Miscellaneous: EMA Mod 6 revisions; drug-device AEs; getting AEs in clinical trials

Jun 27, 2013
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

In writing these columns I frequently come across topics that warrant a few words but not a whole posting.  So today, we’ll catch up on some of these.

EMA Module 6 on AR Reporting

In June, the EMA issued an update on its “Guideline on good pharmacovigilance practices: Module VI – Management and reporting of adverse reactions to medicinal products”.  It is out for consultation with changes requested by August 5, 2013.  See http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500144009&murl=menus/document_library/document_library.jsp&mid=0b01ac058009a3dc

This is a very long module covering over 90 pages of material on the specifics of reporting post-marketing and some study serious and non-serious AEs to the EMA and the member states.  This covers what had previously been in Volume 9A.  It is the fundamental “how to” regulation for the EU.  Everyone handling drug safety in the EU must be familiar with this document.

A few small revisions have been published in this draft:

  • A clarification in VI.B.7. on reporting of ICSRs to note that day zero starts when “a receiver is informed of a valid ICSR, irrespective of whether the information is received during a weekend or public holiday.”  The following statement has been removed: “In practice, this is the first business day the receiver becomes aware of the information.”

    Clearly some folks were interpreting this to mean the clock starts on the next business day.  This was a surprising comment in the original document and really contravened 20 years of “calendar” day requirements where the clock starts when the valid case arrives whether a working day or not.


  • A clarification in VI.C.1.2 on AEs collected from non-interventional post-authorisation studies such as patient support, disease management programs, registries, surveys, named patient use etc.  The EMA revision makes clear that t”he member state and the MAH must ensure that there is a system in place to collect full and comprehensive case information on AEs that are actively sought in post-authorisation studies.”

    That is, safety data has to be collected from these studies, interventions etc.


  • In the same section there is a clarification that academic sponsors need only follow local requirements regarding the reporting of suspected ARs and not this module.  On the other hand, “where a study is directly financed, initiated, managed (fully or partially), or where its design is influenced by a marketing authorisation holder…, the MAH should be considered as sponsor.  In this context, the MAH should fulfill the requirements detailed in this module.”

    That is, a purely academic study need not follow this module but any time an MAH is involved, the usual requirements for PV are required by all parties.


  • In section VI.C.1.2.1 on non-interventional studies, the EMA makes clear that non-academic studies must specify in the protocol any AEs/SAEs that are to be actively sought and reported by HCPs or consumers.  In addition, the previous requirement that “Only reports of ARs suspected to be related to the studied medicinal product should be reported.  Reports of AEs should only be summarized in the study report, where applicable”, has been removed.  For non-interventional studies based on secondary use of data, ICSRs should not be reported.  Rather AEs and ARs should be summarized in the interim or final study report.

    This confusing section now seems to require that only valid ICSRs of ARs (not just SARS) suspected to be related to the studied medicinal product and specified in the protocol should be reported (as solicited reports) by the sponsor.  All other serious and non-serious AEs not actively sought according to the protocol should only be summarized in the interim or final study report and not reported as ICSRs.


  • In section VI.C.2.2.2. on solicited reports, the EMA makes clear that the MAH should have mechanisms in place to handle solicited reports from all sources not just post-authorisation studies.


  • In section VI.C. on languages, the EMA clarifies that when suspected ARs are reported by the primary source that is not English but is one of the EU official languages, the “original verbatim text” should be included in the ICSR if requested by the member state where the reaction occurred or the agency.


  • In section VI.C. on reporting from organized data collection systems, the EMA has added market research programs to the list of such systems and AEs must be actively sought, handled and reported.


  • Section VI.App3.1.1 contains a table on interim arrangements applicable to MAHs regarding reporting of ICSRs in early 2013.  This complex table with varying requirements by country, by source of the AE/SAE and whether the drug was approved by the centralized or other methods is now removed and no longer effective.

Drug-Device AEs

A question: We are developing a device that is surgically implanted but can only be used with our drug.  We expect this to be treated as combo product in the US but EMA will treat it as a separate device and drug.   We are trying to decide how to handle AE reporting for the device, the drug and those AEs that are ascribed to both the device or drug (or cannot clearly be ascribed one or the other)?

A good question and not clear that there is a good and consistent answer that is applicable throughout the world.  The consensus seems to be that if the AE is clearly drug related it should be handled as a drug event and so reported and if it is clearly device related it should be handled as a device problem (note that the definitions of “bad things” with devices are quite different from drugs and are much less harmonized globally).  If the case is unclear in terms of whether it could be drug or device related or if it is due to both (e.g. the needle broke off and some of the drug extravasated into the nearby skin causing a local injection site reaction or an implanted pump malfunctioned giving an overdose of drug to the patient) then this should be reported both as a device and drug problem.

One is advised to verify this in the areas where such studies or approved products are used as the rules vary and the device regulations (in particular) are changing rapidly now around the world.

 Soliciting AEs in Clinical Trials

In clinical studies, how should the investigator get AEs from the patients/subjects?  Should they actually solicit AEs (e.g. did you have headache? did you develop a rash?) during a study visit the investigator await voluntary suggestion from the patient on headache etc?  Similarly, is it appropriate to solicit AE from the patient with a patient diary during the study?

Two questions here really and the second one is the trickier one.  The first one was answered many years ago and is now well accepted good PV practices though not really formalized in most regulations.  This concept basically states that the patient should be asked an open ended question by the investigator at the visit, to the effect: “How have you been since the last visit? Any problems or issues?” In particular, a checklist or specific question (“Did you have any chest pain?”) should be avoided unless the protocol specifically states that such detailed questions will be asked.  What should be done, however, is pointed questions on previously reported, ongoing AEs or such: “Did the headaches you reported on the last visit stop?”  It was found that using a checklist or asking pointed, specific questions introduced biases and suggestions and appeared to give an elevated (and arguably false) level of AEs.  As noted, this is now well accepted in clinical research.

The CIOMS VI working group addressed this question and came to the following conclusion (Management of Safety Information from Clinical Trials,Report of CIOMS Working Group VI, 2005, Genva. Page 93):

“It is probably best to frame questions to the patients in general terms rather than to invoke the possibility that study treatment maybe responsible for ill effects.  For example: “How have you felt since I laws you last?  Is there anything new that you wish to discuss?” 

Although it is not advisable to read a specific list of possible ADRs when soliciting the patient’s recent experience, patients should be alerted to known signs and symptoms indicative of medically important suspected or established ADRs in order to alert the investigator as early as possible.”

The question of diaries, however, is trickier.  In general, diaries are given to record specific issues, findings, symptoms etc.  So if one is using the diary to track particular effects (both good and bad) such as palpitations during holter monitoring then it is entirely appropriate to ask specific questions.  Again, as above, this should be defined in the protocol and clearly specified to the patient.  Another tricky area in diaries (whether electronic or paper) is free text.  If the patient has the ability to write down unsolicited comments (e.g. margin notes: had a nasty headache today) then the diaries must be examined for unreported AEs.  At each visit the investigator should look at the diary to be sure no AEs are missed.

That’s it for now.  If there are questions or tricky issues you would like addressed that the readership might be interested in, please send them to us.