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AACE Patient Safety - Editorials

Potential Thyrogen Contamination

2010-01-12 15:16:45
By: Alan Garber, MD, PhD
Editor, AACE Patient Safety Exchange

We have recently been notified that Thyrogen for injection by Genzyme contains, in rare instances (approximately 1% of vials), particulate contamination. This is not a new problem for Genzyme products, whose sole source enzyme products for patients with inborn errors of metabolism also have been noted previously to have the same issue of particulate contamination.

A letter from Genzyme to healthcare practitioners states that all vials of Thyrogen should be inspected for contamination prior to administration. Herein lies the problem for our members and patients alike. Since the contamination appears to involve multiple if not all lots of Thyrogen, continued use of this product places practitioners and patients alike at some risk. Although no adverse effects have been reported to the FDA, we are at early stages with the Thyrogen contamination issue and thus, cannot be sure that harm will not be noted in the future.

Concerns have been raised by AACE members regarding the Genzyme directive to examine all vials of Thyrogen prior to administration. This statement seems to transfer or expand liability for the contamination and its effects to the practitioner rather than have it remain solely with Genzyme. As noted by AACE Legal Counsel, the administering physician must now accept potential incurred liability for the contamination of this product. To AACE, transfer of such liability is not a desirable or even acceptable concomitant of Thyrogen use.

AACE has discussed the issues with Genzyme and is encouraged by its awareness and sensitivity to the liability concerns this creates for physicians and the steps the company is taking to improve product quality control and inspection. In the meantime, alternatives do exist for clinicians to avoid this dilemma. First, we could defer Thyrogen based screening until such time as Genzyme has implemented new internal controls in its manufacturing process which hopefully will produce particulate free Thyrogen. Alternatively, we may revert to older methods of withdrawal of therapy for thyroid cancer screening and evaluation. Although this approach may involve more inconvenience for the patient, it does obviate concerns regarding the unknown potential for as yet undefined adverse events from the existing particulate contamination of current lots of Thyrogen while preserving our ability to evaluate and treat patients appropriately.

AACE will follow closely the FDA’s ongoing surveillance of this issue and its interactions with Genzyme regarding corrective steps the company is taking to ensure increased quality control in the production of Thyrogen and other injectable biologic therapies.

Christopher L. Nuland, Esq.
AACE Legal Counsel

On November 11, 2009, the FDA and Genzyme alerted physicians that foreign particles had been found in batches of Thyrogen and warned physicians of the potential problem and associated risks. Genzyme also suggested that physicians perform a visual inspection of all Thyrogen vials to determine if any contaminants are present and to not use any such medication if foreign matter is detected as it always had done through its product insert. While one may question the ability of a physician to detect minute material through a visual inspection, physicians are urged to do so as a precautionary measure and record it in the patient’s record.

Ordinarily, the physician is insulated from liability if he/she follows the manufacturer’s suggestions for use, precautions, etc. To suggest that physicians perform visual inspections of each vial to detect minute amounts of foreign matter, which could not reasonably be expected to be detected in this manner, is seen by many physicians as an attempt by Genzyme to transfer the liability associated with its manufacturing to the physician, who is without the means to detect matter that often cannot be seen by the naked eye. While ideally Genzyme would be able to provide physicians a more practical and responsible method of detecting contaminants or to accept the ultimate responsibility for the quality of its products, no such method has yet been developed and Genzyme legally cannot accept responsibility for the product once it has left its possession. In the meantime, however, physicians are urged to perform the visual inspection to protect both themselves and their patients.

Letter to AACE
from Martin I. Surks, MD

My colleagues and I have concerns about the recent FDA alert and Genzyme letter addressed to health care practitioners regarding foreign particle contaminants found in several products manufactured by Genzyme Corporation (see attached)

I discussed this with several key Genzyme medical officers, who told me the following:

This guidance from the FDA applies to any company whose products are made and packaged by the same method, not just Genzyme.
Health care practitioners, themselves, must inspect the products for contaminants even though it was not eminently clear what the contaminants looked like
No reactions to Thyrogen had been reported, but reactions may be unreported by patients and/or their physicians. (This is certainly understandable in light of our own screening and treatment protocols wherein patients are not necessarily seen for weeks after receiving Thyrogen).

