Agency and Internal Labeling

Transcription

1 Agency and Internal Labeling Audits Joseph McMillian, MA Heartland Compliance Services LLC Internal Labeling Audits The views and opinions expressed in the following PowerPoint slides are those of the individual id presenter and should not be attributed t to Drug Information Association, Inc. ( DIA ), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. i All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. Drug Information Association 2 1

2 The Purpose For Developing this presentation To educate labeling teams on what will likely occur when they undergo a labeling audit. To provide an auditor s view of labeling audits Drug Information Association 3 Internal and external audits Are very similar in the way they are conducted but subtly different in scope Drug Information Association 4 2

3 Internal versus external audits agency audits are conducted to ensure that the company is meeting regulatory requirements. The purpose for an internal audit is to ensure that defined processes and standards are being followed, including Company procedures industry standards and regulatory requirements. Drug Information Association 5 Internal versus external audits agency audits are conducted to ensure that the company is meeting regulatory requirements. The purpose for an internal audit is to ensure that defined processes and standards are being followed, including Company procedures industry standards and regulatory requirements. Drug Information Association 6 3

4 Internal versus external audits agency audits are conducted to ensure that the company is meeting regulatory requirements. The purpose for an internal audit is to ensure that defined processes and standards are being followed, including Company procedures industry standards and regulatory requirements. Both focus on the product Drug Information Association 7 The importance of up to date labeling Accurate, up-to-date labeling is difficult to maintain. And yet it is important for reasons both ethical and financial. Failure to disclose product safety information, failure to give it sufficient prominence, or delaying the communication of such information, can: put the patient / consumer at significant risk severely damage the image of a company with regulatory authorities and the public be extremely costly to the company diminish shareholder value. Drug Information Association 8 4

5 Everyone knows this So, if everyone knows this, why conduct audits? Drug Information Association 9 Why conduct audits? The reason is simple: When you compare labeling for a product or multiple products in each of the countries in which it is marketed, you ll often see considerable variation in content. agencies know this Companies know it Drug Information Association

6 Labeling variations between countries Labeling variations between countries are common because There is a distribution effect: each point of transfer causes delay authorities in different countries review and approve regulatory submissions at different rates labeling resources compete with other regulatory, marketing and manufacturing activities The result: labeling disharmony Drug Information Association 11 In theory, labeling updates are simple Safety signal Need for a medical labeling update is Identified Core labeling decision is issued to market country business units Implementation is Complete Evaluation Creation of core labeling decision by labeling Team Implementation of changes by global business units Time (The shorter, the better) Drug Information Association

7 In practice, they are more complex Safety signal Evaluation Need for medical labeling update Identified Core labeling decision issued to market country business units Submitted to Ministry i of Health Creation of core labeling decision by labeling Team Local labeling modified Change approved, Implementation begins Implementation Complete M.O.H. Review: changes discussed, negotiated with Ministry of Health Updated labeling issued Advertising Promotional materials Sales Training Compendia Time Summary of Product Characteristics Updated Drug Information Association 13 With multiple countries they are much more complex Sales Web Training sites Web sites Authorities Country Country Marketing Country Marketing Materials Marketing Materials Materials Web Web sites sites Web sites Compendia Compendia Compendia Med Info Med Info Med Info Market Country Marketing Departments Advertising / Promotion Advertising / Advertising / Promotion Promotion Market country Affairs units Export Markets Core Labeling Changes Manufacturing Packaging Services Manufacturing plants Distribution Centers Quality Assurance Units Distributor Markets Drug Information Association

8 Labeling Process in a typical site global reference labeling received from HQ Labeling group global reference labeling compared to current labeling In some companies, this step is required If changes can be implemented within local regulatory standards If not Current Approved Country labeling modified to reflect new requirements Submitted to Authority Approval for new labeling received HQ Labeling group reviews intended variance HQ labeling group notified of intended variance Marketing notified to update promotional and training materials New promotional materials* approved by affiliate; new use date identified New promotional materials put into use Source plant notified to modify insert modified insert artwork approved by affiliate; new use date identified Plant notified to implement Updated insert printed Updated insert packaged in new mfg batch Received in affiliate country Incoming QA To distribution In some countries Non Medical Change requests * Including Journal ads, Sales details aids, Web Sites, Drug compendia Updated artwork submitted to regulatory authority as confirmation Drug Information Association 15 So again - why audits? Two things can create significant issues for a company: Failure to disclose safety information Failure to do it in a timely manner These problems can be minimized by developing clearly defined processes which fulfill the requirements of regulatory and industry standards. Drug Information Association

