Medical Safety Hazard Analyses

Oct 16, 2013

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

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:

  • Any injuries or disease that has already occurred
  • Whether the product problem could contribute to a clinical situation exposing people (or animals) to a safety hazard
  • Risks to particular segments of the population with attention to vulnerable subgroups
  • The degree of seriousness (severity) of the hazard
  • The likelihood of occurrence
  • Possible short or long range consequences

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:

  • Are there any conditions that might mask or hide the adverse effects produced by the product problem?
  • Is the injury or potential injury easily discovered or diagnosed?
  • Is the injury reversible?
  • Is the injury dose related?
  • Is the injury treatable and/or whether medical intervention is required?

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:

  • Someone must be put in charge of the process to provide oversight and the project plan to produce the final document, get the needed resources (often on an emergency basis), be sure the timing is right especially if the document is promised to FDA within a few hours and to keep management informed.  If an “all-nighter” is being done, someone must order out for the pizza and sodas as well as to make sure the building’s heat/AC and electricity do not get turned off.  Often it is a senior regulatory or compliance/quality person who handles this.
  • The team must be constituted and the various tasks assigned (query the database, check animal data, examine the pharmacokinetics and metabolism/absorption, literature search etc.) with the appropriate urgency made clear.  Desired deliverables should be clear, crisp and concise.
  • Someone must handle the writing, collating and editing.  This may be the MD preparing the document or a medical writer.
  • Align the reviewers to be sure they are ready to read the first draft, to comment and to sign off on the final version especially if legal and senior management signs off.
  • For the future, if there is no SOP or work instruction covering this, it should be written and implemented.

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 most basic issue is that this letter gives the company’s medical opinion on a hazard which is often due to a manufacturing or product failure.  The wrong label, the wrong active or excipient ingredient was used, the active ingredient was left out or is out of specification, contamination is present, the wrong dosage or label was put on etc.  This can produce major disease or injury to the public and may clearly be the company’s fault.This produces a legal and liability nightmare for the company and everyone will move into defensive mode.  Some will want the problem minimized and put in a more positive light than seems appropriate.  Since a large part of the analysis involves a scientific estimate (or “guesstimate”) of what might occur to subgroups if exposed (even though none has yet been exposed) some people will want this minimized or left out.

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.

  • The lawyers will wordsmith the document usually saying, in effect, we are not changing your medical judgment or decision but we just want to phrase it in a “softer” or more “neutral” way or put it in the conditional mode (“if it were to occur that…”) rather than stating it clearly and directly.
  • Sometimes there simply is not enough information to make a clear medical judgment or the judgment cannot be made until certain data is obtained (e.g. testing of retain and returned specimens).  As is common in medicine, the MD must make a medical judgment with very incomplete information.  This is obviously not easy, particularly if the document is due in a few hours and many folks are looking over your shoulder.
  • The personnel at the agencies see all of these analyses from all sorts of companies and clearly recognize which analyses are meritorious and which are not.  It is not wise for the company to show FDA or other agencies that the company is not acting in particularly good faith.
  • The MD and all the others involved in the analysis must stick to their guns and do what is right for public health.

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.