focus Pharmacovigilance Focus

Transcription

1 focus 2 Pharmacovigilance Is there a difference in perceived practices between innovative and generic industries? Part 1: Analysis of spontaneous reporting practices in innovative and generic companies This series of articles is based on a dissertation prepared for the TOPRA MSc in Regulatory Affairs* Author Carol Tsang Correspondence to Carol Tsang ctsang@rogers.com Key Words Pharmacovigilance, innovative companies, generic companies, adverse reaction reporting practices, side effects Abstract Spontaneous reporting is a prolific source of information and is a cornerstone of pharmacovigilance. Under the current regulatory environment, both innovative and generic companies are mandated to follow the same set of pharmacovigilance regulatory requirements. Since there are some innate differences between the innovative and generic industries, the real-life practice on spontaneous reporting may deviate between these two groups. To investigate the current industry practice, a literature review was conducted and a specially-designed questionnaire was sent to 8 innovative and generic companies. Based on the results collected (response rate: 37.5%), it was found that a majority of the respondents agreed that both innovative and generic companies should be responsible for ADR reporting. For the expectedness review, approximately 7-8% of the innovative and generic companies conducted their review based on country-specific labelling. Of those, approximately 7-8% conducted ADR review at their local offices. Only a few companies chose to perform the assessment at the global offices or outsourced it to contract research organisations. With regards to literature reviews, at least 87.5% of the innovative and generic companies have established processes. About 5% and 35% of both industries reviewed literature on a weekly and biweekly basis, respectively. In general, Medline, EMBASE and Reactions (weekly) are commonly used databases for literature review as identified by the two groups. In general, no significant differences were observed between the two industries with regards to spontaneous reporting. *The MSc in Regulatory Affairs is validated and awarded by the federal University of Wales, UK. For further details regarding the University and its validation services, please log on to validation or validation@wales.ac.uk Introduction Pharmacovigilance is aimed at identifying, detecting, characterising, monitoring and communicating drug risks to foster rational and safe use of medicines. It allows new findings to be rapidly incorporated into therapeutic-decision making by regulators, pharmaceutical companies, physicians, and patients. 1,2 Spontaneous reporting of suspected adverse drug reactions (ADRs) plays an important role in the post-marketing regulation and in identifying significant safety concerns arising with marketed medicines. 3 Since the 196s, spontaneous reporting has proven to be a main source of pharmacovigilance information and served as an early warning system for possible drug-induced disaster. After the thalidomide disaster in the 196s, national pharmacovigilance centres were established by World Health Organisation (WHO) Member States to collect and evaluate ADR case histories in a central database. This spontaneous reporting approach was aimed to improve the medicine safety profiles and to avoid further disasters. 1,2 Despite the differences in product development and the incidence of unexpected ADRs in innovative versus generic products, marketing authorisation holders (MAHs) in both industries are mandated to follow the same set of regional and international pharmacovigilance requirements The real-life practice of innovative and generic companies in processing spontaneous reporting is investigated in this article. Methods Available published literature and regulatory requirements pertaining to pharmacovigilance, as well as innovative and generic industries, were identified and reviewed. Keywords used include: pharmacovigilance, adverse drug reactions, drug safety, spontaneous reports, side effects, innovative and generic.