Ultimately, my logical question regarding the assumed manufacturer’s responsibility to inspect the powder for contaminants and withhold the distribution of questionable products was not answered. In addition, I was not given a response to my concern that inspection of said products was completely infeasible and impractical at our medical center, which is comprised of four hospitals, and a number of outpatient facilities where the product is administered without the supervision of an MD.

In light of the lack of clarity about how to inspect and what to look for, adequate and strategically located dedicated staff to inspect Thyrogen vials, until these issues are resolved, we have placed the use of Thyrogen on hold. Inexplicably, it appears that the FDA and Genzyme have shifted the onus of their product manufacturing and quality assurance problems to the health care practitioner.

Because Genzyme has ‘no safety signal,’ physicians employing and patients receiving Thyrogen could benefit from AACE, in conjunction with the American Thyroid Association and The Endocrine Society, strongly encouraging Genzyme to accept greater responsibility for inspecting their products and removing contaminants. Doing so would not only allay our anxiety about Thyrogen, but, most importantly, enhance our patients’ safety.

Genzyme’s Response to Concerns of Thyrogen Contamination

In response to questions that have been raised regarding the letter sent by Genzyme to health care practitioners on November 11, 2009, we would like to reassure health care practitioners by clarifying a few points.

It is impossible to completely avoid the presence of foreign particles in injectable biologic therapies. While our aseptic filling suite is highly controlled, it is not a completely particle-free environment. Because of this, Genzyme performs 100% vial inspection of every lot of Thyrogen® prior to shipment to customers and removes vials where particles may be present. However, particles may not always be detected in this inspection process, and therefore our labeling for Thyrogen® has always stated that vials should be inspected and should not be used if foreign particles are found. This requirement for visual inspection prior to use is common for many other biologic injectable products, and is not a new step in the administration of Thyrogen®.

The rate of foreign particles in lots of Thyrogen® identified by Genzyme is approximately 1%. This rate has not changed over time and is in line with industry experience for injectable products. Nonetheless, Genzyme is committed to reducing the frequency of foreign particles in Thyrogen® and all its products. Efforts toward that goal include establishing additional internal controls and updating fill/finish capabilities at our Allston facility.

Genzyme conducted an extensive review of its global safety database (January 1, 2004 – November 5, 2009) and did not identify any safety concerns that could be related to intramuscular injection of foreign particles. For example, the number of injection site reactions such as pain, rash and uritcaria reported to Genzyme was less than 10 per year and did not substantially change over the 2004-2009 time period.

We hope the points above answer your questions regarding the information contained in the November 11, 2009 letter and alleviate your concerns. Should you have additional questions, please contact Genzyme Medical Information at 800-745-4447 (option 2).

Leave a Comment

There are 7 comments

Prasanna Rao-Balakrishna – UK

July 14, 2009 - 17:23

Subject: Preventing Hypoglycaemia is as important as the tight glycaemic control

Preventing hypoglycaemia is as important as the tight glycaemic control. It is important to note that glycaemic control depends on the insulin regimen, patient's own counter regulatory hormone response & insulin resistance status, the calorie intake, frequency of testing for blood glucose, interpretation and acting on the results. During acute illness it is not possible to control the counter-regulatory hormone response and the insulin resistance status, but with adequate training, frequent testing and appropriate structured response should be possible, thereby preventing a hypoglycaemia. A trial which focuses as much on hypoglycaemia avoidance as well as tight glycaemic control is needed.

Reply to Prasanna Rao-Balakrishna

Richard Hellman MD

July 16, 2009 - 11:25

Subject: RE: Preventing Hypoglycaemia is as important as the tight glycaemic control

Dr Rao-Balakrishna makes a very interesting suggestion, that preventing hypoglycemia is as important as the tight glycemic control, and suggests a trial that focuses on two end-points, the avoidance of hypoglycemia as a co-equal goal in importance to tight glycemic control.

In fact, there is a great deal we do not know about hypoglycemia in critically ill states, and it is far from clear what the short and long term consequences are of mild, moderate, or even brief periods of severe ypoglycemia for critically ill patients. We do know that severe hypoglycemia can be a marker for increased mortality, as it was clearly shown in the VADT trial, but interestingly, those deaths did not usually occur during the hypoglycemic episodes, and the relationship between severe hypoglycemia and subsequent mortality was strongest in the conventional therapy group, suggesting that the hypoglycemic events may have been a consequence of an underlying vulnerability rather than the cause of mortality.

