Letter from the Chairman, Medicines and
Healthcare Products Regulatory Agency to the Clerk of the Committee
In your letter of 21 December you asked for
additional information in advance of my appearance before the
Health Select Committee. I am pleased to be able to answer your
questions and supply the documents requested.
I should preface my answer to your first question
regarding the assessment of data submitted by the applicant and
the reliance on summaries of data by explaining that European
law does not require that actual raw data is submitted as part
of the application. It requires, instead, that marketing authorisation
holders must arrange for clinical trials documents (including
case report forms) to be kept by the owners of the data. Clinical
trials carried out and results obtained from the raw data for
each study are written into a final clinical study report signed
by the investigators and submitted as part of the application.
Article 8 of Directive 2001/83/EC sets out the
procedure for obtaining a marketing authorisation for a medicinal
product. Annex I of the Directive, requires that applications
for a new drug must be accompanied by the following particulars
and documents in respect of clinical documentation: These data
are presented as a series of modules including a Clinical Overview
(a critical analysis of the clinical data included in the clinical
summary and all the clinical documentation), a Clinical Summary
(a detailed summary of the all the clinical information) and the
Clinical Study Reports. In this module, all reports of individual
clinical studies must be provided. The textual part of each study
report can be 50-60 pages or more and can be supplemented by several
volumes of appendices and supplementary tabulations and listings
of data. In a new drug application, the number of volumes of clinical
documentation could be in the hundreds.
If considered necessary, companies are required
to make all raw data and documents available to relevant authorities
upon request. During the conduct of clinical trials, inspectors
from MHRA will often go to companies and clinical trial sites
to audit them to ensure complete and accurate documentation of
data and records.
With this in mind the number of cases where
there has been significant partial reanalysis of raw data is very
low indeed compared to numbers of products licensed. This has
happened in the cases of the revocation of the Marketing Authorisations
for Evening Primrose Oil and in the case of the Review of SSRIs.
Turning to your second point regarding the licensing
process and the extent to which the Agency's assessors might be
informed of all of the trials undertaken on a product, applicants
are not allowed to be selective in the data which they submit.
The applicant is obliged by Directive 2001/83/EC to supply all
relevant information for evaluation of the product, whether favourable
or unfavourable and especially if there are incomplete or abandoned
trials which may not have been published. It is a criminal offence
not to comply with these requirements of the Directive.
I am enclosing the Assessment Reports presented
to CSM and the Medicines Commission (the other main medicines
advisory body) on human albumin, evening primrose oil and sertraline.
These Assessment Reports are sent in confidence as we have not
redacted them to remove personal or commercially confidential
information in view of the time available, or to seek permission
for such information to be released into the public domain. However,
should these documents be published as part of the final evidence
of the Inquiry I would be grateful for the early opportunity to
ensure that personal or commercially confidential information
is removed and/or relevant permissions sought. You will note of
course, that the history of these products goes back to the late
1980s in some cases.
You have asked about the relationship between
the MHRA and NICE. Since the establishment of the MHRA (in April
2003), there has been one meeting at CEO level (with other senior
management) where a range of general issues of mutual interest
were discussed (June 2004). Agenda items included a general update
on events in each organisation and a more targeted examination
of ways of involving each Agency in the other's business where
appropriate, through the discussion of a series of possible future
interactions. The next meeting at this level is in March 2005.
More specific operational level meetings have also taken place.
For example, the MHRA and NICE have worked closely together on
an ad hoc basis where it is necessary to ensure a joined up approachmost
recently in the MHRA's review of the safety of SSRIs and the NICE
clinical guidelines on the treatment of depression, where NICE
were observers on the CSM Expert Group. The MHRA also sits on
a number of NICE working level committees.
You have asked which of the recommendations
from the National Audit Office inquiry into the MHRA have been
implemented. A table showing the main recommendations and the
extent to which they have been implemented is attached (at annex
A). While very few of the recommendations have been completed
in their entirety (partly because of their very nature), they
have been influential in setting the direction of the new Agency
and, overall, there has been a great deal of progress. You will,
of course, be aware that the NAO Report was only published in
January 2003 and the PAC Report in June 2003.
Turning to your final point about benzodiazepines,
it is not possible to determine how many deaths have been caused
by benzodiazepines using data from the Yellow Card Scheme. It
is important to note that not all reported adverse reactions were
caused by the drug. Health professionals are asked to report "suspected"
adverse reactions regardless of doubts they may have as to whether
the drug caused the suspected reaction. Also, there is an unknown
degree of underreporting associated with the Scheme which varies
depending on a number of factors, including how long the drug
has been on the market and any media attention surrounding the
drug. The number of reports of suspected adverse reactions should
be seen in the context of the millions of prescriptions for benzodiazepines
over the last 40 years.
The table below shows the number of reports
of suspected adverse reactions received for benzodiazepines since
the beginning of the Yellow Card Scheme, and how many of those
had a fatal outcome. A number of the substances named are no longer
licensed in the UK and these are marked with an asterisk.
TABLE SHOWING THE NUMBER OF REPORTS OF SUSPECTED
ADVERSE REACTIONS TO BENZODIAZEPINES SINCE 1964, AND THE NUMBER
OF REPORTS WITH A FATAL OUTCOME
|Benzodiazepine||Year of first
|Total number of reports
||Total number of reports|
with fatal outcome
Data lock point 22 December 2004
*There are currently no licensed products for these drug
11 January 2005