2 3 Databases (eg, MEDLINE, IDRAC, UTCat*, Google) as well as regulatory agency (eg, FDA, TPD, EMEA, and EC) and international organisation (eg, ICH and WHO) websites were accessed to identify regulations, published literature or reference books on pharmacovigilance. Based on the literature research, a questionnaire was designed in November 25 as an instrument to capture an accurate picture of the pharmacovigilance practice employed by the innovative and generic companies. Any changes in regulations after November 25 were excluded from this research. An assumption was made that the survey companies were already in compliance with the current regulatory requirements; thus questions concerning mandatory pharmacovigilance practices were excluded from the questionnaire. Eighty copies of the questionnaire were sent to 4 innovative companies and 4 generic companies in the EU and North America. The study was conducted from December 1, 25 to March 31, 26. Descriptive statistics were employed to present the frequencies and the associated percentages of each variable tested. Inferential statistics were used to answer the research question (ie, whether the pharmacovigilance practices employed by the innovative and generic industries are similar). Due to the small sample size, the Fisher s exact test was selected for the statistical analysis of this study. The data were analysed using SAS Version 8.2. The significance level was set at p-value less than or equal to.5 using two-tailed tests. Demographics Of the 8 questionnaires distributed, 31 completed responses were received, a response rate of 38.8%. Responses (n = 3; 37.5%) received prior to the cut-off date of March 31, 26 were included in the statistical and data analysis. One response received after the cut-off date from a Canadian innovator was excluded from the analysis. Of the 3 analysed questionnaires, 13 (43.3%) were from Europe, another 13 (43.3%) were from North America and four (13.3%) did not identify the company locations. Sixteen (53.3%) responses were from innovative companies and 14 (46.7%) were from the generic side. Nine (3%) directors, seven (23.3%) managers, six (2.%) associates, two (6.7%) qualified persons (QPs) of pharmacovigilance, and two (6.7%) Vice Presidents of global pharmacovigilance responded. Four (13.3%) respondents did not identify their positions. For the number of employees in the pharmacovigilance departments, 8% or more of the innovative (8.%) and generic (91.7%) companies had one to five employees at the local offices. More employees were located in the global offices. About 38.5% innovators had over 2 employees; whereas 23.1% innovators and 54.6% generics employed 11 to 2 employees in the global pharmacovigilance departments (see Figure 1). One innovative company indicated that they have over 24 employees at their global office responsible for pharmacovigilance. No statistically significant difference was observed (p = 1. for local affiliates and p =.12 for global offices) between the two study groups. Figure 1 Number of employees in pharmacovigilance department local (left) versus global offices (right) Note: Local offices 15 and 12 responses received from the innovators and generics, respectively Global offices 13 and 11 responses received from the innovators and generics, respectively > >2 Number of employee - Local (left) vs. Global (right) Innovative Generics Local: p-value = 1. Global: p-value =.12 * UTCat is a catalogue of the holdings of University of Toronto electronic information resources. It includes books, journals, government publications, audio-visual materials, etc. STEVE PINDER CONSULTING Clinical development planning, regulatory authority liaison, clinical overviews and summaries, responses to questions and due diligence services. Training in regulatory affairs, medical writing and drug development. Suite 5, The Sanderum Centre, 3A High Street, Thame, Oxon, OX9 3EX Tel: +44 () Mobile: +44 () info@stevepinderconsulting.com Regulatory Rapporteur January Issue 27

3 4 focus For the general ADR processing practice, 31.3% innovators and 28.6% generics processed reports centrally at one location for the entire company; and 43.8% innovators versus 42.9% generics processes ADRs at affiliate offices before forwarding them to the central pharmacovigilance department for dissemination. The rest of the companies processed ADR reports using different combinations of the two methods and the verbatim statements received are presented in Table 1. No difference was observed (p = 1.) between the two study groups (see Figure 2). Table 1 Additional methods for ADR processing verbatim statements Innovative Majority of the reports are processed centrally at one location for the entire company. In some countries, products only marketed in those individual countries are processed locally. Cases processed in UK, US, France, Germany and Belgium and electronically uploaded from Japan Combination of the two [ie, centrally and locally]. Domestic [ADRs] received by Medical Information are processed internally; affiliates forward international SAEs to Canadian Regulatory operations for processing internally; US operations outsource their processing and reporting and provide copies of reports for their pharmacovigilance departments and copies of