One of the limitations of an approach focused just on the outcomes of glycemia is that from the patients' standpoint, the most important issues are their clinical outcomes: mortality, morbidity, and disability. In contrast, those outcomes may not match the relative frequency of hypoglycemia at all. For example, there is a disconnect between the very high frequency of hypoglycemia in the Van Den Berghe RCT's in critical care published in 2001, 2006, and 2009. Both the surgical ICU study of 2001 and the 2009 pediatric studies showed very excellent outcomes with respect to mortaliy and morbidity in the presence of relatively frequent hypoglycemia.

I again would like to thank Dr Rao-Blakrishna for pointing us again to this very unsettled issue of the importance of hypoglycemia prevention, for the debate as to what we can and should do rages on. There are many creative ideas that have been proposed, but we need more data to guide us as to how to obtain the best clinical outcomes with the tools we have without either unacceptably high levels of hypoglycemia or hyperglycemia.

Richard Hellman MD
Editor-In-Chief
Patient Safety Exchange Website

MRR – Texas

March 31, 2009 - 16:29

Subject: NICE_SUGAR

Several interesting points came to mind when I reviewed the NICE-SUGAR study; the degree of severe hypoglycemia, the degree of cardiovascular mortality, the conventional group’s blood glucose levels are significantly lower than the vast majority of other outcome studies, and the number of severe septic patients in the intensive control branch of the study. According to the 2008 sepsis guidelines, the glycemic control target level for the septic patient is already in question and perhaps sepsis should be an exclusion criteria?

I was tasked with the development and oversight of a Tight Glycemic Control Program pilot study from May 2006 through April 2008 for a South Texas community hospital/level 2 trauma center. This included a 14 bed CCU, 12 bed M/S ICU and 12 bed trauma ICU as well as 4 M/S wards. Clinical inertia was our most difficult element to overcome and for the most part this was never accomplished. Clinical inertia was not only evident on physician's part, but also administration, nursing, nutritional services, pharmacy, and the patients themselves. Accountability to noncompliance to protocols was lacking as well. The philosophy that inpatient glycemic control was not necessarily treating diabetes, yet acute hyperglycemia was never fully accepted. When results like ACCORD, ADVANCE, and VADT were released, I would usually take the phone off the hook and leave the hospital because those wbeepdo not support inpatient glycemic control would come out en mass wishing to compare apples to oranges. That is not necessarily the case with NICE-SUGAR. In our Trauma ICU, where support was highest, for the entire year of 2007, we had only 7% BG > 200mg/dL, less than 2% hypoglycemia under 50 mg/dL, and nearly 75% BG between 80 - 150 mg/dL.

Overall, I applaud the NICE-SUGAR research team for a job very well done and thank them for their contribution to this ongoing discussion. I do support further research to differentiate specific glycemic control target ranges for specific diagnosis, but I too fear this could cause a pendulum swing in the opposite direction resulting in less facilities participating in inpatient glycemic control resulting in less data for differentiation.

NISSIM GABAY – VENEZUELA

March 26, 2009 - 15:25

Subject: NICE -SUGAR

I think that the central goal of the ADA/AACE impatient glucose targets is safe with the protocols .
Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia.
Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of
insulin is preferred in critically ill patients.
Be careful with this trial [NICE -SUGAR] to overcome clinical inertia.

Dr. Orlin Sergev – Charleston, SC

March 16, 2009 - 16:28

Subject:

