Periodic Report Summary 2 - CARING (CAncer Risk and INsulin analoGues)
Project Context and Objectives:
Several studies have linked the use of insulins to the risk of cancer, and it is certainly plausible that as a growth factor, exposure to administered insulin could stimulate neoplastic growth. However, meta-analyses of randomized clinical trials comparing different insulin analogues were too small to quantify the risks, especially the proportion of patients that were followed for more than 6 months. Hence, the European Medicines Agency has requested urgent research to determine the risks of cancer for users of insulin and insulin analogues, and investigate possible mechanisms of cancer promotion.
The overall objective of CARING is to quantify the risk of cancer associated with the (long-term) use of insulin and insulin analogues. In addition, we aim to elucidate biological mechanisms for the adverse effect.
The specific objectives of this project are:
1. To review a) the published evidence on the risk of cancer and different cancer types associated with diabetes mellitus, in order to estimate the background risk of cancer in the patient population using insulins and b) the clinical evidence from published studies on the risk of cancer associated with the use of insulin and insulin analogues to identify methodological issues in available clinical trials and observational studies and to summarize knowledge gaps, which need to be resolved to take regulatory or treatment decisions.
2. To develop methods to combine various pharmacoepidemiological databases with long-term follow-up, in order to increase power to study the cancer risk associated with insulin and insulin analogues in detail.
3. To study the effects of daily dosage, time and/or intensity of insulin treatment on the likelihood of developing cancer.
4. To study the influence of potential confounders on the association between insulin and cancer risk in observational studies, and to develop methods for external adjustment for unmeasured confounders in databases with missing information on certain confounders.
5. To develop methods for screening/predicting patients at high risk of developing cancer by identification of predictors (risk factors) for developing cancer in patients with diabetes mellitus treated with insulins.
6. To review the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues.
7. To study the hazard patterns of cancer risk associated with the use of insulin and insulin analogues over time, to test plausible biological mechanisms of initiation/promotion in clinical practice.
8. To study tumour characteristics of breast cancer occurring in female diabetic patients in order to elucidate the biological mechanism (cancer initiation/ promotion), by immunohistochemical and genetic profiling of tumour tissue.
9. To disseminate the findings of this study as follows:
a. To write a report for the European Medicines Agency, in which all the study results are presented.
b. To disseminate the findings to diabetes patients throughout Europe.
c. To disseminate the findings to medical doctors in clinical, peer reviewed medical journals, and on a scientific conference.
Project Results:
In the first 18 months of the CARING project progress the following work was performed:
• Search strategies and methods for the three literature reviews were developed. Protocols were hence registered in the international prospective register of systematic reviews (PROSPERO);
• Principles of a Common Data Model with a focus on Nordic data were developed and discussed. Furthermore, a way of integrating data from the Clinical Practice Research Datalink (CPRD) in this framework was developed and a structure of a concept dictionary for the project was created;
• An overview of potential confounders was created;
• For the study of tumour characteristics of breast cancer patients, the necessary ethical approvals for the Danish data set were obtained and protocols were written, discussed and updated for the selection of patients, the selection of tumour tissue and the subsequent use of the tumour tissue. A pilot study of DNA isolation and assessment of DNA quality was performed and the current techniques are being evaluated for genetic profiling of tumours.
• A common study protocol was developed that will be used in all five different databases and a first version of a detailed Statistical Analyses Plan was created.
• A logo was designed for CARING that can will used in presentations and other communication and a website was developed;
• The CARING project plan was presented at the European Medicines Agency, and together with three other research groups working in the field of safety of diabetic medication we organised a symposium at the International Conference of Pharmacoepidemiology (ICPE) in Barcelona titled “European initiatives to study adverse events of treatment for Diabetes Mellitus”.
During month 19 to 36 of the CARING project, the following work was performed:
• Systematic reviews were delivered and resulted in scientific publications (see below);
• The Common Study Protocol was finalised and registered in the ENCePP E-register of studies;
• The Common Data Model for the multi-country analyses was finished and is ready to use;
• Datasets from each country were established and validated;
• A new method for adjusting for unmeasured confounding has been developed for the situation where data on outcome and exposure are available for a large population, but data on confounding variables only for a subset of this population (validation data set);
• All Danish tumour blocks for molecular analyses were shipped to the Netherlands Cancer Institute where DNA was isoated and Tissue Micro Arrays have been constructed.
• Five CARING related scientific manuscripts were published and a sixth was accepted:
- A systematic review of risks of different cancer types in diabetic patients (D2.2);
- A systematic review on cancer risk associated with the use of insulin and insulin analogues (D2.3)
- A mini-review on diabetes, cancer and treatment;
- A study on the use of metformin and survival of diabetic women with breast cancer;
- A study on the effect of treatment duration on the association between anti-diabetic medication and cancer risk;
- A study on colorectal cancer in type 2 diabetes (Accepted).