9 So again - why audits? Two things can create significant issues for a company: Failure to disclose safety information Failure to do it in a timely manner These problems can be minimized by developing clearly defined processes which fulfill the requirements of regulatory and industry standards. Audits help ensure that these defined policies, processes and standards are being followed. Drug Information Association 17 How audits are conducted The auditor, either external or internal, will: Study the regulatory requirements for the country in which the product is marketed Compare the company s processes to see if they meet the requirements Make note of any issues of non-compliance Issue a report at the conclusion of the audit Expect the company to correct any problems Come back in the future to see if they did it. Drug Information Association

10 What is an audit? An audit is simply a systematic review of documents or a process An audit may be conducted by A regulatory agency inspector A company employee A contract auditor hired by the company A representative for an industry Association Drug Information Association 19 Internal versus external audit reporting External [regulatory agency] audits will note and report issues of non-compliance Internal audits, to be most effective, should note and report the good as well as the bad. Drug Information Association

11 Internal versus external audit reporting External [regulatory agency] audits will note and report issues of non-compliance Internal audits, to be most effective, should note and report the good as well as the bad. Drug Information Association 21 The way agency audits are conducted Their process is deceptively simple: Agency auditors evaluating labeling processes will usually take a couple of adverse reactions that have been reported and see how they were incorporated into company labeling Drug Information Association

12 agency audits Colleagues in various companies have relayed the following information about their experience with European agency labeling audits when inspecting headquarters' operations: [From Europe and the U.S.] The agency evaluated The transition of the safety evaluation process into labeling decisionmaking Timely signal evaluation process Appropriate decision making regarding a confirmed safety signal s implications on the labeling. Timelines between signal confirmation and submission of a safety variation Availability of appropriate Quality Documents and Archiving systems Training of staff involved in safety evaluation and labeling Drug Information Association 23 agency audits [From Asia] The agency evaluated Variations between regions in labeling content Timeliness of medical evaluation of safety signals CCDS Version control Availability of current CCDS for relevant personnel Availability of CCDS for all global products Documentation of medical committee evaluations The process for the handling of urgent safety issues Whether or not a mechanism exists in the labeling SOP for European urgent safety restrictions. Documentation from the dispatch of an implementation letter to submission of a variation in country organizations. Drug Information Association

13 agency audits The most active agency in conducting labeling audits is the U.K. s Medicines and Healthcare products Agency [MHRA]. Due to their expertise, they often conduct audits on behalf of the European Union. They provide a wealth of information about their activities on their website: The information they provide includes key issues that have seen in inspections. On the above site enter inspection findings in the search window. Drug Information Association 25 High level view of MHRA inspection findings In May 2008 they provided an in-depth listing of significant issues found during their pharmacovigilance / labeling inspections. A summary of those related to CCDS: Following identification of new signals and MAH decision i to update the CCDS, delays in submitting variations to update the SPCs. Delays of over a year have been observed. Delays in implementing SPC and PIL changes following approval of safety variations. Poor processes for ensuring that the minimum core safety information in the CCDS is consistently represented in local product information. Unwarranted inconsistencies in safety information between reference documents [e.g., CCDS, SPCs and Investigator Brochures]. Use of inappropriate reference safety document for the determination of expectedness. Wrong version of the SPC made available to health care professionals [e.g., on the emc web site]. Drug Information Association

14 High level view of MHRA inspection findings And there were many more related to Safety signals and updated reference safety information Processing of ICSRs Literature t searching Quality management systems PSURs Contracts and agreements IT systems Product Quality Medical information Detailed description of pharmacovigilance system Drug Information Association 27 High level view of MHRA inspection findings Examples of MHRA s observations in these other areas: Inadequate safety data exchange with affiliates / subsidiaries No timescales or process for the transfer of safety information No quality assurance auditing of affiliates Lack of / late reporting of ICSRs and PSURs No QPPV identified Lack of training / experience Inadequate oversight of the PV system Roles and responsibilities not formally defined SOPs do not agree with the system in place Inadequate access to medically qualified personnel No signal detection except at PSUR production Documentation related to signal evaluation Delays in reporting significant new safety findings Drug Information Association