applicable reports are simultaneously [sent] to Canadian regulatory operations for files and reporting to Health Canada if required. Generics Globally developed/in-licensed products are handled by central location; locally developed products are handled locally. Local affiliate gathers case information and reports to local authorities. Central department enters cases into database and disseminates to all affiliates. Regional drug safety groups processing cases from their regions into one central database, according to global entry instructions All ADRs received are processed locally and forwarded to US PV for central database entry. PV US group is central database for North America. [ADRs are processed] at three sites, it is not centralised Note: information presented in [ ] is added for clarification purposes. It is not the verbatim statement from the respondents. Results The comparison of expectedness review for spontaneous ADR reporting showed that a majority of the innovative (n = 11; 68.8%) and generic companies (n = 11; 78.6%) used country-specific labelling to review expectedness. No significant difference (p =.69) between the innovative and generic practices was observed (see Figure 3). Figure 2 Industry practice: ADR processing Generics (14) p-value = Centrally Local Other

4 5 Of the 11 innovative and 11 generic companies that determine expectedness using country-specific labelling, 72.7% innovative (n = 8) and 81.8% generic (n = 9) companies conducted ADR review at their local offices. Only a few companies chose to perform the assessment at the global office (27.3% innovators versus 9.1% generics) or outsourced (9.1% generics) it to CROs. No statistically significant difference (p =.59) was detected between the two groups (see Figure 4). For the review frequency of published literature, most innovative and generic companies conducted their review either on a weekly or biweekly basis. Of the 15 innovative companies, seven (46.7%) reviewed literature weekly and five (33.3%) conducted their review biweekly. Similarly, seven (5.%) and five (35.7%) generic companies performed literature review weekly or biweekly, respectively. Only a few companies screened the literature either daily or monthly. Two (13.3%) innovators reviewed the literature daily, and one (6.7%) innovative plus two (14.3%) generic companies performed review monthly. No statistical significant difference (p =.72) was observed between the two groups (see Figure 5). Among the identified databases used for ADR screening, Medline and Reactions (Weekly) were most commonly used. Almost all innovative (n = 12; 92.3%) and generic (n = 11; 84.6%) companies used Medline as a key database for literature screening. Reaction (Weekly) was also selected by nine (69.2%) innovative and 1 generic (76.9%) companies. More generics (n = 11; 84.6%) used EMBASE as compared to the innovators (n = 7; 53.9%). Conversely, four (3.8%) innovative versus none of the generics used Current Contents for ADR review. Only % from both groups used Science Citation Index. Other databases identified by one innovative company included Derwent Drug Files, Biosis and Psycho Info. One generic company also used Biosis. The distribution of databases used by the two industries sectors was not statistically different (p =.38). See Figure 6 for details. Figure 3 Country-specific labelling review for ADR reporting Yes No Generics (14) p-value =.69 Figure 4 ADR assessment for expectedness (global versus local review) Global Local Outsource Figure 5 Published literature review frequency Innovative (11) Generics (11) p-value =.59 Innovative (15) Generics (14) p-value = Daily Weekly Biweekly Monthly Regulatory Rapporteur January Issue 27

5 6 focus In situations when there are multiple manufacturers (including generic companies) for a medicinal product, the industry opinions on the ADR reporting responsibilities were collected. Fourteen (87.5%) innovative and 13 (1%) generic respondents considered that both industries were responsible for ADR reporting. Only two (12.5%) innovative companies regarded the ADR reporting as their sole responsibility and none of the companies considered that only the generic companies should perform the ADR reporting. No statistically significant difference (p =.49) was detected on the opinions between the two groups (see Figure 7). From the results collected, a majority of the innovative companies (n = 14; 87.5%) and all (n = 13; 1%) generic companies have established processes for timely access to and review of the published literature for expedited reporting (ie, within 15 calendar days from recognition of a valid case). No statistical difference (p =.49) was observed between the two groups (see Figure 8). Discussion The real-life practice on spontaneous reporting in innovative and generic drug companies were extensively analyzed and compared. This is of particular importance because spontaneous reporting of suspected ADRs plays an important role in the post-marketing regulation and in identifying significant safety concerns arising with marketed medicines. 