Comment and reply on: Dosing accuracy of two insulin pre-filled pens

Dear Sir,

The recent publication by Asakura et al. reports a small-scale laboratory experiment comparing the dosing accuracy of two insulin injection devices1 (FlexPen [FP], and SoloSTAR [SS]), suggesting that FP is more accurate than SS. However, there are numerous elements that should be taken into consideration when interpreting the results and the authors’ conclusion.

As part of the approval process for introducing an insulin injection device to the market, accurate dose delivery must be demonstrated. This is commonly achieved through studies that show that the device meets the requirements of a technical laboratory standard developed by the International Organization for Standardization (namely DIN EN ISO 11608-1 for pre-filled/disposable insulin pen devices)2.

SS met the ISO requirements for dose accuracy at each dose tested under all conditions. The compliance of sanofi-aventis data with the ISO requirements is documented by the data submitted, reviewed and approved by the relevant regulatory authorities.

The publication by Asakura et al., however, makes reference to the respective ISO standard by referring to the tolerance limits (i.e. ±1 unit for doses dialled of 0–20 units or ±5% for doses of 20 units or more), but neither the design of this laboratory study nor the evaluation of the results completely follow ISO 11608-1.

Firstly, ISO 11608-1 requires a minimum of 15 pen devices to be tested in a laboratory setting repeatedly across three specified doses, for 60 single doses at each dose level. In contrast, Asakura et al. used only three pen devices at each dose level. Each pen was tested only for dispensing one specific dose instead of the whole range of doses. Furthermore, Asakura et al. did not reach the required number of 60 single doses for the highest dose chosen by the authors. With the inconsistency in the number of doses, 126 at 5 units, 75 at 10 units and 27 at 30 units, comparing the percentages of inaccurate doses is misleading. No clear rationale was provided for why additional pen devices were not tested, particularly at the 30-unit dose, to ensure equal numbers of doses tested.

Secondly, each pen device should be tested repeatedly across the range of doses, to deliver doses at the minimum, middle and maximum. For SS, this translates to doses of 1, 40 and 80 units and for FP, 1, 30 and 60 units. However, in the study by Asakura et al., the accuracy of both pen devices was determined at 5, 10 and 30 units, neglecting the higher doses.

Finally, when evaluating the data, all single values were measured by Asakura et al. against the defined limits for dose accuracy individually, whereas ISO 11608-1 does not evaluate the individual measurements, but rather the mean value and the standard deviation. ISO 11608-1 is a standard for design verification purposes and acknowledges the fact that, given the limited number of data points, the accuracy can only be stated with a certain confidence level. Consequently, ISO 11608-1 claims that a defined proportion has to be within the tolerance limits (97.5%) and thereby recognises that individual values may be outside the limits without affecting the overall accuracy of the device. Asakura et al. applied the limits defined in the standard, but did not follow the respective statistical process.

The authors refer to a study by Bell et al.3 to support the suggestion that ‘dose accuracy is better at the higher doses and poorer at the lower insulin doses’. However, in that study, the authors compared the dose accuracy of split-mix versus premixed insulin delivered via vial and syringe by diabetes or healthcare professionals. Therefore, that study reflects user error rather than device accuracy. Indeed, it has been shown that insulin devices are consistently more accurate than the vial and syringe4–7.

When considering the potential investigator bias and potential user variability that Asakura et al. openly declare they cannot comment on, they identify the need to confirm the results with other users in other experimental or real-world situations.

Such a study, which goes beyond a pure laboratory test setting by also taking into consideration the real user situation, was recently presented at the DDG (The German Diabetes Society) meeting8. In that study, a group of 60 patients delivering six different doses each (5, 15 and 30 units with Apidra [insulin glulisine] and 10, 40 and 80 units with LANTUS [insulin glargine] SS), were able to deliver every single dose (100% of 360) within ISO specifications.

Similarly, in a usability study presented at the Diabetes Technology Meeting in October 20079, it was shown that after training, a group of 86 patients were able to deliver three doses each with >99% of total doses within ISO specifications.

