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An issue that has been, and continues to be, an area of some controversy is what sort of medical review of individual case safety reports (ICSRs) should be done?  Some of the comments heard around the industry and during audits and inspections I have heard include:

“There’s no requirement for a medical review in the regulations”.

“We have a nurse or pharmacist look at all the cases”.

“Only expedited reports should be seen by a physician”.

“Generic drug ICSRs don’t need a medical review”.

“Non-serious cases are not important enough to require any sort of medical review”.

“The case is processed by a medical professional who is fully capable of doing the medical review while handling the case”.

“Physicians need only look at clinical trial cases”.

“We review the cases at the time of the preparation of the PADER, PSUR”.

“Non-serious expected cases don’t need medical review.  In fact they aren’t even submitted to FDA”.

So let’s have a look at the situation.

To my knowledge there is no actual regulation in the US, EMA or MHRA regulations that requires a physician to review some or all cases that are received by companies in the post-marketing setting.  Although someone in the company may be required to be responsible for safety and safety reporting in the eyes of the law (e.g. the QPPV in the EU) this person need not necessarily be a physician and need not necessarily review each case.  Similarly, CIOMS (particularly CIOMS V) does not seem to address this question.  The issue here revolves primarily around spontaneously reported cases.  Other adverse events, such as those from clinical trials, solicited post-marketing cases, patient support cases etc. usually are reviewed by medical personnel.

Having said that, let’s look at the need for a medical review of a post-marketing case. In the post-marketing setting, cases may come in from a variety of sources: patients, consumers, family of patients, health agencies, lawyers, poison control centers, literature, physicians (“medics” as they are sometimes known in the UK), nurses, pharmacists, dentists, podiatrists and other health care professionals (HCPs).  The bulk of the cases come in from health care professionals and patients in most countries.

For cases reported by HCPs there is, obviously, a “medical review” done by the reporter.  For cases not coming in from HCPs, for many years countries discounted these cases unless they were medically confirmed (which is defined as being corroborated to some degree by an HCP).  Nowadays, non-HCP reports are usually databased and handled like other spontaneously reported cases.

In my experience in the industry as a drug safety professional responsible for safety and, now, as a consultant doing safety and PV audits and gap analyses around the industry, there is a surprisingly large variation in the actual day to day medical review practices.  Here are a few generalities:

In other words, pretty much every situation is possible and occurs.

Before commenting further on whether a physician should do a medical review, let’s take a look at what the medical review of an ICSR should include, no matter who does it:

Clearly, for complex or equivocal cases, a physician with experience with the drug and with the disease/indication is necessary.  Sometimes several physicians must weigh in and even then a clear judgment may not be possible.

And, to be very fair, some physicians are not very good and do a poor job and some nurses and pharmacists are absolutely superb at this.

So what should be done? What are the possibilities?

Final thoughts and recommendations:

For those who read these postings regularly, you know that my views are quite conservative.  My view in this area is a simple one: All cases should be reviewed by a physician, usually looking at the source documents and doing a serious quality review after processing and review by an HCP.

One step down would have this thorough MD review done for all serious cases and all non-serious unexpected cases.  I would still be nervous and would want the non-serious expected cases reviewed periodically (at least as a line listing).

Finally, an HCP review of all cases with selected cases going to an MD for review would be my third and “least bad” choice.

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