Download Manuscript "Fast-track drug approval in inflammatory bowel diseases"

Manuscript "Fast-track drug approval in inflammatory bowel diseases"
Point-by-point response to the comments of Reviewer A:
Dear reviewer,
We are very grateful for your valuable comments and constructive criticism that have
substantially helped to improve our manuscript.
-Following your suggestions the manuscript has been restructured and the
differences between fast track approval of new drugs and the process of approving
biosimilar medications have been more clearly outlined.
-Furthermore, the section on the role of objective endpoints for clinical trials in IBD
and the use of central reading was modified as well. We gave careful though on how
to link these sections.
1) The concept of treat to target as a means to enhance patient
outcome is a therapeutic strategy and is not directly linked to approval of
specific biologic drugs per se
This was added to our manuscript. (please see page 15)
2) There is clear evidence that central reading of images increases
the quality of clinical trial data in IBD and other fields. However, the
link by which central reading may enhance fast track approval apart from its
impact on robust clinical trial output is not clear
The following statement was added to our manuscript: “According to this data there is
clear evidence that central reading of images increases the quality of clinical trial
data in IBD and other fields. However, the link by which central reading may
enhance fast track approval apart from its impact on robust clinical trial output is not
always clear. In fact, FDA, EMEA and other drug approving authorities have not
implemented central reading of images as a mandatory prerequisite for fast-track
drug approval.” (please see page 17)
3) The section on ‘applying fast track approval to IBD’ reviews
the process for fast track approval in general, but does not focus on its
application to IBD
a) Clarity
is
required
to
distinguish
‘fast
track
approval’,
‘accelerated approval’ and ‘Priority review’. Please define each
process and highlight their differences
‘Fast track approval’, ‘accelerated approval’ and ‘Priority review’ were further
defined and distinguished. (please see pages 5 & 6)
b) Tumor shrinkage is highlighted as an appropriate surrogate marker for
oncology trials. What would the evidence based equivalent be for IBD
The evidence based equivalent for IBD is difficult to define. The gold-standard
would probably be complete histological healing. Complete mucosal healing
with absence of any signs of other intestinal or/and abdominal damage could
be a meaningful outcome in clinical practice. (please see page 8)
c) Which currently (or soon to be) approved IBD drugs would have met the
criteria for fast track review and what would the outcome have been if they
had been subject to this process
This is a very interesting question. The following statement was added in our
manuscript. “An interesting question would be whether the currently -or soon
to be- approved IBD drugs would have met the criteria for fast track review
and what would the outcomes have been. Although it is difficult to predict, the
author’s opinion is that fast track is a promising concept for IBD treatment but
probably difficult to apply at present time. IBD drugs have to be carefully reevaluated in clinical practice and the “yellow cards” reporting any possible or
probable drug-related adverse reaction should be meticulously completed by
every physician who is treating patients with IBD.” (please see page 9)
4) It is not clear to me why IBD in general is appropriate for
orphan drug status – surely this just refers to sib groups of IBD patients
ie pouchitis
Thank you for your comments. “Products treating IBD patients in general are not
appropriate for orphan drug status. However there are distinct groups of IBD patients
such as those with pouchitis, severe malabsorption due to short bowel, and other
severely disabling complications in whom disease significantly affects life expectancy
and quality of life and for whom orphan drug status may apply.” The above statement
was added in our manuscript (please see page 10)
5) More detail of the regulatory requirements for the approval of
biosimilar status and the impact that this has across all indications for
drug use would be helpful
This was added to our manuscript. (please see page 13-14)
6) It is not clear what the relevance of the fast track approval of
oncology drugs that have a targeted approach ie the BRAF therapies or
treatments for advanced melanoma have to IBD drug development. Are there
similar targeted IBD therapies being developed?
Thank you for this great point. To our knowledge, there are no similar targeted IBD
therapies as of yet. What our manuscript tries to stress is that as opposed to
Oncology that there are already targeted therapeutic approaches developed, in IBD
there is lack of studies using well-defined molecular targets or mucosal or histological
healing as their primary end point.
7) It would be important to give concrete examples of misleading
trial results that have been generated by NOT using central endoscopy reads
to highlight the value of this process.
Thank you for this important point. The majority of clinical trials in IBD has not used
central reading and many phase I-III studies have failed for reasons other than
absence of central reading of endoscopy (i.e did not reach primary end-point). Please
allow us not to refer to all these studies, favoring others that used central reading
since the importance of using central endoscopy is still debated by industry and
several experts and has not been officially implemented as prerequisite in FDA or
EMEA for IBD drug approval.
We would like to thank you again for your time and valuable comments that helped
substantially to improve the quality of our manuscript.
Sincerely,
The authors