3 The purpose is to make regulators, pharmaceutical companies, healthcare professionals and the general public aware of any new, important information on serious reactions related to drug use. Such reporting generally involves events that are serious and previously unobserved or undocumented (ie, unexpected). According to the ICH E2A, expedited reporting for additional occurrences of the reaction(s) is required until the source documents (ie, approved product labelling) are amended; 5 thus country-specific labelling is considered an important document for expectedness evaluation for national ADR reporting. From the responses collected, it is surprising to observe that only approximately 7% of the innovative and 8% of the generic respondents review expectedness based on country-specific labelling. Of those who conducted country-specific labelling review, 7-8% conducts it at the local affiliate office. The reason for those companies (31.3% innovators and 21.4% generics) Figure 6 Review of published literature databases Current Contents EMBASE Reactions (Weekly) Medline Innovative (13) Generics (13) p-value =.38 Science Citation Index Others (Note: One innovative company identified Derwent Drug Files, Biosis, Psycho Info as additional databases and one generic company also used Biosis Figure 7 Industry opinion: ADR reporting responsibilities Generics (13) p-value = Innovative Generics Both Figure 8 Established process for literature review Yes Generics (13) p-value =.49 No

6 7 not conducting the expectedness review using the country-specific labelling may be explained as follows: First, in the EU and Canada, sponsors are required to report domestic ADRs that are both serious and expected (see Table 2). Companies located in these countries may not conduct the expectedness review, as reporting is required regardless of the case expectedness. Closer examination shows that all responding companies that do not conduct expectedness review using country-specific labelling are from the EU or Canada. Another explanation may be associated with the CIOMS V Working Group recommendation. It suggests that companies assess cases as expected or unexpected based on the appropriate reference safety information (RSI). The RSI can be the Company Core Safety Information (CCSI ) in a marketed product, or the official local data sheet (eg, US Package Insert or EU SmPC). 14 Thus, companies may choose to use the CCSI for expectedness review instead of the country-specific labelling. In reality, the literature review practice is fairly similar between the two study groups. First, all generics and 87.5% innovators have company-established literature review processes. Additionally, about 5% of the innovative and generic respondents conduct weekly literature review and another onethird conduct biweekly review. Approximately 1% of the innovators perform daily review but around 6-14% of the innovative and generic respondents conduct monthly review. Based on the EU weekly literature review requirement, one (7.69%) innovative and two (15.38%) generic companies who conduct biweekly literature review and one (7.69%) generic company that conducts monthly review are out of regulatory compliance. Conversely, those that conduct literature reviews less frequently than weekly but are located in North America are in compliance, since by regulation, no literature CCSI contains all relevant safety information contained in the CCDS prepared by the MAH and which the MAH requires to be listed in all countries where the company markets the drugs, except when the local regulatory authority specifically requires a modification. It is the reference information by which listed and unlisted are determined for the purpose of periodic reporting for marketed products, but not by which expected and unexpected are determined for expedited reporting. (source: CIOMS V(14)) Table 2: Spontaneous serious adverse reactions subject to expedited reports EU * US Canada Serious ADRs (expected or unexpected) occurring in EU Serious and unexpected reactions occurring outside EU Serious and unexpected ADRs, foreign or domestic * Volume 9a, Part I, section 1.2 and draft Volume 9a, Part I, Section 4 8 Code of Federal Regulations, section Food and Drug Regulations, section C Serious ADRs (expected or unexpected) occurring in Canada Serious and unexpected ADRs outside of Canada Figure 9 Industry practice: Use of literature databases innovative versus generic companies review frequency is specified in the US and Canadian regulations. Also, no companies review the literature less frequently than monthly, which is consistent with the CIOMS V recommendation. 14 From the responses received, the most popular literature databases for the responding innovators and generics are presented in descending order in Figure 9. The results collected are fairly consistent with the CIOMS V report 14 that the Medline and EMBASE are the two most widely used biomedical databases for literature search for spontaneous adverse reactions. The Reactions (Weekly) are also fairly commonly used (69.23% innovative and 76.92% generic), followed by the Current Content that is used by approximately one-third of the innovators. Significantly fewer companies used additional databases, such as Derwent Drug Files, Biosis and Psycho Info. Based on the industry s opinion, a majority of the respondents agreed that both innovative and generic companies should be responsible for ADR reporting. Only about 1% of the companies believe that this is the sole responsibility of the innovators. This mentality is consistent with the current requirements that require both innovative and generic manufacturers to review and report appropriate literature information to the regulators. In reality, however, this may lead to an increase of duplicated reports in the regulator and manufacturer databases. The CIOMS V working group recommendations to minimise report duplication should be considered and are summarise in Table 3. Regulatory Rapporteur January Issue 27