• CARING results were presented at several scientific conferences:
- Five abstracts were presented at the ICPE conference in Montreal, Canada, in August 2013;
- One of these was also presented at the EASD conference in Barcelona, Spain in September 2013;
- One abstract was presented at Norwegian Epidemiological Conference in Olso, Norway, in October 2014;
- Two abstracts were presented at the ICPE conference in Taipei, Taiwan, in October 2014.
Potential Impact:
Expected impact part 1:
Project results should lead to important new knowledge on major and serious adverse drug reactions that constitute public health concerns i.e. those impacting on the balance of benefits and risks of medicinal products. This should be directed towards regulatory decisions on marketing authorisations for medicinal products including the warnings in product information for doctors and patients.
The deliverables will provide the necessary input to EMA decisions concerning the future regulation of use of insulin and insulin analogues, including marketing authorisations and amendments to product information for healthcare professionals and patients. EMA has played a lead role in the formulation of objectives for topic HEALTH.2011.4.2-2 and is expecting to receive this data, along with the findings of its sister projects investigating other classes of drugs. The EMA will have in place the plans and the capacity to act on the findings of the project, and the project partners will closely collaborate with EMA in the realisation of this impact.
The results of project will detail the relative and absolute risks to insulin users of cancer, for specific, relevant populations.
Much of the activity required to translate the results of the project into policy decisions within Europe will be in the hands of the EMA. The project partners will be available for consultation by EMA on their findings, publicity actions and other contributions.
Since July 2012, M.L. De Bruin (project coordinator) has been functioning as an independent scientific expert in the Pharmacovigilance Risk Assessment Committee (PRAC), where she can share important findings of the CARING project directly with the relevant bodies within the EMA.
Expected impact part 2:
A safer and more effective use of medicines should result with positive implications for public health.
Since the exact size of the problem of cancer risk associated with insulin and insulin analogues is currently poorly defined, it is hard to make sure statements about the absolute impact that the results of the project will have for public healthcare. Indeed, this will be a question for the project to answer, and the information will help public and private healthcare providers to review policy for prescribing insulin and insulin analogues concerning risks and benefits.
On an individual level, the adverse drug reactions studied in CARING present an additional complication for the health, quality of life and/or survival of patients.
In CARING, the classification and profiling of breast tumours of diabetics, and their expected related breast cancer prognosis, may provide input to improved information for health professionals and female patients making decisions concerning the benefits and risks of different diabetic treatments, such as alternative treatments or intensive screening.
List of Websites:
http://www.caring-diabetes.eu(odnośnik otworzy się w nowym oknie)
Several studies have linked the use of insulins to the risk of cancer, and it is certainly plausible that as a growth factor, exposure to administered insulin could stimulate neoplastic growth. However, meta-analyses of randomized clinical trials comparing different insulin analogues were too small to quantify the risks, especially the proportion of patients that were followed for more than 6 months. Hence, the European Medicines Agency has requested urgent research to determine the risks of cancer for users of insulin and insulin analogues, and investigate possible mechanisms of cancer promotion.
The overall objective of CARING is to quantify the risk of cancer associated with the (long-term) use of insulin and insulin analogues. In addition, we aim to elucidate biological mechanisms for the adverse effect.
The specific objectives of this project are:
1. To review a) the published evidence on the risk of cancer and different cancer types associated with diabetes mellitus, in order to estimate the background risk of cancer in the patient population using insulins and b) the clinical evidence from published studies on the risk of cancer associated with the use of insulin and insulin analogues to identify methodological issues in available clinical trials and observational studies and to summarize knowledge gaps, which need to be resolved to take regulatory or treatment decisions.
2. To develop methods to combine various pharmacoepidemiological databases with long-term follow-up, in order to increase power to study the cancer risk associated with insulin and insulin analogues in detail.
3. To study the effects of daily dosage, time and/or intensity of insulin treatment on the likelihood of developing cancer.
4. To study the influence of potential confounders on the association between insulin and cancer risk in observational studies, and to develop methods for external adjustment for unmeasured confounders in databases with missing information on certain confounders.
5. To develop methods for screening/predicting patients at high risk of developing cancer by identification of predictors (risk factors) for developing cancer in patients with diabetes mellitus treated with insulins.
6. To review the published pre-clinical in vitro and in vivo evidence for plausible mechanisms underlying the risk of cancer associated with insulin and insulin analogues.
7. To study the hazard patterns of cancer risk associated with the use of insulin and insulin analogues over time, to test plausible biological mechanisms of initiation/promotion in clinical practice.
8. To study tumour characteristics of breast cancer occurring in female diabetic patients in order to elucidate the biological mechanism (cancer initiation/ promotion), by immunohistochemical and genetic profiling of tumour tissue.
9. To disseminate the findings of this study as follows:
a. To write a report for the European Medicines Agency, in which all the study results are presented.
b. To disseminate the findings to diabetes patients throughout Europe.
c. To disseminate the findings to medical doctors in clinical, peer reviewed medical journals, and on a scientific conference.
