Blood beta-ketone, electrode strips, MediSense Optium® Ketone Blood β-Ketone Electrodes® March 2006
Public Summary Document for Blood beta-ketone, electrode strips, MediSense Optium® Ketone Blood β-Ketone Electrodes® March 2006.
Page last updated: 04 July 2006
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Public Summary Document
Product: Blood beta-ketone, electrode strips, MediSense Optium® Ketone Blood β-Ketone Electrodes®
Sponsor: Abbott Diagnostics Division (MediSense Products)
Date of PBAC Consideration: March 2006
1. Purpose of Application
The submission requested a restricted benefit listing on the Pharmaceutical Benefits
Scheme (PBS) for quantitatively measuring blood ketones in diabetic patients who are
on insulin therapy.
2. Background
This diagnostic agent has not previously been considered by the Pharmaceutical Benefits
Advisory Committee (PBAC).
3. Registration Status
Blood beta (β)-ketone indicator electrode strips were listed as a device on the Australian Register of Therapeutic Goods on 1 June 2000.
4. Listing Requested and PBAC’s View
Restricted Benefit.
For quantitatively measuring ketones in diabetic patients who are on insulin therapy
for their diabetes, and who are at risk of diabetic ketosis or ketoacidosis, or for
use during the management of diabetic ketosis or ketoacidosis, and who thus require
an estimation of ketones in the blood.
The PBAC’s view was that there were doubts about the predicted usage of the product,
both in terms of patient numbers and frequency of use, based on the requested restriction.
5. Clinical Place for the Proposed Therapy
Blood β-ketone electrodes provide an alternative to urine ketone indicators.
6. Comparator
The submission nominated Keto-Diastix and Keto Diabur Test 5000 urine test strips
as comparators. The PBAC accepted this as appropriate.
7. Clinical Trials
The submission presented two key randomised clinical outcomes trials and five supportive
diagnostic accuracy studies. These studies had been published at the time of submission,
as follows:
Trial/First author |
Protocol/Publication title |
Publication citation |
---|---|---|
Key randomised trials | ||
Laffel LMB et al, | Sick day management (SDM) using blood (beta-hydroxybuyrate (beta OHB) vs urine ketones significantly reduces hospital visits in youth with T1DM: A Randomized clinical trial. | Diabetic Medicine 2006; 23(3) 278 – 84. Diabetes. 2002; 51(Suppl. 2):A105-A105. |
Vanelli M et al | The direct measurement of 3-beta-hydroxybutyrate enhances the management of diabetic ketoacidosis in children and reduces time and costs of treatment. | Diabetes Nutrition and Metabolism. 2003; 16(5-6):312-316. |
Supottive diagnostic accuracy studies presented | ||
Taboulet P et al | Urinary acetoacetate or capillary beta-hydroxybutyrate for the diagnosis of ketoacidosis in the Emergency Department setting. | European Journal of Emergency Medicine. 2004; 11(5):251-8. |
Fineberg SE et al | Comparison of blood beta-hydroxybutyrate and urine ketones in 4 weeks of home monitoring by insulin-requiring children and adults. | Diabetes. 2000; 49(Suppl. 1):A105-A106. |
Harris S et al | Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis. | Diabetic Medicine. 2005; 22(2):221-224. |
Guerci B et al. | Accuracy of an electrochemical sensor for measuring capillary blood ketones by fingerstick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients. | Diabetes Care. 2003; 26(4):1137-1141. |
Bektas F et al | Point of care blood ketone testing of diabetic patients in the emergency department. | Endocrine Research. 2004; 30: 395-402. |
8. Results of Trials
In the more directly relevant randomised, but unblinded trial (Laffel et al) there
were more emergency room visits and hospitalisations in the urine ketone testing group
compared with the blood β-ketone testing arm. The reasons for the hospitalisations
and emergency room visits were not given, although it is stated that they included
both hyperglycaemia and hypoglycaemia.
Emergency visits and hospitalisations during 6 months’ follow-up testing of blood
ketones compared to urine ketones in Type 1 diabetic patients in the key randomised
trial
Laffel et al (in press) |
Blood ketone (n=29.9 patient-years) N=62 |
Urine ketone (n=29.1 patient-years) N=61 |
---|---|---|
All cause emergency visits and hospitalisations | ||
Emergency visits |
8 |
14 |
Per 100 patient-years |
26.8 |
48.1 |
Hospitalisations |
3 |
8 |
Per 100 patient-years |
10.0 |
27.5 |
Total episodes |
11 (in 10 patients) |
22 (in 15 patients) |
Per 100 patient-years |
36.8 |
75.6 |
Likelihood ratios were calculated during the evaluation to facilitate comparison between
the arms of the supportive diagnostic accuracy studies. In general, the blood β-ketone
electrodes had higher positive likelihood ratios than urine ketone testing, but with
similar negative likelihood ratios. This suggested that patients who test positive
with the blood β-ketone electrodes were more likely to have diabetic keto acidosis
(DKA) than those who test positive with the urine ketone test. However, the criteria
for diagnosing DKA were not uniform in the studies and the study quality was relatively
low with the potential for significant bias affecting the results.
