Introduction
Over the last decade, there have been significant changes in the legislation governing the development of pharmaceutical and biologic products—many of these aimed at improving patient safety. A number of these changes have focused on developing, more quickly, a better understanding of the benefits versus the risks of prescribing a medicine to individual patients, post-approval.1,2 This has elevated the importance of an effective pharmacovigilance system as a factor in considering whether or not to grant regulatory approval of both new chemical entities and new indications for existing drugs.
However, there is often a poor understanding of just how much can be known about the relative benefits and risks of a new medicine prior to marketing approval. Due in part to recent high profile cases of approved drugs being withdrawn from the marketplace, there is a common perception among patients and healthcare providers that post-approval safety surveillance is ineffective.
The increasing complexity of clinical trials, involving greater numbers of patients frequently situated across multiple continents, coupled with the trend towards out-sourcing what were previously considered core functions has made effective oversight by sponsors more crucial than ever before. A further complicating factor is the drive to contain pharmaceutical development costs, which can result in shrinking budgets, reduced resources, and increased employee workloads.
Recognizing these challenges, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have issued guidance documents on the use of risk-based approaches to quality management and oversight of clinical investigations.2,3 These documents advocate the use of both on-site and centralized (remote) monitoring of investigational sites as part of the sponsor’s oversight program. While the focus of these particular documents was the oversight of clinical trials, the sweeping legislative changes introduced by the EMA through the Good Pharmacovigilance Practices guidelines encourages the use of the same principles for oversight of the pharmacovigilance system.1,4
Significantly, in 2013, the EMA issued a ‘Points to Consider’ document5 offering guidance on the conduct of regulatory pharmacovigilance system inspections during crisis situations. This guidance states “Under situations such as transport restrictions or situations which give rise to concerns of inspectors’ safety (eg, pandemics, natural disasters, high criminality areas), distant/virtual inspections could replace on-site inspections.”
The objective of this study was to identify the benefits and understand the limitations of conducting pharmacovigilance system audits remotely, in terms of maintaining effective oversight while managing resources more effectively.
Methods
A total of 14 remote audits were included in our analysis; 6 of these were local affiliate (local country office) audits, 4 were vendor audits, including patient orientated programs, and 4 were audits conducted as part of a licensing opportunity due diligence; included in this latter group were a CRO, a generic manufacturer and 2 biotech companies. The scope of these audits was equivalent to that of a face-to-face pharmacovigilance system audit, but there were some notable differences in the way in which these remote audits were conducted.
Most of the audit sites had prior experience with face-to-face audits, but few of them were familiar with the concept of a remote audit. Consequently, during the planning phase, management at the audit site were made aware of the differences between a remote and an actual onsite audit so that any concerns could be addressed before the audit was undertaken. Two of the sites had previously been subject to a face-toface audit by one of the authors. Where necessary, the agreement of the EU QPPV was obtained, and standard operating procedures addressing audits were amended to incorporate the remote process.
Audit preparations were more extensive than would normally be expected for a face-to-face audit, with additional documentation requested upfront to ensure that the auditor had an in-depth understanding of the local organization, particularly the roles and responsibilities of those directly involved in the pharmacovigilance system. Documents were generally supplied to the auditor through a validated document management system, such as shared drives, e-rooms or other secure remote access technologies; where this was not possible, documents were scanned and sent by secure email, and facsimile transmission was only used during one of these audits. Logistical arrangements focused largely on ensuring effective communications because of the need to conduct interviews remotely: for the audits included in this analysis, video-conferencing was not used, and interviews were conducted by teleconference. Digital photographs were requested of the facilities, including the general work environment, along with file and archival rooms. Local IT-support was requested and confirmed for the length of the audit, and communications were tested as part of the pre-audit preparations; in addition, teleconference ground rules were established with participants in the audit. An attendance sheet was prepared for all teleconferences and formed an integral part of the audit documentation.
The conduct of the remote audit did not differ significantly from the normal face-to-face audit. Interviewees were asked to explain processes, illustrating their answers by referencing source documents, or by accessing computer systems. The auditor also examined scanned copies of source documents to verify that standardized procedures and regulatory guidelines were being adhered to. Where available, screensharing technologies were used to enable interviewees to illustrate their answers. Audit opening and exit meetings were held, together with daily progress meeting where this was deemed necessary. Following the exit meeting, a draft report was circulated for comment, before being finalized as would normally be the case for a face-to-face audit.
Results
It is common practice to allow up to 5 days for the conduct of a routine pharmacovigilance system audit, including a nominal 2 days for travel to and from the site. When compared to this standard, it was determined that a routine audit of either a corporate affiliate or a vendor could be completed in 3 days using the remote auditing process without any reduction in either audit scope, or the quality of the oversight. Without the need to travel, there was an estimated saving of 28 days over the course of 14 audits. Additional benefits included a significant reduction in travel-related costs and the ability to audit sites that were not readily available due to factors such as political unrest or health risks. The time allowed for audits associated with licensing, merger, and acquisition activities was more variable, but the same cost savings were realized.
Once the management at the audit site and audit participants were made aware of the differences between a virtual and an actual site visit, they were very supportive. During the remote process, the comprehensive upfront document requests allowed the auditor to better understand local processes and to prepare a comprehensive list of questions prior to conducting the interviews. With local affiliate audits, compliance with applicable global procedures was also verified. Secure access to documentation, either through a web-based validated document management system or through scanning and email was an essential component of this process; comprehensive IT-support, including adequate communication bandwidth, was particularly critical. Not all of the audit sites could be accessed by secure email and using facsimile machines added significantly to the administrative burden. Interviews were conducted by teleconference, with screen-sharing technologies proving effective in allowing interviewees to demonstrate process steps. However, document requests from the auditor made during the audit phase often took longer to fulfill and some of the interviewees were less able to illustrate their answers by reference to materials that they had brought with them, especially when these materials had not been previously shared with the auditor.
