Purpose of Background Page

The purpose of this section of the website is to provide a short history and additional commentary to assist interested parties in their review of the paper and examination of the study data.

A detailed description of the study, the rationale, the approach, the questionnaire (see also the Life Event History Calendar CAPI document), patient information sheet and informed consent are contained in the original Study Protocol.

Overview

C-TOR (Case-Control Study – Tobacco Overview of Risk) was designed as a multi-centre, epidemiological study with its focus on determining if there is a significant difference in the risk of developing lung cancer associated with smoking ultra-low tar cigarettes (ULTs) compared with traditional or so-called full flavour (FF) products. For the purposes of this study, a ULT is defined as having 3.0 mg of tar or less and an FF as having 10.0 mg of tar or more. Both are machine measured values in accordance with the International Organization for Standardization (ISO) or the essentially equivalent US Federal Trade Commission (FTC) standards.

It was identified that each phase of the study would require significant resources and expertise. It was therefore decided that the data collection would be carried out by clinical research organisations (CROs) and that the statistical analysis by a specialised firm that carried out such work for the pharmaceutical industry. For a complex and large study such as this, the design was critical, as was the data collection tool/questionnaire. A team of some 20 specialists was assembled including experts in epidemiology, questionnaire design and survey sampling, statistical analysis and clinical research of pharmaceuticals. The creation of this group involved meetings and discussions with over 40 different individuals and organisations until a team was assembled.

Study Design

A team was assembled with the necessary expertise to ensure that the study would be acceptable to those in charge of various medical centres where the study would be run. It also needed to be approved by the independent ethics committees (IECs) responsible for oversight of studies at these centres (see box for additional background on IECs). Notwithstanding that this was an epidemiological study, it set out to use the same standards for the design and execution necessary to make the outcome of a drug trial acceptable to regulatory authorities.

The study was sized at 26,000 participants and a study protocol was developed explaining the scientific value of the study together with its design, execution, organisation and management. As with drug trials, this was the key document used to recruit the trial centres to the study and was also the basis for the approvals by the IECs who judged that the study was justified, protected the rights and well-being of participants and was scientifically robust. This study design phase lasted about 18 months.

The Study

The study began in December 2005 and continued until October 2008. Over that period, totals of 4,450 valid cases and 3,605 valid controls were recruited at 230 study sites in France (73), Germany (78), Greece (35), Italy (30), and Slovenia (14). These countries were selected because market penetration data indicated a relatively high use of ULT cigarettes for at least 8 years prior to the study launch. In recruiting patients, approval for the study was obtained from 73 independent ethics committees across these countries.

The Progress of the Study

The study obtained its first IEC approval in August 2005. The first patient was enrolled in November 2005. The study continued until the financial sponsor withdrew support in October 2008 after the contract related to the study expired. Recruitment began slowly as the total number of sites were initially small and the recruitment rate gradually increased as additional sites were added and as significant support was provided to sites in their patient recruitment efforts. This recruitment rate proved slower than predicted, reflecting the fact that this study did not have the network of existing investigators that are available to most pharmaceutical companies when they initiate clinical trials. It should be noted that while 272 sites were part of the study, only 230 recruited patients. By the time the financial sponsor withdrew its support, the recruitment rates were in excess of 500 per month such that the remaining approximately 18,000 patients could have been recruited in additional 3 years.

The reasons given for the withdrawal of support by the financial sponsor were that the study was much behind schedule, had not enrolled the necessary number of participants and was running significantly over the targeted budget, which was in excess of 50 million Euros. As no analyses had been carried out at this point, none of the parties were aware as to what the data analysis might reveal. However, it was agreed that in light of the commitments given to the various stakeholders, of the amount and quality of the data and of the important public health issues involved, it would be inappropriate for the data not to be analysed. The financial sponsor agreed to the additional funding for this analysis and for the reporting of the findings.

To this end, a new Statistical Analysis Plan (SAP) was developed in 2010 and it was on this basis that the data was analysed. The paper on this website reports on the results of that analysis.

Who was Involved?

Across five countries, 272 centres agreed to participate in C-TOR, ranging from small specialist clinics to large university teaching hospitals. Each site typically involved between 6 and 10 individuals comprising healthcare professionals, support and medical administrative staff. The study was approved by 73 independent ethics committees, each with typically 10-14 members. Finally, 8,424 patients were enrolled in the study.

Databases

The collection of data to support this study had a number of critical elements:

• Market penetration of ULTs: While ULTs have been available in many markets since the early 1990s, there were a limited number of countries in which ULTs had sufficient market penetration for at least a period of 8 years prior to the start of the study in 2005. This data was necessary to select countries where there was the best chance that ULT smokers would be included in the study. This market penetration data, provided by the financial sponsor, was critical in determining the extremely large sample size required and resulted in selecting the countries identified in the protocol and where the study was ultimately run.
• The tar database: As indicated in the paper, the study relied on the Cigarette Information Reports produced by Philip Morris International (PMI), which are available, in the main, on the Legacy Tobacco Documents website. PMI also provided records of laboratory analyses carried out on their own and competitor products. These records go back more than 35 years and some were only available in hard copy from the original laboratory workbooks. The database contained tar values on 532 brand groups, with tar values changing typically 4 to 6 times over the period under consideration, but exceptionally up to 15 times.
• The pack image database: Images were collected, from a variety of sources, of the various packs that were on the market in the countries where the study was carried over the previous 40 years. This was part of creating the optimal data collection strategy and was a very significant factor in enhancing patient recall. This database ultimately contained 4,593 images.

Data Quality

A key aspect of this study was the attention to data quality. To insure quality, the interviewers were trained using a certified training programme developed by the Free University of Amsterdam. Their performance was also monitored by the University and feedback provided via the CRO interviewer management system. A detailed description is contained in the Life Event History Calendar CAPI document. PRA International, an experienced CRO was responsible for data management which included performing checks for consistency and accuracy, data cleaning resolving queries and ultimately, data lock prior to transmission of the data set to Axio Research for analyses. The procedures followed were those normally employed in a drug clinical trial.

Additional Information

Recognising that any study funded by a tobacco company would be subject to extreme scrutiny, every effort was made to insure that the role of the financial sponsor was limited to just that. The data is the property of The Weinberg Group and safeguards were put in place to protect the study’s independence and integrity. Neither Philip Morris International nor any of its affiliates or associate companies had any involvement in the data collection or its analyses. A condition of the contract related to the study was that PMI would not receive any advance information concerning the results and would only receive a copy of the final paper when it was submitted to a journal for publication.

On completion, the paper was submitted to four peer review journals for publication between 2010 and 2012. Three journal editors rejected the paper without peer review and the fourth journal following peer review. Therefore, the decision was taken to place it on this website and to provide access to the data to qualified researchers, because the Data Oversight Committee, which is formed by independent experts, were of the view that the study contained significant data on an important public health issue and also because it was in keeping with commitments given as a part of the process of site recruitment.