No toxicity results were presented. Since the blood β-ketone electrodes were used
externally it was appropriate not to consider toxicity. However, if a diagnostic test
produced false negative or false positive results, this may have a clinically relevant
impact on the patient. This possibility was not considered in the submission.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that the MediSense Optium Ketone Blood β-Ketone electrodes
had significant advantages over the main comparator, the urine ketone test strips.
Toxicity was not a relevant issue for diagnostic agents.
For PBAC’s view of this claim, see Recommendation and Reasons.
10. Economic Analysis
A preliminary economic evaluation was presented based on the results of the Laffel
et al study. The incremental cost per emergency room visit or hospitalisation avoided
over 100 patient years was calculated in the submission to be less than zero (i.e.
to represent an overall saving to Government)
A modelled economic evaluation was not presented. The PBAC considered that this was
not appropriate since diabetes is a chronic condition and a 6-month study period as
used in Laffel et al may be inadequate to capture the full clinical and economic consequences
of the tests.
The PBAC considered that the cost effectiveness of the blood β-ketone electrodes based
on a price at about twenty times the cost of the comparator was unacceptable, given
the doubts about the clinical claims, and that the corresponding claimed cost off-sets
would be unlikely to be realised in an Australian population.
11. Estimated PBS Usage and Financial Implications
The estimated financial cost per year to the PBS (excluding co-payments) is < $10
million per year. The PBAC considered these to be likely underestimates and had doubts
about the predicted usage of the product, both in terms of patient numbers and frequency
of use.
12. Recommendation and Reasons
The PBAC noted that the premise of the submission is the higher sensitivity of the
proposed test, which would translate into a better detection rate of early diabetic
keto-acidosis (DKA). The patient relevant outcomes of interest would be fewer or less
severe cases of DKA occurring, fewer hospital admissions with DKA, or lower mortality
rates with DKA. Other examples of clinical benefits would be the avoidance of unnecessary
treatments for DKA or better diabetes control.
The PBAC considered that it was likely that the blood β-ketone electrodes provided
better diagnostic accuracy than the urine ketone tests with the caveat that the evidence
presented in the submission was relatively weak. It was noted that in the more directly
relevant randomised, but unblinded trial (Laffel et al) there were more emergency
room visits and hospitalisations in the urine ketone testing group compared with the
blood β-ketone testing arm. The reasons for the hospitalisations and emergency room
visits were not given, although it was stated that they involved both hyperglycaemia
and hypoglycaemia. As ketone testing is used for the earlier detection or prevention
of DKA (ie hyperglycaemia and not hypoglycaemia), the PBAC considered that there was
uncertainty regarding the magnitude and the relevance of the emergency room visit
and hospitalisation data, including whether a less frequent use of these facilities
necessarily indicates better management of the clinical condition. Further, the confidence
intervals of the incidence density ratios (calculated during the evaluation) for the
all-cause emergency visits and hospitalisations include unity, suggesting there was
no statistically significant difference between the groups for these outcomes.
Based on the evidence provided, the submission’s claim that blood β-ketone electrodes
have significant advantages in clinical effectiveness compared with urine ketone tests
was uncertain as the evidence of effectiveness was limited to a single trial on Type
1 diabetic patients aged 3 to 22 years and uncertainty existed as to whether the results
would be reproducible in the Australian setting. The PBAC considered that the patients
in the trial would be a highly trained group and the results may not be reproducible
in a general population in Australia, where any training effect would be less and
likely to diminish further over time beyond the 6-month time horizon of the trial.
No evidence was presented to suggest that patients would be more compliant with use
of the blood β-ketone electrodes over the comparator or that Australian patients would
necessarily follow either the trial-recommended practices involving the conditions
for or frequency of the use of ketone testing or the trial-recommended practices following
the detection of abnormal ketone readings. Also, the potential for clinically important
outcomes arising from false negative or false positive test results (with a potential
for increased toxicity) was not considered in the submission.
Thus, the overall benefits of the proposed product were uncertain because they were
based on only one relevant trial, which was small and of poor quality and of uncertain
applicability to Australian patients in the longer-term, and where the results, presented
as event rates were difficult to interpret and likely to be overestimated for the
reasons outlined above.
The PBAC considered that the cost effectiveness of the blood β-ketone electrodes based
on a price at about twenty times the cost of the comparator was unacceptable, given
the doubts about the clinical claims, and that the corresponding claimed cost off-sets
would be unlikely to be realised in an Australian population. There were also doubts
about the predicted usage of the product, both in terms of patient numbers and frequency
of use.
The PBAC thus rejected the submission because of uncertain clinical benefit and uncertain
and unacceptable cost-effectiveness.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
The sponsor disagrees with the position of the PBAC regarding clinical benefit and cost effectiveness, and is exploring options for a way forward.