15 Internal versus external audit reporting External [regulatory agency] audits will note and report issues of non-compliance Internal audits, to be most effective, should note and report the good as well as the bad. Drug Information Association 29 Internal versus external audit reporting External [regulatory agency] audits will note and report issues of non-compliance Internal audits, to be most effective, should* note and report the good as well as the bad. * Not every auditor does Drug Information Association

16 A good internal auditor will capture all observations Many auditors only report negative findings in audit reports without making note of the activities that were in compliance Without a denominator - reporting the negative without noting the positive - it is difficult to determine an overall compliance profile Auditors should make note of everything they observe and whether or not the activity observed was in compliance Doing so gives credit to the auditee for the things they are doing correctly Doing so also enables the auditor to establish a compliance baseline for comparison to other sites or to future audits Drug Information Association 31 Capturing all observations isn t difficult Some internal auditors will say that you cannot write down everything you looked at. But listing all of the observations isn t that difficult. An observation can cover a significant portion of the audit and still be simple and concise. For example: The SOP was reviewed for compliance with local regulatory and corporate requirements. All requirements were reflected in the SOPs and responsibilities were clearly delineated. No concerns were seen. No further action is needed. Drug Information Association

17 Using internal audits to measure compliance over time Example Of How Audit Observations can be used to measure compliance performance over time of observations per audit 12 Jan Jun Feb Jun 2010 Number Percentage Of Observations Which Required Corrective Actions Drug Information Association 33 Using internal audits to measure compliance over time Example Of How Audit Observations can be used to measure compliance performance over time of observations per audit Number 12 Jan Jun Feb Jun 2010 Assuming the same elements were measured during these 4 audits, they indicate a significant decline in compliance over time Percentage Of Observations Which Required Corrective Actions Drug Information Association

18 If you are audited Ask the auditor to note positive findings in the report as well as the negative. A professional auditor won t mind doing so. Drug Information Association 35 How internal audit priorities are established Internal audit priorities should be based on: Identified compliance issues The level of exposure to the company s drugs Products with greater safety issues Not: FDA jurisdiction every developed country has defined labeling requirements Country size The degree of regulatory scrutiny Drug Information Association

19 Internal Audit Standards For internal labeling audits, there are commonly 4 standards for the auditor to use: requirements Company policy Corporate SOPs Local affiliate SOPs and work instructions Drug Information Association 37 Types of internal labeling audits There are basically 3 types of labeling audits: Desk / Text audits of labeling content Audits of labeling processes at the affiliate office Audits of implementation by marketing and manufacturing Drug Information Association

20 Text Audits versus Process Audits Audits of labeling texts Usually performed at the company headquarters An in-depth comparison of an approved country labeling text to the company s Core Data Sheet Require understanding of medical terminology Require extensive translations of labeling documents Commonly involve searching local labeling for hundreds of required warning or adverse event statements Do not take into consideration local procedures or regulations simply whether or not the labeling agrees with the CCDS. Audits of labeling processes Performed at the affiliate office Are in-depth reviews of company policies and procedures for labeling and specific country labeling regulations Are comparisons of local procedures (SOPs) for agreement with company and regulatory requirements Are comparisons of local records to local SOPs Are in-depth reviews of the labeling li process Drug Information Association 39 Labeling Process in a typical site global reference labeling received from HQ Labeling group global reference labeling compared to current labeling In some companies, this step is required If changes can be implemented within local regulatory standards If not Current Approved Country labeling modified to reflect new requirements Submitted to Authority Approval for new labeling received HQ Labeling group reviews intended variance HQ labeling group notified of intended variance Marketing notified to update promotional and training materials New promotional materials* approved by affiliate; new use date identified New promotional materials put into use Non Medical Change requests Source plant notified to modify insert modified insert artwork approved by affiliate; new use date identified Plant notified to implement Updated insert printed Updated insert packaged in new mfg batch Received in affiliate country Each of these steps should be defined in a written SOP Incoming QA In some countries To distribution * Including Journal ads, Sales details aids, Web Sites, Drug compendia Updated artwork submitted to regulatory authority as confirmation Drug Information Association

