Summary. Sandra Funning 1, Anders Grahnén 1,, Karin Eriksson 2 and Åsa Kettis-Linblad 1

Transcription

1 Quality Assurance within the Scope of Good Clinical Practice (GCP) What is the Cost of GCP-related Activities? A Survey within the Swedish Association of the Pharmaceutical Industry (LIF) s Members Sandra Funning 1, Anders Grahnén 1,, Karin Eriksson 2 and Åsa Kettis-Linblad 1 1 Departments of Pharmaceutical Biosciences and Pharmacy, Faculty of Pharmacy, Uppsala University, PO Box 591, SE Uppsala, Sweden 2 The Swedish Association of the Pharmaceutical Industry, PO Box 17608, SE Stockholm, Sweden Summary The bureaucracy that the Good Clinical Practice (GCP) system generates, due to industry over-interpretation of documentation requirements, clinical monitoring, data verifications etc. is substantial. The aim of this study was to estimate the percentage cost of all such GCP-related activities within phase III clinical trials performed in Sweden in Method: An electronic questionnaire on ICH GCP-activities and their related costs was sent to 47 of the 60 member companies of the Swedish Association of the Pharmaceutical Industry (LIF). Results: The number of respondents was 29, giving a response rate of 62% and covering 97% (n 5 250) of phase III trials performed in Sweden in Approximately 50% of the total budget for a phase III study was reported to be GCP-related. 50% of the GCP-related cost was related to Source Data Verification (SDV). A vast majority (71%) of respondents did not support the notion that these GCP-related activities increase the scientific reliability of clinical trials. Copyright r 2009 John Wiley & Sons, Ltd. Key Words: cost; GCP; Sweden; SDV Introduction *Correspondence to: Anders Grahnén, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, PO Box 591, SE Uppsala, Sweden. anders.grahnen@farmbio.uu.se The five main players in Sweden in 2005 in the market for clinical trials in all phases were AstraZeneca, Pfizer, Novartis, GlaxoSmithKline (GSK) and Roche. The cost of clinical trials in Copyright r 2009 John Wiley & Sons, Ltd. Qual Assur J 2009; 12,

2 4 S. Funning et al. Sweden has been investigated by the Swedish Association of the Pharmaceutical Industry (LIF) since The total costs during 2005 and 2006 were 718 million USD and 762 million USD respectively. The number of clinical trials (all phases) performed in Sweden in the year 2005 was 510 (Phase I 67; Phase II 90; Phase III 256, Phase IV 97) The global average cost of development of one new drug, has recently been estimated to billions USD and the cost for the clinical part (all clinical phases) was estimated to 879 million USD [1]. ICH GCP Criticism Lörstad is one critic who questions the industry application of ICH GCP [2]. The criticism is mostly related to the over-interpretation of the ICH GCP guideline. He also claims that the bureaucracy is extensive in the quality system. From the general regulatory demand, the individual pharmaceutical companies interpret the extent of what needs to be controlled. It is a widespread misunderstanding that the quality in a clinical trial is dependant on the degree of errors discovered. Many companies apply a perfectionist approach whether errors are important or not for the outcome of a trial [2]. The present system focuses on doing things right rather than doing the right things. The focus tends to be set more on format than on contents. Using clinical trial simulation, Grahnén and co-workers showed that a large random transcription error with a frequency up to 5% in source data do not have any significant influence on the outcome of a trial [3]. In today s evidence-based climate there is little hard evidence that supports the ICH GCP guideline [3,4]. The ever-increasing bureaucracy in clinical research is a large problem which gains increasing attention. The critique of the interpretation the ICH-GCP guideline is an expression of a general reaction against a widespread evaluation mania in today s society. Considerable time and effort is put on collecting data in a routine fashion, but the underlying logic of the evaluation system itself is seldom questioned. The aim of this study was to assess the costs related to ICH GCP procedures, selection of source data, use of e-crfs, and the relationship between ICH GCP procedures and scientific outcome. A secondary objective was to identify suggestions for improvements of the system. Methods The questionnaire included questions aimed at characterising ICH GCP procedures (with respect to clinical monitoring, data verification etc.) with regard to cost and cost distribution, source data, quality structure, Case Report Forms (CRF) and scientific outcome. The questionnaire was pilot-tested at Quintiles AB, Uppsala, Sweden, by letting staff familiar with the ICH GCP system fill it out and comment on its clarity and content. A revised version of the questionnaire was transferred to a web-based format. The practical design of the web page was performed by the company IT-arkitekterna, Uppsala, Sweden, and it was sponsored by LIF. The study included the members of LIF, the trade association for the pharmaceutical industry in Sweden. The year 2005 was chosen for the study since the cost of clinical research 2006 was not yet published when the study started. At the time this study was initiated, LIF had 60 members. Five of those only handled veterinary pharmaceuticals and they were therefore excluded from the study. Eight companies were also excluded due to lack of clinical trials the year of The web-based questionnaire was sent out to 47 companies together with an containing the web link to the questionnaire, username, password and a letter which explained the purpose of the study and instructions for the questionnaire. Data on total cost of clinical trials in Sweden 2005 was received from LIF. Estimated percentages of costs pertaining to different ICH GCP activities, median, average, maximum value, minimum value, standard

