for Harmonization (ICH) guidance on good clinical practice (GCP), which, among other things, helps safeguard the rights, safety, and well-being of study participants. If conducted as designed, the associated data should be reliable and reproducible and support clear interpretation of the results, while maintaining the participants’ protection. In light of this, one might reasonably assume that deviations from this protocol could be harmful to the participant or the accuracy of the data and should therefore be avoided.

However, the reality is that within clinical trials, protocol deviations do happen, despite best efforts in designing and conducting the clinical trial. According to the ICH E3 Q&A R1, the protocol deviation is defined as: 

"A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol.

Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's rights, safety, or well-being."

In the early days, the term 'protocol violation' may be used and is still used in some clinical trial documents. According to the ICH E3 Q&A R1, the term 'protocol violation' should be replaced with 'protocol deviation'

"To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”,

There is considerable variability regarding the interpretation, and classification of what an important protocol deviation is, which creates challenges in the identification, collection, and reporting of deviations - resulting in over-reporting PDs that could potentially delay the identification of important patient safety information by increasing the noise in the system or under-reporting PDs that could influence the reliability of the study results and patient safety signals.

In order to reduce the variability in what, when, how the PDs should be collected, it might be helpful to take a look at how the data about the PDs are analyzed and used. 

After the protocol deviation data is collected, the data will be mapped into the CDISC data sets (DV data set in SDTM and ADDV data set in ADaM). Then a data listing will be generated to list all protocol deviations by subjects including the date the protocol deviation occurred, the description of the protocol deviation, the category of the protocol deviation (out of visit window, informed consent issue, SAE safety reporting issue, ......), and the classification of the protocol deviations (minor, major, critical, or important).  A statistical summary table will then be generated for all protocol deviations and for major protocol deviations. 

The protocol deviation data will then be used in the following aspects: 

For the clinical study report (CSR):

CSR must include a section to describe the protocol deviations that occurred during the conduct of the study. According to  ICH E3 (Structure and Content of Clinical Study Reports), the protocol deviations section is an essential part of the CSR. 

10.2 Protocol Deviations 

All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient managements or patient assessment should be described. 

In the body of the text, protocol deviations should be appropriately summarized by center and grouped into different categories, such as: 

• Those who entered the study even though they did not satisfy the entry criteria. 
• Those who developed withdrawal criteria during the study but were not withdrawn. 
• Those who received the wrong treatment or incorrect dose. 
• Those who received an excluded concomitant treatment. 

In Appendix 16.2.2, individual patients with these protocol deviations should be listed, broken down by center for multicenter studies. 

For FDA BIMO of NDA/BLA submission under Center for Drug Evaluation and Research (CDER):

The FDA Office of Scientific Investigations (OSI) requests that the by-site data and listing are provided for Bioresearch Monitoring (BIMO). The by-site data is used by OSI to select the investigational sites for inspections for CDER submissions.

The FDA Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA investigators who conduct those inspections. This information is requested for all major
trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials).

One critical piece of the BIMO data is the protocol deviation data by site. The number of protocol deviations or important protocol deviations can be an indicator of protocol compliance and the study quality for specific investigational sites. According to BIORESEARCH MONITORINGTECHNICAL CONFORMANCE GUIDE Technical Specifications Document", the following protocol deviation data should be provided:

"Subject-level data line listings, by clinical site, should include consented subjects, treatment assignment, discontinuations, study population, inclusion and exclusion criteria, adverse events, important protocol deviations, efficacy endpoints, concomitant medications, and safety monitoring, as further described below"

7. Important Protocol Deviations Contains Nonbinding Recommendations 

This by-subject, by-clinical site listing should include all protocol deviations. The listing should include a description of the deviation and identify whether the sponsor considered the deviation to be an important or non-important protocol deviation.  

Clinical Site Data Elements Summary Listing

"Total number of important protocol deviations at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change. This value should include multiple deviations per subject and all major deviation types. Important deviations are those deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, or well-being"

"Total number of protocol deviations, excluding important protocol deviations, at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change."

FDA's Good Review Practice: Clinical Review Template listed the protocol violation information as part of the review items for assessing the GCP compliance and the impact of the protocol violations on the data quality and the safety and efficacy results. 