SS is a safe and accurate insulin injection device, when used according to the instructions for use and with the correct needle; this has convincingly been shown in both laboratory10 and clinical settings8,9. The company's analysis of patients’ feedback indicates a high level of confidence with respect to correct use and dose accuracy.

Given the limitations of the comparative laboratory experiment by Asakura et al. and the discrepancies between presented results and existing clinical data, the authors’ conclusions should be treated with caution when considering the real-world use of insulin pen devices by patients with diabetes mellitus.

Acknowledgement

LV is an employee of sanofi-aventis, Paris, France. Editorial support for the preparation of this Letter was provided by Medicus International. The author was involved in the drafting of this Letter, and has read and approved the final version. In addition, the author is grateful to Paul-Gerhard Kibat and his team (sanofi-aventis, Frankfurt, Germany) for input provided on this Letter.

References

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Authors'reply

Dear Sir,

We thank Laurent Vaur for his response to our paper on the dosing accuracy of FlexPen (FP) and SoloStar** (SS)1. The main point made by the authors of the Letter is that SS adheres to ISO standard (ISO 11608-1), which we do not dispute. However, ISO standards are intended only to verify the manufacturer's ability to manufacture one lot of pens that conforms to the necessary standards2, and by definition cannot be used for comparative assessments that will require different statistical analyses, different study sample sizes, and, as in our study, may be performed to simulate real-world clinical use by following manufacturers' instructions (although dose accuracy limits were based on ISO standards). Our head-to-head study led us to the valid conclusion that, in this setting, FP was more accurate than SS. The fact that 0.4% of doses delivered by FP were below pre-specified limits whereas 14.5% of doses delivered by SS were below these limits (even if mean values were within the limits), seems of potential importance to patients with diabetes. However, as we clearly acknowledge in the original article, the impact this could have on patients' well-being needs to be investigated in randomized controlled clinical trials.

The response goes on to mention data on the accuracy of SS from two recent abstracts3,4 and a review article5, and states that there is a discrepancy between these reports and our publication1. None of these reports included a comparison between SS and FP, and therefore, there is no contradiction between our study and those quoted by Vaur – a comparison between these studies is simply not valid. Furthermore, it is not clear if any of these studies used the pens according to manufacturers' instructions, and in Schwartz and Vlajnic4, self-trained individuals delivered 12% of doses with SS outside the pre-specified limits of this study. However, the most important fact is that another recent study compared the accuracy of FP with SS and confirmed that FP is more accurate than SS when used according to manufacturers' instructions6. Thus, the only two published comparisons of FP and SS both show that FP is significantly more accurate for the delivery of insulin1,6.

Another criticism made of our study is that the number of dose accuracy measurements made with each pen was too small. As highlighted before, we did not conduct our study according to ISO guidelines as these are not appropriate for comparative studies. Instead, the number of measurements made in this study were based on power calculations made before conducting the study and based on our previous experiences of dose accuracy investigations7.

In conclusion, FP and SS comply with ISO standards, but these are minimum requirements of an insulin delivery device, and there is scope for greater levels of accuracy among approved pens. Our study1, and other published evidence6, have shown that FP is a highly accurate insulin delivery device that appears to be more accurate than SS.

Acknowledgements

The study commented upon here was supported by an unrestricted research grant from Novo Nordisk to Niigata University of Pharmacy. The publication of the study and this Letter was supported by Novo Nordisk A/S (Bagsværd, Denmark) with editorial assistance from ESP Bioscience (Sandhurst, UK). All the authors declare that they do not have any relevant financial interests related to the content of the article (or this Letter). In addition, with regards to the study, the authors were wholly responsible for study design, technical measurements, analysis and scientific evaluation. All authors have read and approved the final draft of this response Letter.

Notes

* FlexPen is a registered trade name of Novo Nordisk, A/S, Bagsværd, Denmark; SoloSTAR is a registered trade name of sanofi-aventis, Paris, France

* Apidra and LANTUS are registered trade names of sanofi-aventis, Paris, France

** FlexPen is a registered trade name of Novo Nordisk, A/S, Bagsværd, Denmark. SoloSTAR is a registered trade name of sanofi-aventis, Paris, France