In the recent article published in British Journal of Ophthalmology,
Agrawal et
al1
reported two cases of desegmentation of Ozurdex implant in vitreous
cavity.
In this report, the authors comment that Allergan confirmed that fractured
implants in the applicator have not been found to date during the quality
control
process.
We recently reported2
also two cases of implant fragmentation in response t...
In the recent article published in British Journal of Ophthalmology,
Agrawal et
al1
reported two cases of desegmentation of Ozurdex implant in vitreous
cavity.
In this report, the authors comment that Allergan confirmed that fractured
implants in the applicator have not been found to date during the quality
control
process.
We recently reported2
also two cases of implant fragmentation in response to a
Roy et al3
. These authors reported a broken implant at the end of the injection.
They postulate that the reason for breakage could be friction at the tip
of the
needle or some drug loading problem
Our first case showed similar fundus image, dexamethasone implant
fragments
within vitreous cavity one month after injection In the second case, the
implant
broken after the ejection during an instructional wet-lab, outside
surgical
conditions. This event was recorded in a video that is available with our
report.
Therefore, this video proves that for a break to happen during the
implantation
is utterly feasible and .taking into account the comment of Allergan,
reinforces
that the friction at the tip of the needle during de ejection must be the
reason for
breakage.
We agree with the authors that these patients with defragmented implants
should be followed up carefully to monitor for unexpected complications,
even
more in patients with zonular dehiscence.
REFERENCES:
1. Agrawal R, Fernandez-Sanz G, Bala S, et al. Desegmentation of
Ozurdex implant in vitreous cavity: report of two cases. Br J Ophthalmol.
2014;98:961-3
2. Cabrerizo J, Garay-Aramburu G. Re: intravitreal dexamethasone implant
fragmentation.Can J Ophthalmol. 2013;48:343.
3. Roy R,HegdeS. Split Ozurdex implant: a caution. Can JOphthalmol.
2013;48:e15-6
As an ophthalmologist for many years, I continue to find the
diagnosis of dry eye difficult unless it is severe. I have spoken to
colleagues who have the same experience. As detailed in this paper there
are many things going on in the pathophysiology of which dryness may be
one.
Can I suggest it might be helpful to our understanding and approach to
sore eyes, to be less dogmatic about attributing dryness as the reason f...
As an ophthalmologist for many years, I continue to find the
diagnosis of dry eye difficult unless it is severe. I have spoken to
colleagues who have the same experience. As detailed in this paper there
are many things going on in the pathophysiology of which dryness may be
one.
Can I suggest it might be helpful to our understanding and approach to
sore eyes, to be less dogmatic about attributing dryness as the reason for
discomfort in these eyes. The discomfort may be caused by a host of
factors which may or may not include dryness.
Dr Cho and colleagues present data on a very small cohort of patients
with wet AMD that have switched treatment from either bevacizumab or
ranibizumab to aflibercept. Of note, this subgroup comprised approximately
8% of the total number of patients switched to aflibercept.
Any retrospective review is likely to be heavily biased by the
anticipated 'treatment benefit' of a new therapy particularly if, as in
this ca...
Dr Cho and colleagues present data on a very small cohort of patients
with wet AMD that have switched treatment from either bevacizumab or
ranibizumab to aflibercept. Of note, this subgroup comprised approximately
8% of the total number of patients switched to aflibercept.
Any retrospective review is likely to be heavily biased by the
anticipated 'treatment benefit' of a new therapy particularly if, as in
this case, the readers of retinal optical coherence tomography (OCT) scans
have the ability to manually correct and alter data that were originally
generated by semi-automated methods. In this study, the magnitude of
change observed in central foveal thickness was of marginal clinical
relevance (7.8% reduction from Baseline) after 1 injection and was further
attenuated by 6 months; these results suggest that the retinal OCT scan
reader was an important source of bias. This view is further supported by
the observation that visual acuity, which may be less liable to
investigator related bias, remained unchanged throughout.
Retrospective reviews are of scientific value when conducted in a
rigourous and independent manner. Selective reporting of data from this
study inevitably undermines any clinical conclusions regarding the
relevance of switching patients from anti-VEGF therapies to aflibercept.
Conflict of Interest:
I have consulted for a number of pharmaceutical companies including Novartis, the MAH of ranibizumab in the EU.
We read with interest Jackson and Morris's response to our letter.
The author's indicated that it was not possible to conduct a repeated
measures ANOVA using SPSS. However, SPSS provides several ways to analyze
repeated measures ANOVA through the general linear model command. There
are several excellent texts that illustrate how to conduct an ANOVA using
a repeated measures design in the SPSS environment....
We read with interest Jackson and Morris's response to our letter.
The author's indicated that it was not possible to conduct a repeated
measures ANOVA using SPSS. However, SPSS provides several ways to analyze
repeated measures ANOVA through the general linear model command. There
are several excellent texts that illustrate how to conduct an ANOVA using
a repeated measures design in the SPSS environment.
Second, they posed a question about whether it was reasonable to
assume that the data collected 18 months post surgically was specifically
related to data collected previously. To answer, yes, any time several
measurements are collected over time on the same subject, the data points
within each subject are related. Therefore the use of statistical
procedures that account for this clustering must be used. The fact that
the study was exploratory in nature does not preclude the application of
basic statistical principles. On the other hand, the authors correctly
noted that they had also analyzed the data using a 2x3 design. This
approach is reasonable. Unfortunately, the actual p-values were not
provided for the readers in the original article or in their response to
our editorial.
We would like to thank Dr. Geitzenauer for his comments and concerns
regarding our study.
