Svar modtaget fra EMA pr. mail den 8. februar 2016
Question 2:
Comments on the Responsum by Dr Brinth
The Responsum document written by Dr Brinth and dated 15 December 2015 presents a detailed reply to
the PRAC Assessment Report (AR) on the referral concerning complex regional pain syndrome (CRPS)
and postural orthostatic tachycardia syndrome (POTS) in young women given human papillomavirus
(HPV) vaccines. However, it does not provide any new data or information in relation to the said HPV
vaccine referral. Therefore, the conclusions in the PRAC AR and the interpretation/analysis supporting
those conclusions are not affected.
More specifically, please note that Sections 2.1 to 2.3 of the Introduction of the Responsum document
are background sections that do not provide any new data or information that is pertinent to the HPV
vaccine referral.
Section 3 presents the work and approach of the Syncope Unit at Bispebjerg and Frederiksberg Hospital
(Section 3.1) and also provides further information and some clarification of the chronology of the first
two papers from Dr Brinth and her colleagues (Section 3.2).
Some of the comments made in this document suggest that there are several aspects of the PRAC
discussion regarding the Brinth publications that appear to have been misunderstood; for example, case
series methodology will always suffer from important limitations as it lacks a comparator group and also
are known to be vulnerable to selection bias, regardless of whom conducts the analysis. The latter
remains an issue with the Brinth and colleagues case series despite the efforts that they took to minimise
this; another example is that Dr Brinth took as direct criticism of the work, the potential of
misinterpretation of data due to the likelihood of recall bias, which is something innate to the used
methods, and is partly driven by the patient awareness.
The document does highlight that there are possibly many more cases that have been referred to the
Syncope Unit (the figure of 650 included in figure on page 16), but no further information on these cases
and whether or not they occurred in HPV vaccinated individuals have been provided. However, the
observed versus expected scenarios for Denmark suggested that the 650 figure included by Dr Brinth is
within the range of expected scenarios. Furthermore, as both POTS, CRPS and Chronic fatigue syndrome
(CFS) are issues that remain under close scrutiny and will be subject to updated observed versus
expected analyses, any further cases reported to regulatory authorities or industry will be factored into
future regulatory assessment and decision making.
The approach taken in this referral procedure by applying the observed versus expected analysis allowed
the PRAC to use the most sensitive detection of a possible excess of the natural background rates and
account for a range of possible under-reporting up to 99%.
Regarding Section 4 of the document provides Dr Brinth’s, it comments on how it is alleged that the
PRAC has misunderstood and, in some places, misinterpreted the Uppsala Monitoring Centre (UMC)
report. We would like to note that what is included in the PRAC AR reflects the assessment of the PRAC
and therefore the PRAC took into account the data from UMC accordingly.
In addition, Section 5 of the Responsum document highlights what is considered as an apparent
discrepancy between what is included in the European public assessment report (EPAR) for Gardasil 9
and the PRAC AR with regards to cases of POTS and CRPS (3 cases of POTS and 1 of CRPS quoted in the
EPAR but only 2 cases of POTS quoted in the PRAC AR). In this respect, we would like to clarify that the