How does PMI run clinical studies?
What guidelines does PMI use in its clinical research program?
All of our clinical studies follow the internationally recognized guidelines for Good Clinical Practice (GCP) issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). These are a set of principles that regulatory bodies around the world expect researchers to follow when conducting clinical studies. PMI abides by these principles for our clinical research, as well as following the recommendations in the 2012 draft guidance for Modified Risk Tobacco Product (MRTP) applications issued by the U.S. Food and Drug Administration’s (FDA's) Center for Tobacco Products.
PMI’s quality management processes are based on these standards, requiring that our researchers perform their work ethically, use scientifically sound methods, and describe the aim of the research upfront in a clear and detailed study protocol. All information related to the research must be recorded in accurate records which are properly stored and protected from tampering. The records serve as indispensable documentation of the conduct of the research, provide evidence that the collected data is traceable and credible, and that the rights, safety, and well-being of all study participants are protected.
For each clinical study, we establish a PMI study team that focuses on both designing individual studies and overseeing the conduct of the study, as required by the GCP. As is common practice, we outsource study-related activities to qualified Contract Research Organizations (CROs), including recruitment of participants and the actual conduct of the study. Throughout the course of the study, the PMI study team works closely with their CRO counterparts.
The details of all the clinical studies we are conducting and have conducted are published on the largest online repository of clinical studies, ClinicalTrials.gov and can be found in our publications library (filter for publication type: clinical studies). The results from the studies are also published in the ClinicalTrials.gov repository once the data are obtained and the study reports are finalized.
How does PMI ensure the safety of its research participants?
One of the key principles in the GCP and related guidelines is that the safety of study participants must be ensured. For this reason, our clinical studies are all conducted under continuous medical oversight under the responsibility of a trained and board-registered physician in the role of the Principal Investigator (PI).
All participants undergo a process of informed consent and selection by the PI using predefined inclusion and exclusion criteria, as defined in the study protocol. The PI is also responsible for managing and documenting potential adverse events (expected or unexpected medical effects occurring during the course of the study) which may or may not be associated with the product being tested. As a sponsor of the research, PMI is responsible for what happens during a study, and so we may provide opinions or suggestions but, ultimately, we must defer to the PI’s medical judgement. The sponsor can never overwrite the PI's evaluation of the medical condition of the study participants.
Case study: Participant safety
One such situation illustrating the relationship between PMI and the PI occurred in a 2013 clinical study. During the study, a few participants produced an excessive quantity of urine in a 24-hour period, which is quite uncommon. The participants confirmed drinking increased amounts of water during each of the study days, all medical tests came back normal, and the study participants did not show any signs of medical concern. The PI therefore did not initially consider these events to be adverse. However, as the recorded urine volumes were unusual, PMI followed GCP procedure and initiated an investigation to understand the underlying cause of these cases.
The PMI study team discussed these cases with the CRO and decided that a study audit should be performed by PMI’s quality assurance team. The audit concluded that the study site had correctly followed all processes as required by the study protocol and the GCP, and the PI and staff had properly documented the cases and their response to the issues.
After discussion with the medical monitors of the study, as well as PMI, the PI ultimately decided to mark these incidences as adverse events, and to monitor consumption of water for the remaining participants.
How can the public know that PMI’s data are not tampered with?
The GCP provides clear guidance on how to document clinical research. The guidelines require significant documentation, also called “essential documents,” at every point of the research process to provide a reliable record of events. All documentation on clinical studies should follow ALCOA principles (Attributable, Legible, Contemporaneous, Original, and Accurate). This is to ensure data integrity and traceability and, in consequence, the validity of the research.
The GCP requirements hold the research sponsor accountable for the study, independent of the sponsor’s level of involvement. This means that, as a research sponsor, it is our responsibility to ensure the safety and well-being of our study participants and the integrity of the research. As mentioned before, the sponsor’s role during the execution of the study is oversight. In other words, the sponsor does not create records linked to study participants, so it goes without saying that this also excludes the possibility of a sponsor altering such records undetectably.