As he has pointed out, in a non-inferiority study there is potential
for bias which may narrow down the difference in efficacy. Therefore,
conducting a superiority study simultaneously would be difficult, unless
sufficient quality is ensured during study planning, conduct as well as
data analysis.
We would like to thank Dr. Geitzenauer for his comments and concerns
regarding our study.
As he has pointed out, in a non-inferiority study there is potential
for bias which may narrow down the difference in efficacy. Therefore,
conducting a superiority study simultaneously would be difficult, unless
sufficient quality is ensured during study planning, conduct as well as
data analysis.
However, our study in question was a well-controlled study, with a
reasonable non-inferiority margin specified in advance, and conducted in
accordance with applicable Guidelines. Therefore we believe our study
method is acceptable.
The study plan was sufficiently evaluated as a double-masked
comparison study, and the study itself was conducted according to the
study protocol and in compliance with GCP (Good Clinical Practice).
Further, non-inferiority and superiority were verified for different
endpoints, Fluorescein staining score and Rose Bengal staining score,
respectively, and the methods were specified beforehand in the protocol.
In consideration of multiplicity, significance level was maintained by
adopting a closed testing method, by which superiority would be verified
only if inferiority has already been verified.
EU regulatory authorities have also accepted the simultaneous data
analysis for non-inferiority and superiority if it is a well-controlled
study, using previously specified analytical methods 1).
Therefore, we believe that the verification methods used in our study
are acceptable.
1) Committee For Proprietary Medicinal Products (CPMP) , Point to
consider on switching between superiority and non-inferiority, EMEA 2000;
July.
Takamura et al. report in a recent edition of the BJO about a "multi-
center, randomised, double-masked, parallel study" which leads to both a
non-inferiority and a superiority claim of the ophthalmic solution being
tested (diquafosol ophthalmic solution).(Reference 1) From a
methodological standpoint, the conclusions reached by the authors are not
in agreement with current accepted standards in th...
Takamura et al. report in a recent edition of the BJO about a "multi-
center, randomised, double-masked, parallel study" which leads to both a
non-inferiority and a superiority claim of the ophthalmic solution being
tested (diquafosol ophthalmic solution).(Reference 1) From a
methodological standpoint, the conclusions reached by the authors are not
in agreement with current accepted standards in the field of randomised
controlled trials.
It is methodologically unacceptable to draw conclusions about superiority
and non-inferiority at the same time using the same set of data. Already
at the design stage a decision has to be made whether a non-inferiority or
a superiority trial is to be conducted. Hence, claiming both non-
inferiority and superiority at the end of such a trial, as tempting as it
may be, violates fundamentals of clinical trials methodology.
Non-inferiority trials have specific characteristics which make emphasis
on rigorous methods even more important than in superiority
trials.(Reference 2) In a superiority trial, the objective is to detect a
difference, whereas in a non-inferiority trial, the objective is to fail
to detect a difference. These different objectives, among others, have
important implications with regard to the analysis and conclusion of a
trial. It is flawed to analyse and present data mixing up both approaches.
Recommendations for improving the quality of reporting of parallel-group
randomised trials, noninferiority and equivalence trials are published and
freely accessible on the internet. (References 3 and 4) Adoption of the
CONSORT statement in the editorial policy is likely to be beneficial to
the high standards of the BJO and would certainly be welcomed by this
reader.
Wolfgang Geitzenauer MD MSc FEBO
1 Takamura E, Tsubota K, Watanabe H, Ohashi Y. A randomised, double-
masked comparison study of diquafosol versus sodium hyaluronate ophthalmic
solutions in dry eye patients. BJO; 96(10):1310-5.
2 Fleming TR. Current issues in non-inferiority trials. Stat Med;
27(3):317-32.
In the recent article published in British Journal of Ophthalmology, Agrawal et al1
reported two cases of desegmentation of Ozurdex implant in vitreous cavity. In this report, the authors comment that Allergan confirmed that fractured implants in the applicator have not been found to date during the quality control process. We recently reported2
also two cases of implant fragmentation in response t...
As an ophthalmologist for many years, I continue to find the diagnosis of dry eye difficult unless it is severe. I have spoken to colleagues who have the same experience. As detailed in this paper there are many things going on in the pathophysiology of which dryness may be one. Can I suggest it might be helpful to our understanding and approach to sore eyes, to be less dogmatic about attributing dryness as the reason f...
Dr Cho and colleagues present data on a very small cohort of patients with wet AMD that have switched treatment from either bevacizumab or ranibizumab to aflibercept. Of note, this subgroup comprised approximately 8% of the total number of patients switched to aflibercept.
Any retrospective review is likely to be heavily biased by the anticipated 'treatment benefit' of a new therapy particularly if, as in this ca...
We read with interest Jackson and Morris's response to our letter.
The author's indicated that it was not possible to conduct a repeated measures ANOVA using SPSS. However, SPSS provides several ways to analyze repeated measures ANOVA through the general linear model command. There are several excellent texts that illustrate how to conduct an ANOVA using a repeated measures design in the SPSS environment....
We would like to thank Dr. Geitzenauer for his comments and concerns regarding our study.
As he has pointed out, in a non-inferiority study there is potential for bias which may narrow down the difference in efficacy. Therefore, conducting a superiority study simultaneously would be difficult, unless sufficient quality is ensured during study planning, conduct as well as data analysis.
However, our st...
Dear editors,
Takamura et al. report in a recent edition of the BJO about a "multi- center, randomised, double-masked, parallel study" which leads to both a non-inferiority and a superiority claim of the ophthalmic solution being tested (diquafosol ophthalmic solution).(Reference 1) From a methodological standpoint, the conclusions reached by the authors are not in agreement with current accepted standards in th...
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