Evaluation
Table 1. Summary of Benefits of Conducting Pharmacovigilance Audits Remotely
Table 2. Summary of Limitations of Conducting Pharmacovigilance Audits Remotely
Conclusions
The audits conducted during this program addressed both routine pharmacovigilance activities (including case processing, risk minimization activities, safety data exchange, documentation reviews, and patient-oriented programs) and the follow-up of remedial action plans (CAPA). Conducting pharmacovigilance system audits remotely has proved to be a cost-effective way of maintaining oversight of on-site pharmacovigilance activities irrespective of whether these were being conducted by a company affiliate, a vendor responsible for patientoriented programs, or were being evaluated as part of a licensing opportunity due diligence. The remote auditing process also lends itself to other relevant pharmacovigilance system activities including regulatory inspection preparedness or auditor training, and we are in the process of exploring these additional opportunities. Without the need to travel, there was a saving of 2 days per remote audit over the course of this program. Additional benefits included a significant reduction in travel-related costs (flights, meals, and accommodation), the ability to reschedule audits more easily since travel arrangements were not a factor, and the ability to audit sites that were not readily available due to factors such as political unrest, inaccessibility or local health risks such as Ebola outbreaks.
However, there are significant limitations to conducting audits remotely, and cost savings should not overshadow these. Perhaps the single most important limitation is the reliance on communications technology, especially teleconferencing. Even with the very best telecommunication facilities, it is not possible for an auditor to read the body language of interviewees, and this is sometimes the first indication to an experienced auditor that a site may have issues. In addition, where English is not the first language of the participants, long distance communication can prove challenging, and this needs to be considered during audit preparations. For some of our audits, a local company representative with pharmacovigilance experience was present at the site and able to provide support under the direction of the auditor. Sitting in the same room as an interviewee also makes it easier for them to illustrate their answer to the auditor’s questions using aids that they have brought with them. In our experience, computer desktop sharing technologies go some way towards facilitating explanations, but only if the interviewee is proficient in using them. Video-conferencing facilities would remove many of the limitations inherent to teleconferencing, and although this technology is commonly available within larger companies, it is currently cost-prohibitive for many smaller companies.
Another potential challenge is the sharing of documents. While centralized electronic document management is widespread in larger pharma and biotech companies, smaller companies, affiliates, and vendors may still operate a paper-based system. This can make sharing documents during the pre-audit and audit phases problematic, since exchanging documents using facsimile machines, while secure, is not a workable solution. In addition, emailing scanned documents outside of a secure company network does not preserve confidentiality and cannot be considered a viable way of distributing audit documentation. Digital photographs of the audit site also have limitations. For example, a photograph of an archive from the outside may show a closed access-controlled door, when in reality the door is frequently propped open to allow staff easy access through the door because their arms are often full of folders. Another example that may not be readily visible in digital photographs is where source data files are left on desks overnight instead of being locked away. We have not yet requested a live video tour of a facility during a remote audit, but the technology is readily available, and may offer advantages over digital photographs.
It should be remembered that many auditors use their travel time to review audit documentation or draft reports, so while cost savings are real, travel time savings may be less than they initially appear. Additionally, although auditors do not have to cope with travel-induced jet lag during a remote audit, conducting an audit according to local business hours can be challenging, particularly from a home office.
In conclusion, remote auditing at this point in time is particularly well suited to lower risk sites such as local affiliate offices, and when used as a follow-up to a face-to-face audit or to monitor progress on a CAPA. Although feedback from those participating in the remote audits was positive, this process does not replace the need for on-site audits; it does however allow a more sustained degree of oversight when integrated into a carefully planned, risk-based pharmacovigilance system audit program.
References
- Guideline on good pharmacovigilance practices (GVP), Module I – Pharmacovigilance systems and their quality systems, European Medicines Agency; EMA/541760/2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129132.pdf. Accessed July 27, 2014.
- Guidance to Industry: Oversight of clinical investigations – A risk-based approach to monitoring, U.S. Department of Health and Human Services, Food and Drug Agency; 0910-07333, 2013. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf. Accessed July 27, 2014.
- Reflection paper on risk based quality management in clinical trials, European Medicines Agency; EMA/INS/GCP/394194/2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500110059.pdf. Accessed July 27, 2014.
- Guideline on good pharmacovigilance practices (GVP), Module IV – Pharmacovigilance audits, European Medicines Agency; EMA/228028/2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/12/WC500136233.pdf. Accessed July 27, 2014.
- Distant/virtual pharmacovigilance inspections of MAHs during a crisis situation – Points to consider, European Medicines Agency; EMA/INS/119905/2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/02/WC500138892.pdf. Accessed July 27, 2014.
Dr. Alun Tanner has more than 30 years of experience in all phases of pharmaceutical drug development including the support of M&A activities. Currently an independent consultant, he advises CROs, biotech, and pharma companies on how to maintain compliance and implement industry best quality practices in the complex regulatory environment of pharmacovigilance.
Dr. Bora Sever has more than 18 year of experience in all aspects of the clinical development cycle. He has conducted more than 200 compliance audits spanning all aspects of pharmacovigilance and risk management, including corrective action planning, documentation reviews, Good Clinical Practice, and business due diligence in support of M&A activities.