Improvement is needed for risk management guidance for in vitro medical devices

November 4, 2007

When either a manufacturer or a clinical laboratory performs risk management, it is implied in the risk management standard ISO 14971 (and other literature) that risk management (1-4):

·         Identifies any product component or process step that has unacceptable risk

·         Through mitigations, reduces all remaining risk to an acceptable level

The purpose of this entry is to show that this doesn’t always happen and to suggest what to do about it.

Note 1: in order to understand ISO 14971, you need to learn ISO speak (“globally harmonized terminology”). For example, there are no lab “test results” or “assay results” – these are called “examination results.”

Note 2: ISO 14971 is intended for manufacturers. The section about risk management for clinical laboratories is based on my discussions with clinical laboratory directors.

The problem frame – ISO 14971 has a figure (H.1, page 61), which shows that there are three possibilities to prevent harm to the patient – the medical device manufacturer, the clinical laboratory, and the physician. ISO 14971 describes a mitigation* as either a way to prevent or detect an error. ISO fails to include recovery (5), which is a serious omission.

* I use here the word “mitigation” but should point out that mitigation has been banned from ISO speak and isn’t in ISO 14971.

An example problem– hCG (human chorionic gonadotropin) is an assay used to test for pregnancy. Such assays are subject to interferences, with HAMA (human anti-mouse antibody) a common example. In one case, a woman with an elevated hCG was diagnosed as having cancer and underwent chemotherapy, hysterectomy, and partial removal of one lung (6). Eventually, it was determined that she did not have cancer and all of the hCG assay results were incorrect due to HAMA interference – her actual hCG was not elevated. Cole studied this problem and found that it has occurred multiple times (7).

Manufacturer – One of the most difficult problems for manufacturers to overcome is lack of analytical specificity. This means that for many assays, a few results will be way off due to substances in the specimen that interfere with the assay. The fact that the rate of occurrence of this error is low is good, but as seen above, the consequences can result in severe harm to the patient. It is standard practice for manufacturers to accept the small rate of erroneous results and deal with the issue by stating these limitations in the product labeling (the package insert).

ISO 14971 provides the use of stating limitations as one method – albeit the least desirable method  – of risk reduction (H.4.1.c p70).

In the case of HAMA and other interferences, this warning is of little value to the laboratory since a laboratory has no information as to which specimens have HAMA or other interferences and it would be prohibitively expensive to try to determine this information (e.g., the recovery will fail). (I once had roof rack straps for my car which had a warning on the package – “stop every 25 miles to make sure the straps are secure”).

Clinical Laboratory – It was a surprise to me to learn from some clinical laboratory directors that:

·         They know that occasional erroneous hCG results are reported to clinicians, which ultimately causes patient harm

·         There is a quality control possibility to test a specimen for HAMA interferences by diluting it and rerunning it, but this is rejected as too expensive

·         Thus, clinical laboratory directors recognize the risk as unacceptable, but live with it

Analysis – The manufacturer is doing the right thing. If they could economically develop an assay without interferences, they would. Regulators who approve the assay are doing the right thing. Rejecting the assay would cause more harm to patients due to the lack of information of no assay result than the harm caused by a small number of erroneous results. The clinical laboratory directors are doing the right thing. If they reran too many samples, their costs would be too high and the laboratory would go out of business (more likely the laboratory director would be fired first and the rerunning process stopped).

The manufacturer notification of limitations, while necessary and conforming to ISO 14971, is ineffective to prevent risk. The clinical laboratory either does nothing to prevent risk or could potentially do the same thing as the manufacturer – issue a warning about potential interferences in the assay report to physicians.

Proposed Solutions – Recognize the problem. The current status quo of the risk management scheme is that after risk management has been performed there is no issue, which is wrong. Issuing limitations that are ineffective in reducing risk must be so acknowledged. The outcome of this risk management task for either the manufacturer or the clinical laboratory must result in the HAMA event as an undesirable* risk. It should be acknowledged that it is a work in progress to come up with a method – which must be economical – which reduces this risk to an acceptable level.

*Use of the term unacceptable risk makes no sense, since no one would tolerate unacceptable risk. Hence, a risk management program could through mitigations reduce previously unacceptable risk events to some combination of acceptable risk events and undesirable risk events.

The role of the physician and patient – I will leave the role of the physician to someone else. I suggest that the ISO figure above is wrong. It should have one more cascade; namely, the possibility for the patient to detect and recover from a problem and if this fails, then harm will occur. One should not discount patients as being not knowledgeable enough.  Through the use of the Internet, there is a growing movement for patients to take more control of their health. This includes assessing laboratory results which are playing an increasing role in medical decision making (for one example see reference 8).  So as part of a risk management program, one should include the patient.


1.       ISO 14971

2.       Can’t afford to buy ISO 14971? Then read summaries in Ref. 2-4



5.       See Figure 4 in Krouwer, JS. An Improved Failure Mode Effects Analysis for Hospitals. Archives of Pathology and Laboratory Medicine: Vol. 128, No. 6, pp. 663–667. See

6.       Sainato, D. How labs can minimize the risk of false positive results. Clin Lab News 2001;27:6-8.

7.       Cole, LA Rinne, KM Shahabi S.and Omrani A. False-Positive hCG Assay Results Leading to Unnecessary Surgery and Chemotherapy and Needless Occurrences of Diabetes and Coma. Clinical Chemistry. 1999;45:313-314.