3 Quality Assurance within the Scope of Good Clinical Practice 5 What is the percent of the total budget for a typical phase III trial that is related to GCP activities (monitoring, QA/QC, SDV etc. included payment/travels for CRA)? How many percent of monitoring-/qa-activities are SDV? How many percent of monitoring-/qa-activities are control of formalities (e.g. control of dates and signatures)? If you perform trials in several phases, do you use different monitoring principles depending on which phase it is? How many Data Clarification Forms (DCFs) do you estimate that you use for a representative trial? Do you think that the present quality system for clinical trials principally is concentrated to guarantee a reliable scientific outcome?.box 1. Questions included in the questionnaire deviation and a 95% confidence interval (CI) were calculated. For questions with a yes/no option, the percentage distribution was calculated. The open answers to question about suggestions for improvements of the system were analysed qualitatively, by grouping similar statements into three different emerging categories: The relationship between the authorities and the industry. Source Data. Primary variable of the study. The questionnaire was bilingual in Swedish and English. The questions in English language are presented in Box 1. Results The response rate was 62%, covering 97% of Phase III trials performed in Sweden The questions were answered by Clinical Trial Managers and/or Medical Directors of the companies. Cost and cost distribution The estimated percentage of the total budget for a typical Phase III trial that is related to Table 1. Cost and cost distribution with regard to GCP-related activities Sample size Median Average (95 CI d ) GCP a % of budget (47 65) SDV b % of GCP (51 67) Formalities c % of GCP (15 29) a Good Clinical Practice-related activities. b Source Data Verification activities. c Dates and signatures. d Confidence Interval. GCP activities investigated in this study was 50% (Table 1) as was the estimated proportion of source data verification (SDV) activities out of all GCP activities. The cost for these GCPrelated activities for a phase III program is estimated at 180 million USD, and the total cost for SDV is estimated at 90 million USD, based on the results. Control of formalities (dates and signatures) constituted between 15 and 29 % of the total monitoring/quality Assurance (QA) activities and the cost can be estimated to approximately 40 million USD. Source data, quality structure and case report forms (CRF) Of the 28 respondents 25% used a statistical method in the selection of source data to be monitored (see Table 2) while 79% used a fixed sample without a formal statistical process. Source data which were controlled to 100% was Informed Consent (IC), Adverse Events (AE)/Serious Adverse Events (SAE), primary variable and inclusion/exclusion criteria. A few companies answered that they performed 100% SDV on all data. The majority of the respondents (72%) did not use different monitoring principles depending on phase of the clinical trial. The median estimated percentage of the budget pertaining to CRF correction was 20%. The number of Data Clarification Forms (DCF) used in a representative trial could not be estimated due to the small sample size.