3.2 Compliance With Good Clinical Practices

This section should include comments on compliance with good clinical practices, including informed consent, protocol violations, site-specific issues, and whether the clinical trials were conducted in accordance with acceptable ethical standards. 

If a DSI audit process and report is not requested, provide a brief summary on the quality and nature of other methods used to audit or check the applicant’s data and/or analyses. 

For DSI-requested audits, include a brief summary of the rationale for DSI audits and site selection such as: 

• A specific safety concern at a particular site based on review of adverse events, serious adverse events, deaths, or discontinuation 

• A specific efficacy concern based on review of site-specific efficacy data

 • A specific concern for scientific misconduct at one or more particular sites based on review of financial disclosures, protocol violations, clinical trial discontinuations, or safety and efficacy results  

For defining the per-protocol population for Sensitivity or Supplemental Analyses

Efficacy analyses are usually performed in full analysis set or intention-to-treat population. However, to test the robustness of the statistical results and to assess the impact of the protocol deviations on the statistical results, additional sensitivity or supplemental analyses are usually performed on the per-protocol population. 

According to ICH E9 (Statistical Principles for Clinical Trials), the per-protocol population is defined and sensitivity analyses based on per-protocol population are suggested:  

Per protocol set (valid cases, efficacy sample, evaluable subjects sample): The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements, and absence of major protocol violations.

In practice, the per-protocol population is usually defined as "all randomized subjects who have no major protocol deviations" or "all randomized subjects who have no major protocol deviations that may have an impact on the efficacy assessment". The decision on the inclusion of subjects in per-protocol population needs to be decided before the database lock and study unblinding. The protocol deviation data may be reviewed at the blinded data review meeting. Subjects who are excluded from the per-protocol population need to be documented in the blinded data review report.

ICH E9 Addendum also discussed the per-protocol set (PPS) and analyses based on PPS are included as supplemental analysis: 

The meaning and role of an analysis of the per protocol set is also re-visited in this addendum; in particular whether the need to explore the impact of protocol violations and deviations can be addressed in a way that is less biased and more interpretable than naïve analysis of the per protocol set

Section 5.2.3. indicates that it is usually appropriate to plan for analyses based on both the FAS and the Per Protocol Set (PPS) so that differences between them can be the subject of explicit discussion and interpretation.

Additional Reference: Transcelerate Protocol Deviations

Declaration of Helsinki and FDA

The newly released Declaration of Helsinki was issued by the 59th World Medical Association General Assembly in October 2008. This document details ethical principles for medical research involving human subjects.

Section 19 requiring every clinical trial to be registered before recruitment of the first subject. Also note Section 30 on the obligation to make public the results of research on human subjects and requirements for publications. The additional contents are in line with the recent push for registry of the clinical studies and publication of the clinical trial results.

http://www.wma.net/e/policy/pdf/17c.pdf
http://www.wma.net/e/index.htm
http://en.wikipedia.org/wiki/Declaration_of_Helsinki

However, the FDA is moving away form the Helsinki accords because of what it says about placebo. The following two links discussed this issue.
http://www.socialmedicine.org/2008/06/01/ethics/fda-abandons-declaration-of-helsinki-for-international-clinical-trials/
In 21 CFR 312, "Human Subject Protection; Foreign Clinical Studies Not Conducted Under an Investigational New Drug Application- Notice of Final Rule", FDA states
" The final rule replaces the requirement that these studies be conducted in accordance with ethical principles stated in the Declaration of Helsinki (Declaration) issued by the World Medical
Association (WMA), specifically the 1989 version (1989 Declaration), with a requirement that the studies be conducted in accordance with good clinical practice (GCP), including review and approval by an independent ethics committee (IEC)."

A article on EMBO report (7(7), 2006) titled "The Battle of Helsinki" is worth to read.

North Carolina's Triangle Business Journal (2/19, Gallagher) reports that "the study also questions the decision by the US Food and Drug Administration in 2008 to abandon the Declaration of Helsinki, a set of standards adopted by the World Medical Association in 1984 that required trials to compare new drugs with the most effective alternative." The Food and Drug Administration "dropped the Helsinki standards in favor of the policy of Good Clinical Practice adopted by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. That policy, which allows drug manufacturers to compare the results of the new drug with those of a placebo, is considered by some to be less stringent than the Declaration of Helsinki."