21 What an experienced auditor looks for during an audit Defined responsibilities who is responsible for implementing core labeling decision requirements Written, comprehensive procedures that reflect regulatory and company requirements Review and approval of labeling changes Documentation of the review and approval Submission to the local regulatory authority Following approval by the local authority, changes to product associated materials. Archived documentation that proves compliance with procedures Resolution of issues from previous audits Drug Information Association 41 Effective SOPs Should: Define and be in compliance with company policy Clearly l define the process for labeling li changes Define who has the ability to initiate changes to labeling Designate approvers of labeling changes Discuss and define approval documentation Define the timing for reviewer approval Define the regulatory submission procedure Define the process for patient information (if required) Define the location and responsibility for archiving labeling records Define notification of labeling changes to affected affiliate departments Drug Information Association

22 Commons issues seen in internal labeling audits Labeling changes have not been implemented often because the site is waiting until license renewal before implementing the change SOPs are out of date SOPs do not match actual practice Archive files are incomplete Labeling updates have not yet been communicated to marketing, sales training and/or manufacturing Marketing and/or manufacturing have not updated the PI as requested Drug Information Association 43 Marketing Materials Marketing materials are any form of media that are used to promote a product Marketing materials must reflect current authorized labeling Timing for implementing changes is determined by local regulations and company policies Drug Information Association

23 Marketing Materials Marketing materials are any form of media that are used to promote a product Marketing materials must reflect current authorized labeling Timing for implementing changes is determined by If a marketing piece mentions a product and its use, it is considered promotional Drug Information Association 45 Common issues seen during internal audits of promotional material labeling Archive files incomplete Significant variations in compliance between product teams Not all materials are submitted to the copy approval committee for review and approval Changes required by the Copy Approval committee are not made Outdated materials are still in use Drug Information Association

24 How the Manufacturing Labeling Process should work regulatory agency reviews, approves and controls content of Approved Country Lbli Labeling [ACL]and associated PI Affairs submits update to regulatory agency regulatory agency approves new ACL sends PI change notice to manufacturing site customs inspection and approval Product shipped to local distribution facility Manufacturing site implements change per affiliate agency specifications Product shipped to affiliate country Into open distribution in Into open distribution in the Into affiliate open distribution country in the Into affiliate open distribution country in the affiliate country the affiliate country Export labeling: Manufacturing site country regulatory affairs submits updates to their regulatory agency Manufacturing site country Agency approves new ACL affairs sends PI change notice to manufacturing site Manufacturing site implements change per local regulatory agency specifications Manufacturing Site notifies export countries of change Manufacturing site country controls content If affiliate agency requires any change, this process of ACL and converts to the Route 1 process above Associated PIs affairs affairs units units affairs affairs units submit units submit affairs new affairs new units submit units submit Product new PI to affairs new local units PI submit to affairs local units Product submit new PI to affairs new local units PI to local agencies Manufacturing Into open distribution in shipped Product to MOHs submit new MOHs submit new PI to local PI to local MOHs submit new MOHs accept new PI Site Into open distribution in shipped to the Into affiliate open distribution country in affiliate shipped to PI to local PI to local MOHs PI to local MOHs as local ACL implements the affiliate Individual country affiliate the affiliate country countries; affiliate MOHs MOHs new PI country packs countries; customs countries; customs agencies inspections customs inspections inspections and Into open distribution in and Multi country, approvals; and Into Manufacturing the affiliate country approvals; Multi language packs into approvals; local Drug Information Association Site country into local distribution47 into local distribution distribution distribution Common Gaps in the Manufacturing Labeling Process (plant specific) regulatory agency reviews, approves and controls content of Approved Country Labeling [ACL]and associated PI Affairs submits update to regulatory agency regulatory agency approves new ACL sends PI change notice to manufacturing site customs inspection and approval Product shipped to local distribution facility Manufacturing site implements change per affiliate agency specifications Product shipped to affiliate country Into open distribution in Into open distribution in the Into affiliate open distribution country in the Into affiliate open distribution country in the affiliate country the affiliate country Export labeling: Manufacturing site country regulatory affairs submits updates to their regulatory agency Manufacturing site country Agency approves new ACL affairs sends PI change notice to manufacturing site Manufacturing site implements change per local regulatory agency specifications Manufacturing Site notifies export countries of change Manufacturing site country controls content If affiliate agency requires any change, this process of ACL and converts to the Route 1 process above affairs units affairs affairs units Associated PIs affairs units units submit affairs units submit new submit affairs new submit new units submit Product PI to affairs new local units new PI submit to affairs local units Product PI PI to affairs to local local units new PI to local agencies Manufacturing Into open distribution in shipped Product to MOHs submit new MOHs MOHs submit new MOHs submit new PI to local MOHs accept new PI Site Into open distribution in shipped to the Into affiliate open distribution country in affiliate shipped to PI to local PI to local PI to local MOHs as local ACL implements the affiliate Individual country affiliate the affiliate country countries; affiliate MOHs MOHs new PI country packs countries; customs countries; customs agencies inspections customs inspections inspections and Into open distribution in and Multi country, approvals; and Into Manufacturing the affiliate country approvals; Multi language packs into approvals; local Drug Information Association Site country into local distribution 48 into local distribution distribution distribution 24