Dear Dr Hellman:
I enjoyed all the editorials on patients' safety that you have recently published. I think that they raise questions which we as physicians are not always open about. Safety itself is frequently a topic that we love to discuss but it's never our fault. In this connection, the article about overconfidence and medical errors is timely - especially, at this time of expected health care changes. Briefly, I do not think we as physicians are different from any other specialists in different areas. Lack of adequate knowledge in a special area is always a good reason to be noisy and seemingly overconfident. Most of us agree that the more you know the more you realize how much more you do not know. Overconfident behavior in front of outsiders seem to be the cover of ignorance. I think we have to improve medical education in order to make medical decisions safer. Just remember the pilot of the plane that landed in Hudson river - quiet professional on top of his performance. We in medical profession must lead in patients' safety. In order to do that we have to lead the health care reform. We have to regain our authority, responsibility and accountability. (accountability without authority and responsibility is meaningless - see Dr Hellman's article on Medicare). We have to lead the health education of the society - most of the tragic mistakes in life happen from ignorance. First and foremost, of course, we have to maintain the superiority in medical knowledge. We must improve the quality of medical education. Instead of multiple choice questions we have to put back in place the stern professor wbeepmade clinical judgements based on knowledge, experience, and gut feeling and set up a good personal example for the next generation of physicians. Pilot "Sully" did not read the manual and the guidelines how to handle the critical situation - all his life before, however, prepared him for the right on the spot decision. Decisions based on profound knowledge and experience are the safest! Let's start the health care reform with ourselves.
Do not stop learning and teaching your team about sound and safe medical practices. When we have achieved that, we can confidently go out and regain our authority over various bureaucracies (government agencies-Medicare, insurances, medical malpractice law, etc).

james t poulos – west lafayette in

March 03, 2009 - 15:09

Subject: NICE-SUGAR

There was an article in acta scandinavia in january that showed very little hypoglycemia when intensive therapy is done right! I came across the article on medlinx in mid January, but it was actually published in October 2008. authors: Kaukonen KM et al in acta anaethesiol scandinavia and titled severe hypoglycemia in intensive insulin therapy.

Reply to james t poulos

Dr Hellman

March 04, 2009 - 16:12

Subject: Further thoughts related to the NICE-SUGAR study

Dear Dr. Poulos,

Thank you for calling attention to the study by Kaukonen KM et al. Your excellent point adds to the discussion generated by the NICE-SUGAR study. Their preliminary data analysis showed that error by provider was the most common cause of hypoglycemia. Their data implied, as I stated in my recent editorial, that improving the training and performance of those managing the insulin infusions greatly decreases the threat of hypoglycemia.

In this study by Kaukonen, done at the Helsinki University Central Hospital in Helsinki, Finland, the authors evaluated the incidence of hypoglycemia in all patients treated in two intensive care units between February 2005 and June 2006. They showed that severe hypoglycemia during intensive insulin therapy was rare in clinical practice. Analyzing data for 1124 patients and 61,203 glucose measurements, they found 36 measurements of severe (≤ 2.2mmol/L) hypoglycemia in 25 patients, with an incidence of 0.06% of severe hypoglycemia.

They commented that the frequency of blood glucose monitoring correlated inversely with the frequency and magnitude of severe hypoglycemia. In surgical patients, it is of note that five of the six instances of hypoglycemia occurred when a nurse failed to comply with the protocol.

The Helsinki group’s observations are entirely in keeping with the preliminary data from the NICE-SUGAR study and make a good deal of common sense. When the rate of decrease of glucose is rapid, for example greater than 1mg/dl/minute, simple arithmetic can tell us when the next glucose determination needs to occur to be able to safely avoid severe hypoglycemia. But if the frequency of checking of glycemic levels is arbitrary, and set too low, then hypoglycemia is to be expected much more often. The Kaukonen group avoided this by making sure the blood glucose sampling was relatively frequent.

In our clinical practice setting as well, the principles of safe handling of insulin infusions have been:

1.frequent monitoring, always at least hourly in ICU settings, more often when dealing with lower glycemic levels;
2.intensive training of nurses to make them expert in understanding how best to use algorithms;
3.specific points at which prolonged hyperglycemia or hypoglycemia necessitates immediate consultation with the responsible physician;
4.review of data to indicate variations in performance and appropriate correction and retraining when appropriate.

We too have extensive experience over many years with the safe use of insulin infusions in inpatient settings with relatively rare severe hypoglycemic episodes and little morbidity.

The NICE-SUGAR study should provide important information. We should not get too far ahead of their forthcoming data, but there is already abundant data, such as the important study from Helsinki, which show us that with a safer system of care, more ambitious glycemic control is both achievable and safe.

Kaukonen KM et al. Severe hypoglycemia during intensive insulin therapy, Acta Anaesthesiol Scand. 2009 Jan;53(1):61-65. Epub 2008 Oct 20.