If you want an example of why PV needs to be very closely involved in Patient Support Programs (PSP) or Market Research Programs (MRP), what happened recently to a very large pharmaceutical company should be a wake-up call for checking where you are on this topic.
As a reminder, in early 2012, the MHRA (UK Regulatory Agency), through a routine PV inspection of a large company, found 80,000 uninvestigated adverse reaction reports for medicines marketed in the US. The univestigated reports had been collected through a sponsored patient-support program. These included more than 15,000 reports of deaths, 23,000 suspected adverse drug reactions and 600 clinical trial-related adverse effects. While a subsequent investigation by the European Medicines Agency (EMA) found these events did not impact the benefit–risk assessment of the 19 centrally approved medicines involved, the company is still waiting for a final decision regarding the amount of penalties resulting from these findings, and a second investigation report[1] was recently submitted to the European Commission. In instances such as this penalties can include fines of up to 5% of a company’s preceding year’s revenues and, in the event of continued non-compliance, an ongoing periodic fine of 2.5% of daily revenues until compliance is assured. Even if this case is not as straightforward as it looks, there are still several take away messages for the consideration of any pharmacovigilance organization.
PSPs or MRPs are not always easy to identify and can cover a broad range of activities. These include data collection systems such as registries, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, compassionate use or named patient use, or any information gathering on efficacy or patient compliance. Any adverse reaction reports obtained from any of these data collection systems should be identified and processed.
In the US, handling of cases from PSPs and MRPs should follow postmarketing study rules[2], which require a reasonable possibility of a causal relationship for a serious unexpected AE to be reported on an expedited basis. In the EU, GVP Module VI on AE Reporting clarifies that safety reports from such programs should always be considered as solicited reports[3]. For both regions, the bottom line is that, for all programs that may intentionally or unintentionally gather safety information, all identified AEs should be promptly recorded, documented and reviewed in order for the company to allow meaningful assessment and reporting of individual cases as needed. This has an extremely broad impact on the role PV should have in scrutinizing all PSP and MRP initiatives in order to ensure that this critical expectation will be constantly met.
Knowing what programs take place in your company is therefore essential to demonstrate that your organization is able to capture any safety signal from any program in any part of the organization. For large international groups, capturing this information can be very challenging, but still necessary. For growing organizations, it is much better to establish the right process from the start rather than to rush fixing issues following inspections.
The following is what all organizations should have in place:
PV should be in the approval loop of any PSP/MRP initiative, across all countries and regions, in order to include in the program the adequate process for handling identified AEs. A corporate policy, covering all functions of the enterprise, is better than a departmental SOP. Of note, partnering with finance to identify all these initiatives can be very productive, as all programs are going through financial review and approval at some point.
Departments such as Medical Affairs, Market Research and Marketing should be mindful about the risks, obligations and PV costs resulting from such initiatives. Some companies charge back for PV activities, which makes sense as it should be factored into the actual cost of running a survey or disease registry.
The compliance to these policies should the subject of regular audits from QA. There should be periodic reconciliations to ensure that no initiative bypasses the mandatory process and that all identified AEs are collected and assessed.
These AEs should be part of the signaling process, preferably analyzed as a subgroup rather than added to the mass of other AE reports.
Demonstrating how the company is compliant with these activities should be part of the inspection readiness program.
It is absolutely critical that PV is involved at the earliest stages of the PSP/MRP design and approval. This is the only way to ensure that the safety data information from these initiatives will be collected and analyzed, will contribute to the signal detection activities, and will be reported to the authorities as needed. The cost for non-compliance is potentially very high; the rationale for implementing such a system is quite clear. Procrastination on the topic can be extremely costly. While we are still waiting for the final decision of the European Commission for this specific case, it might be a good idea to check where you are in your organization on this key topic.
[1] http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/07/WC500209635.pdf [2] 21 CFR 310.305(c)(1)(ii), 314.80(c)(2)(iii), 314.80(e), 600.80(c)(2)(iii), and 600.80(e)) [3] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/09/WC500172402.pdf
JP Clement, MD
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