25 The audit report Reporting the results of an internal audit Drug Information Association 49 The significance of audit observations Not all instances of non-compliance are of equal importance. Drug Information Association

26 The significance of audit observations Not all instances of non-compliance are of equal importance. Determining significance of audit observations is simple: Use objective standards: Corporate and regulatory requirements Compare current activities to these standards. Drug Information Association 51 Recommended Categories for Audit Observations None: The audited activity appears to be in compliance with SOPs, Regulations; No recommendations appear to be necessary. Minor: The observed activity does not agree with SOPs and the disagreement is of a minor nature. If identified by an inspector during a regulatory agency inspection, minor observations would be considered something that could ordinarily be corrected during the course of the inspection. Major: There are significant / frequent disagreements between written SOPs or regulatory requirements and actual practice. If identified during an inspection, corrective actions may require a significant resource commitment to resolve the issue. Critical: There is clear evidence of a high level of non-compliance with regulatory requirements, presenting clear risk to the patient and/or a high level of risk to the corporation. If identified during a regulatory inspection, the business would be significantly impacted, resulting in disruption of normal business operations and a high level of resource commitment for resolution. Drug Information Association

27 Using this 4 point scale Enables you to determine compliance over time or across the organization [as discussed in earlier slides] Drug Information Association 53 So what does this mean for the sites responsible for labeling implementation? Drug Information Association

28 Site Responsibility for Labeling Implementation Each affiliate site has the legal and ethical responsibility to provide current usage and safety information on each of the products it markets. 7 October J. McMillian, Heartland Compliance Services LLC 55 Site Responsibility for Labeling Implementation Each affiliate site has the legal and ethical responsibility to provide current usage and safety information on each of the products it markets. 7 October J. McMillian, Heartland Compliance Services LLC 56 28

29 Current and Timely Some affiliates update their labeling: As soon as notifications of labeling change are received When they have accumulated several changes The next time the product license is renewed 7 October J. McMillian, Heartland Compliance Services LLC 57 A review of the process for updating labeling A safety signal is received and evaluated A notice of labeling change issued to the affiliates Local labeling is modified to reflect update The change is submitted to the local regulatory authority The change is approved by the regulatory authority Implementation begins in marketing, sales and manufacturing materials Implementation is complete 7 October J. McMillian, Heartland Compliance Services LLC 58 29

30 A review of the process for updating labeling A safety signal is received and evaluated A notice of labeling change issued to the affiliates Local labeling is modified to reflect update The change is submitted to the local regulatory authority The change is approved by the regulatory authority Implementation begins in marketing, sales and manufacturing materials Implementation is complete 7 October J. McMillian, Heartland Compliance Services LLC 59 Probably the most defensible approach If possible, work with the local regulatory authority to determine how soon they want to see: urgent safety changes, those of minor nature, what they consider to be minor Document their expectations and then meet, or exceed, their expectations. 7 October J. McMillian, Heartland Compliance Services LLC 60 30

31 Probably the most defensible approach If possible, work with the local regulatory authority to determine how soon they want to see: urgent safety changes, those of minor nature, what they consider to be minor Document their expectations and then meet, or exceed, their expectations. And Discuss local requirements with the headquarters labeling team to ensure agreement with the approach. Be prepared to show the documentation to the auditor. 7 October J. McMillian, Heartland Compliance Services LLC 61 And finally. Questions? Drug Information Association