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Today I’d like to discuss the writing of medical analyses of safety issues, particularly those that must be done product withdrawals from the market.  A medical safety analysis is done, usually by an MD or with an MD signing off on it and taking responsibility for its contents, when a pharmaceutical product or a device has posed a problem and a review of the risks and hazards has to be made.

This can occur in many situations including signal analyses, REMS/RMPs and other areas where a safety issue has occurred.  But perhaps the trickiest area in writing such analyses occurs when a product is undergoing recall or withdrawal from the market.

Just to remind you: a recall, which may be voluntary or at the request of the health agency, is the removal or correction of a marketed product that is considered to be in violation of the laws or regulations that apply.  A withdrawal is the removal or correction of a minor violation or no violation at all.

When there is a potential safety issue involved in a recall, the company and the health agency must evaluate the health hazard to see if there is any disease or injury that has already occurred or which might occur.  In particular the analysis looks at vulnerable and at risk subgroups (children, elderly, etc.), assesses the degree of seriousness of the hazard and the likelihood of its occurrence and the immediate and longer-term consequences to the patients.  This then leads to possible regulatory actions including, in the US, classification of the recall, 3-day field alerts, corrective actions etc.

Obviously this can have major consequences for patients, the company, prescribers etc. and can lead to legal action and lawsuits.  Such lawsuits can, of course, be from injured patients against the company but can also be by the sponsor against other companies if faulty material, drug product or packaging etc. was delivered causing or allegedly causing the problem.  In these situations the medical hazard analysis will often be a key document examined in regard to the danger, risk and severity of the problem.

So, in recalls, a medical hazard analysis must be written. The governing regulation in the US Code of Federal Regulations (21CFR7.41) is reproduced below.


To summarize these requirements, the hazard analysis should include information on:

Based upon this and other information the FDA (and other health agencies) will decide whether a recall is required and to what level (wholesaler, pharmacy, patient etc.).  Thus this is a key document.

This document must be scientific and medical and not a marketing document.  It should be factual and fair.  Other information beyond what is noted in the above regulation should be included if it further clarifies the situation, such as:

This analysis may be very complex and may include summaries of the SAEs that have occurred (and which, of course, have been submitted to the FDA and other agencies as required – there should be no expedited report surprises in this document).  It may include other cases the company has seen which are non-serious.  It may include a literature review, etc.  It is always tailored to the situation at hand.  There is no real template or boilerplate that could or should be used.

Usually this document has to be written very rapidly and in crisis or semi-crisis situations, particularly if the recall decision is to be made within minutes or hours and if the reporters are at the company’s door and the internet is buzzing.  It usually requires assistance from others in the company including regulatory, manufacturing, quality, toxicology, pharmacology, clinical research, IT (to write queries and pull data) and others.  Although the business folks (marketing, sales, senior management) will be most interested they really should not play a role in the preparation of this scientific document.

However, the final document must be approved by legal and senior management, particularly if there really is a significant health hazard described in the document.  The hazard analysis itself should not comment on the level of recall but simply state risks.  It is for others to determine how far down the chain the recall must go.

The practicalities:

The problems:

Having been the MD involved in several instances of writing medical hazard letters, it is clear to me that there are some very significant problems that may occur:

The worst cases I have been involved with occurred when some of the senior sales and marketing personnel were medically trained (even being MDs) who disagreed with the medical judgment of the safety MD responsible for making the final medical decision.  The pressure to change or temporize can be enormous.

So the bottom line here is that although many of these hazard analyses are easy and benign, there are occasional ones which do deal with major health risks to the public.  The MD and others involved in the production of the document will be under enormous pressure to minimize the risks and hazards, particularly if a potential global recall down to the patient level with emergency announcements on the 6 o’clock news and on the internet are likely.  These are the situations that test ones moral and ethical stature.

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