Case study: Data discrepancies
The GCP guidelines helped safeguard against what could have been a break in the chain of sample custody that arose in one of our clinical studies in the U.S. in 2015. A PMI-contracted laboratory received a shipment of samples from one of our clinical study sites and found that it contained fewer samples than expected, and the sample labels did not match the shipping manifest provided by the clinical site. As a result, PMI requested a detailed investigation. Under the guidance of the CRO, and with oversight by PMI, the laboratory and the clinical study site developed a reconciliation plan to discover and resolve the discrepancies.
Toward this end, a team assigned by the CRO visited both the laboratory and the respective study site, spending multiple days at each location reviewing every single sample collected from the time of collection to the time of analysis. As a result, the discrepancies were resolved, and the integrity and traceability of the data collected from these samples were confirmed.
What corrective actions does PMI take if necessary procedures are not followed?
If essential elements of the GCP are not followed by the study site, corrective actions are required. In such cases, PMI follows a strict and structured process. This is defined in our quality management system, which is based on the GCP. This begins with a For-Cause audit—an on-site investigation by PMI’s quality assurance group or an external party. If the audit detects nonconformance with GCP guidelines that would impact the safety of study participants or the ethical conduct or validity of our research, then closing a study site might be the outcome.
These types of situations are not unique to the tobacco industry, they also happen in clinical studies conducted by the pharmaceutical and other industries. And this is part of the reason why the GCP principles are so important.
Companies conducting clinical studies, including PMI, have multiple proactive controls in place to ensure study integrity and adherence to the GCP. They guide study teams on a daily basis and ensure that decisions are properly made and documented. These controls are also designed to detect nonadherence to GCP and trigger appropriate remediation actions where issues are found.
Case study: Adherence to study procedures
One case involving adherence to guidelines and protocols occurred very early in the conduct of a 2013 study in Japan, before the study was posted on ClinicalTrials.gov. During a routine site-monitoring visit, the CRO overseeing the study noticed discrepancies in the site’s procedures as compared with the GCP, which triggered a For-Cause audit by quality assurance groups from the CRO and PMI.
The audit confirmed the discrepancies from the requirements of the study protocol and the GCP. As a consequence of these issues, PMI immediately closed the study site. However, we were able to successfully complete the respective study by recruiting the entire number of participants required by the protocol at the remaining study site.
How does PMI ensure that all study sites and personnel are qualified?
The GCP requires that all study personnel involved in clinical research are qualified to ensure appropriate study conduct. Therefore, before starting a study, a so-called qualification visit for each potential study site is performed by our CROs. These are performed as face-to-face visits, where they review and assess the qualifications, experience, and capabilities of the site personnel, and the suitability of the facility to conduct the study. This is then documented in a Qualification Visit Report, which PMI receives prior to approving a site to participate in the study. Each study and any PIs involved are reviewed and approved by an Institutional Review Board (IRB) prior to conducting the study.
To ensure proper understanding by personnel involved in our studies who do not speak English, the protocol, investigator’s brochure (a summary of all relevant information on the product studied), and other study documentation are translated to the local language as appropriate and required. These are provided to the PI and the IRB.
When a language barrier exists, we can, for example, conduct a study training meeting (known as the preinvestigator meeting) in English for the CROs and all supporting study vendors, who are required to have English-speaking personnel. The CRO then performs the training for each study site in the local language. Training includes information on GCP, the study protocol and procedures, and the electronic systems used in the study. All trainings and training records are documented in the Study Master File and are available for inspection by regulators at any time.
PMI’s commitment to high standards
Clinical studies are a complex undertaking, and as in every complex process, it has to be expected that irregularities can and will happen. This is why standards such as the GCP exist: to minimize the number of issues that can occur and to provide guidance on how to address them when they do.
PMI is committed to strictly following these standards. The guidelines are not only integral to maintaining the validity of the data, but also to its transparency, participant safety, and overall ethical conduct of our studies. Our hope is that our adherence to these principles will allow others to see our research for what we believe it is: a significant contribution to evolving today’s scientific knowledge on better alternatives to cigarettes for the millions who smoke around the world.