Project Results:
In the first 18 months of the CARING project progress the following work was performed:
• Search strategies and methods for the three literature reviews were developed. Protocols were hence registered in the international prospective register of systematic reviews (PROSPERO);
• Principles of a Common Data Model with a focus on Nordic data were developed and discussed. Furthermore, a way of integrating data from the Clinical Practice Research Datalink (CPRD) in this framework was developed and a structure of a concept dictionary for the project was created;
• An overview of potential confounders was created;
• For the study of tumour characteristics of breast cancer patients, the necessary ethical approvals for the Danish data set were obtained and protocols were written, discussed and updated for the selection of patients, the selection of tumour tissue and the subsequent use of the tumour tissue. A pilot study of DNA isolation and assessment of DNA quality was performed and the current techniques are being evaluated for genetic profiling of tumours.
• A common study protocol was developed that will be used in all five different databases and a first version of a detailed Statistical Analyses Plan was created.
• A logo was designed for CARING that can will used in presentations and other communication and a website was developed;
• The CARING project plan was presented at the European Medicines Agency, and together with three other research groups working in the field of safety of diabetic medication we organised a symposium at the International Conference of Pharmacoepidemiology (ICPE) in Barcelona titled “European initiatives to study adverse events of treatment for Diabetes Mellitus”.
During month 19 to 36 of the CARING project, the following work was performed:
• Systematic reviews were delivered and resulted in scientific publications (see below);
• The Common Study Protocol was finalised and registered in the ENCePP E-register of studies;
• The Common Data Model for the multi-country analyses was finished and is ready to use;
• Datasets from each country were established and validated;
• A new method for adjusting for unmeasured confounding has been developed for the situation where data on outcome and exposure are available for a large population, but data on confounding variables only for a subset of this population (validation data set);
• All Danish tumour blocks for molecular analyses were shipped to the Netherlands Cancer Institute where DNA was isoated and Tissue Micro Arrays have been constructed.
• Five CARING related scientific manuscripts were published and a sixth was accepted:
- A systematic review of risks of different cancer types in diabetic patients (D2.2);
- A systematic review on cancer risk associated with the use of insulin and insulin analogues (D2.3)
- A mini-review on diabetes, cancer and treatment;
- A study on the use of metformin and survival of diabetic women with breast cancer;
- A study on the effect of treatment duration on the association between anti-diabetic medication and cancer risk;
- A study on colorectal cancer in type 2 diabetes (Accepted).
• CARING results were presented at several scientific conferences:
- Five abstracts were presented at the ICPE conference in Montreal, Canada, in August 2013;
- One of these was also presented at the EASD conference in Barcelona, Spain in September 2013;
- One abstract was presented at Norwegian Epidemiological Conference in Olso, Norway, in October 2014;
- Two abstracts were presented at the ICPE conference in Taipei, Taiwan, in October 2014.
Potential Impact:
Expected impact part 1:
Project results should lead to important new knowledge on major and serious adverse drug reactions that constitute public health concerns i.e. those impacting on the balance of benefits and risks of medicinal products. This should be directed towards regulatory decisions on marketing authorisations for medicinal products including the warnings in product information for doctors and patients.
The deliverables will provide the necessary input to EMA decisions concerning the future regulation of use of insulin and insulin analogues, including marketing authorisations and amendments to product information for healthcare professionals and patients. EMA has played a lead role in the formulation of objectives for topic HEALTH.2011.4.2-2 and is expecting to receive this data, along with the findings of its sister projects investigating other classes of drugs. The EMA will have in place the plans and the capacity to act on the findings of the project, and the project partners will closely collaborate with EMA in the realisation of this impact.
The results of project will detail the relative and absolute risks to insulin users of cancer, for specific, relevant populations.
Much of the activity required to translate the results of the project into policy decisions within Europe will be in the hands of the EMA. The project partners will be available for consultation by EMA on their findings, publicity actions and other contributions.
Since July 2012, M.L. De Bruin (project coordinator) has been functioning as an independent scientific expert in the Pharmacovigilance Risk Assessment Committee (PRAC), where she can share important findings of the CARING project directly with the relevant bodies within the EMA.
Expected impact part 2:
A safer and more effective use of medicines should result with positive implications for public health.
Since the exact size of the problem of cancer risk associated with insulin and insulin analogues is currently poorly defined, it is hard to make sure statements about the absolute impact that the results of the project will have for public healthcare. Indeed, this will be a question for the project to answer, and the information will help public and private healthcare providers to review policy for prescribing insulin and insulin analogues concerning risks and benefits.
On an individual level, the adverse drug reactions studied in CARING present an additional complication for the health, quality of life and/or survival of patients.
In CARING, the classification and profiling of breast tumours of diabetics, and their expected related breast cancer prognosis, may provide input to improved information for health professionals and female patients making decisions concerning the benefits and risks of different diabetic treatments, such as alternative treatments or intensive screening.
List of Websites:
http://www.caring-diabetes.eu(odnośnik otworzy się w nowym oknie)