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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 https://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:








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.

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