4 6 S. Funning et al. Table 2. Selection of source data, quality structure and use of electronic case report forms Question Sample size % Yes % No Median Average (95% CI) Statistical selection, SD Controls % SD (not statistical) Data controlled to 100% 28 Different monitoring principles per phase % of budget related to correction (17 31) Number of DCFs 15 n.a. n.a. Use e-crf Believe e-crf reduces costs SD Source Data, DCF Data Clarification Form, CRF Case Report Form, e CRF-electronic Case Report Form, n.a. not assessed, CI confidence interval. The majority of the companies (82%) use e-crfs and 55% believe that e-crfs reduce the costs related to monitoring and data cleaning. Some of the positive effects of using e-crfs were that the e-crf saves time, reduces transfer errors, and reduces travel costs. Some of the disadvantages were the problems with installing computers, training the staff at the site and that it was difficult to have an overview of all data with e-crfs. Scientific reliability of the outcome A solid majority (72%, n 5 28) did not agree that the present quality system (as applied by industry) for clinical trials is designed to guarantee a reliable scientific outcome. Suggestions for improvements of the system A total of 24 suggestions for improvements were received. Within each emerging category, the following three suggestions were most frequent: Relationship between industry and authorities There must be a better collaboration between authorities and the industry. Sometimes companies have higher demands on themselves than the authorities have on them. Improved harmonisation within EU; today, the demands differ between the countries. There should only be one application per trial to all authorities. Source data SDV must be reduced. If a clinic is doing well without anything to remark on, they don t need to be controlled so much. A study needs to be done with respect to the impact of a reduction in SDV on the quality. Electronic data collection with controls built into the electronic system and directed SDV which can reduce the burden in phase IV studies. Primary variable of the study The focus on the trial must be on the primary variable and safety instead of details like signatures etc. Education of the monitors and the personnel at the clinics is important and reflections should be encouraged. Introduce SDV by statistical sampling ( SDVss ) which would make it easier to quantify and register the quality. Discussion The result of this study is based on a questionnaire. Thus, the outcome must be interpreted with caution due to the inherent bias that questionnaires can give rise to. It is obvious that individual interpretation of questions can differ between individuals/organisations. To reduce this potential bias, the

5 Quality Assurance within the Scope of Good Clinical Practice 7 questionnaire was accompanied by a detailed explanation of each question and subsequent guidance. A pilot test was also performed prior to the study. Still, the respondent s answers are based on subjective estimations that may be biased due to the respondent s obvious company perspective. For example, given that ICH GCP places a burden on the company, costs may be overestimated, whether consciously or unconsciously Overall, this study indicates that the cost of GCP-related activities is high; approximately 50% of the total budget for a phase III study. This corresponds to approximately 180 million USD for one new drug. The study also shows that the prominent cost is SDV, which corresponds to 50% of the GCP budget for GCPrelated activities Statistical methodology is used by less than half of the companies. As Grahnén and coworkers showed in a previous study a large random transcription error with a frequency up to 5% in CRF does not have any significant influence on the outcome of a trial [3]. Using a statistical methodology reduces workload and costs without interfering with the quality. GCP is not viewed as improving the scientific reliability of the outcome. Approximately 70% of the companies did not perceive that the present interpretation of GCP guarantees a reliable scientific outcome of a trial. The doing things right rather than doing the right things analogy seems still to prevail. Some of the suggestions on improvements from the respondents were that there must be better collaboration between the industry and the authorities. Also, introduction of statistical sampling for SDV was suggested. The need for an evidence base (studies) of the system was another important suggestion. Perfectionism is the biggest threat against good quality is a citation from the Swedish MPA Principal GCP Inspector Mr Danielsson [5]. He is also of the opinion that the ICH GCP guideline is sound and rather clear in every section except the ones regarding e-gcp and ownership of data. Despite technical progress, ICH GCP has not been revised. Another opinion regarding the quality of ICH GCP is voiced by Grimes and co-workers. They state that the ICH GCP is not evidence-based and that it needs to be updated [4]. The companies application of the guidelines may also have to be reconsidered, as over-interpretation contribute to bureaucracy beyond what is intended. Finally, a quality system is needed for clinical trials to really guarantee the safety and integrity of the study subjects and the scientific outcome. However, the focus must be changed from today s detail control to more overall quality awareness. Acknowledgements We thank Mr. Richard Bergström, CEO of LIF for both professional and financial support of the study. Special thanks also to Mr. Gunnar Danielsson, GCP Inspector of the Swedish MPA for valuable inputs. References 1. DiMasi JA, Grabowski HG. The cost of Biopharmaceutical R&D: Is biotech different? Manage Decis Econ 2007; 28: Lörstad M. Data quality of the clinical trial processcostly regulatory compliance at the expense of scientific proficiency. Qual Assur J 2004; 8: Grahnén AE, Karlsson K, Bragazzi F. Impact of transcription errors on the outcome of a clinical trial. Clin Pharm Ther Suppl 2007; 81: PI Grimes DA, Hubacher D, Nanda K, Schulz KF, Moher D, Altman DG. The good clinical practice guideline: a bronze standard for clinical research. Lancet 2005; 366: Personal Communication: Mr Gunnar Danielsson, MPA, Uppsala, March 6, 2007.