7 8 focus Table 3 Minimisation of duplicated ADR reports 14 Situations Companies in partnership via licensing agreement Comments Identify partner responsibilities in licensing agreement(s), including screening of databases and local publications, procedures for processing and exchange of reports, and regulatory reporting. Multiple manufacturers (both innovative and generic companies) Try to determine the specific product used by contacting the author(s) if the product source is not specified in a publication (ie, only the generic name is mentioned). Presume it was the company s product in the absence of clarification and indicate in the database and any reports that the specific brand was not identified. Generally, the industry practices pertaining to spontaneous reporting are similar between the two study groups and the industry practices appeared to well-established. Both industry sectors are compliant with the regulatory requirements except the small percentage of those European companies that conduct literature review less frequently than weekly. Improvement should thus be made to tighten their company practices and conduct literature search at least weekly to meet the EU regulatory requirements. For the North American companies that conduct literature review either biweekly or monthly, although not required, it is recommended to employ weekly literature review as good company practices, particularly for the innovative companies. This is to ensure that any newly arisen important safety information would be captured, reviewed and communicated efficiently, and the appropriate action(s) may be implemented as required to protect patient safety. There are a few limitations to this research. First, the research findings were limited to the information obtained through the data from 31 respondents (one response was excluded from statistical analysis) from EU, US and Canada targeted by the questionnaire. Second, only a relatively small sample size with a small number of responses (N = 3; 37.5%) were collected and analysed. To achieve more robust results, a larger sample size including other countries (eg, Japan, Australia, etc) may be considered to achieve better understanding of global pharmacovigilance practices. In addition, interviewing pharmacovigilance experts from both industry sectors and representatives of regulatory agencies might enhance the insight and provide a more in-depth understanding of the differences surrounding the innovative and generic pharmacovigilance practices. Conclusion The analysis of the responses showed that the innovative and generic companies are essentially the same with the various industry procedures for spontaneous reporting and there is no observed difference between the two groups. References 1. World Health Organisation. The importance of pharmacovigilance. Safety monitoring of medicinal products Meyboom RH, Egberts AC, Gribnau FW, Hekster YA. Pharmacovigilance in perspective. Drug Saf Dec;21(6): Waller PC, Tilson HH. Chapter 8. Managing drug safety issues with marketed products. In: Stephens Detection of New Adverse Drug Reactions. 5th edition. Talbot J, Waller P, editors. England: John Wiley & Sons Ltd; 24. p Council for International Organizations of Medical Sciences. CIOMS I. International reporting of adverse drug reactions: introduction of the CIOMS I reporting form for standardized international reporting of individual cases of serious, unexpected adverse drug reactions International Conference on Harmonisation. Harmonised tripartite guideline. Clinical safety data management: definitions and standards for expedited reporting. E2A. October 27, International Conference on Harmonisation. Harmonised tripartite guideline. Post-approval safety data management: definitions and standards for expedited reporting. E2D. November 12, Eudralex. Volume 9 Pharmacovigilance. Medicinal products for human use and veterinary medicinal products. June Eudralex. Public consultation on Volume 9a of the rules governing medicinal products in the European Union: the guidelines on pharmacovigilance for medicinal products for human use [draft]. December 16, US Code of Federal Regulation. 21 CFR Postmarketing reporting of adverse drug experiences. 1. US Code of Federal Regulation. 21 CFR Postmarketing reports. 11. US Federal Register. 21 CFR Parts 31, 312, 314, 32, 6, 61, and 66. Safety Reporting Requirements for Human Drug and Biological Products [draft]. March 14, Health Canada. Canada Food and Drug Act and Regulations. 13. Health Canada. Guidelines for reporting adverse reactions to marketed drugs [revised]. July Council for International Organizations of Medical Sciences. CIOMS V. Current challenges in pharmacovigilance: Pragmatic approaches. Report of CIOMS Working Group V. 21.