Virtual Pharmacovigilance Inspections
On January 18 of this year the UK Medicines and Healthcare Products Regulatory Agency (MHRA) released a short new document from the Office of Compliance and Inspection covering Distant/Virtual pharmcovigilance (PV) inspections of Marketing Authorization Holders (MAHs) during a crisis situation. See: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/02/WC500138892.pdf
For some time now the MHRA has indicated that it may do routine “virtual” or “distance” PV inspections of MAHs. In a July Q&A http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodPharmacovigilancePractice/Frequentlyaskedquestions/index.htm in question 7, the MHRA indicated that it might do a distance inspection if the MAH does not have a UK site: “…then a ‘virtual’ inspection may be performed. This may involve the MAH hiring temporary office space in the UK, or alternatively, the inspection being performed via teleconferences.”
The UK inspection process is a complicated one consistent with other EU PV inspections. In a nutshell, the MHRA contacts the MAH (or inspectee) and indicates they want to do a PV inspection. A date is agreed upon and a large amount of information describing the PV system, approved/authorized products and other company details is sent usually on a CD or DVD. A document called the Summary of PV Systems is also prepared and sent. The MAH may then decide to do or not do the inspection based on the data received. If they do decide on an on-site inspection, then the inspection unfolds as expected. Alternatively they may be satisfied with the the data received and doing additional teleconferences or videoteleconferences” – a virtual inspection.
The MHRA, in the new document, now has released further information on how they will do virtual inspections in crisis situations.
“Crisis” refers to situations where the safety of the inspectors is question or if there are transport restrictions. Examples include pandemics, national disasters and, interestingly, inspections in high criminality areas. In these circumstances, a distance or virtual inspection would be done if the various internal UK government departments agree. Virtual inspections would not be done if high risk MAHs are concerned.
The standard procedures for MHRA PV inspections would be followed with certain changes:
- In the announcement letter the technical details, means of communication, preparations required, documents needed before the inspection and the technical requirements for the virtual facilities would be clarified and agreed upon.
- Technical & Communication Issues: As there will probably be no or minimal actual personal contact with the MAH, reliable teleconference facilities must be put in place and tested before the inspection.
- Documents: Due to the presumed crisis nature of the situation, it may be harder to obtain the needed documents. Nonetheless, arrangements must be made for the documents to be sent to the agency via Eudralink or through the MHRA web portal if appropriate. Presumably, other means to convey the documents would be used if these links are not feasible.
More documents may be requested in the pre-inspection communications than would be requested for an on-site inspection. Normally, during a site inspection, MHRA requests additional documents when they arrive and during the inspection. This is done both to get information that is now needed but also to test the company’s ability to produce valid safety information on the spur of the moment.
Attention should be paid to documents that may need to be translated. The MAH should request that only key documents be translated.
The type and amount of documentation should be decided in advance and the MHRA may put in their schedule additional document review time in order to be better able to ask pertinent and focused questions during the interviews. Line listings and case files should be requested and received in advance. This is usually contrary to the on-site practice of asking for and reviewing these documents during the inspection.
- Have other Competent Authority (Health Agency) PV inspections been done? If so, particularly for triggered (for cause) or GCP/GMP inspections, these reports should be obtained and reviewed. This will allow the MHRA to better tailor their PV inspection.
- Regulatory Intelligence: The MHRA should review compliance data, communications and other information from ex-UK/EU health agencies. In particular, US FDA Warning Letters should be sought.
- Document Access: It may be easiest to arrange for the MHRA to obtain internet access to a company document repository and review the documents from there if company security and access procedures allow this. (If access procedures do not allow this the MAH should have a look at its data security procedures!). If hard copies are needed, they can be sent via email (Eudralink) or the MHRA portal and printed out by the MHRA.
- A formal written agenda will be prepared by the MHRA with time allocated for document review and individual telephone interviews. Language and translation issues should be kept in mind. Additional MHRA personnel may need to be involved also such as the product-specific assessors.
- Internet: A good internet connection is needed at both ends, particularly for document review. Key documents should be safety do a “USB pen” (thumb drive presumably). Confidentiality and data privacy/protection must be assured at all times.
- If there are problems. during crises, it may be necessary for the inspectors to ask fewer questions and do fewer interviews and relying more on the documentation provided. Techniques for the interviewers are discussed: speak slowly, if several MHRA personnel are in the room agree on when and how to interrupt or putting the call on mute. Be sure to summarize the points made to confirm correct understanding.
- Flexibility should be high as schedules change and, in some cases, additional time may be needed for interviews. The inspection may need to be extended in such cases.
- If significant issues are identified, it may be necessary or appropriate for MHRA to do a visit to the MAH after the virtual inspection.
- Reporting: The same procedures for an on-site inspection will be followed by the MHRA.
Comments and Observations
A virtual inspection may indeed be beneficial for both the MHRA and the inspectee. There is less stress, less travel and less time lost. The inspectors can work from their own offices and the company does not have to physically mobilize as much as it would if several inspectors were on site.
Some people do not do as well on the phone and prefer face to face interviews. Skilled interviewers will often say that it is better to do an interview in person as one can watch and evaluate body language, gestures etc. The phone is often harder for non-native speakers to use than in person conversations.
On the other hand, the interviewee can have assistants and “coaches” in the room (using a speaker phone or extensions) to help in tricky moments. The interviewer can also have coaches in the room!
The company should alter its preparations and training of personnel to account for the fact that the conversations will not be face to face. Training should then be done using phones. This is very common in language courses, particularly immersion courses, where some of the classes are done by phone. This is always harder than in person training as the ability to watch the speakers face and lips is lost and often the phone connection is less than ideal. The sound quality may be distorted, particularly on internet (VOIP) connections. The interviewee also cannot see the questioners face to get an idea of whether the responses are satisfactory. “Pregnant pauses” during the conversation can also be more disruptive to the interviewee.
It may also be necessary for the company to demonstrate its safety database in real time. The IT group may need to assist in setting up access at a distance in order for the MHRA to watch a demo (but, of course, not to have free access to the live company database).
If there is indeed a crisis ongoing, the best laid plans may go awry. Expect trouble and be sure the support teams are available to correct any bugs, problems, connectivity issues etc.
As in all inspections, expect the unexpected, have everyone on emergency call and be ready to “run” to get additional, unexpected documents, interviewees and other surprise requirements.
It might also be useful if the MAH has an internal audit/quality team that does PV audits or mock inspections to do some virtual inspections if they do not do so already. The company itself must treat a virtual inspection with the same seriousness and gravity it would with an on-site inspection. The legal ramifications can be just as severe.
US companies with UK or EU affiliates or business partners should be aware of this and may be required to participate in such inspections.
It will be interesting to see how this plays out as both companies and government become virtual!