STN Number: 125280
STN Sponsor: Intercell
STN Title: Japanese Encephalitis Vaccine
To: Paul Wilson, President and CEO, Intercell USA, Inc.
From: Daryll Miller, RPM, CBER\OVRR\DVRPA
Subject: Package Insert and Post-Marketing Commitments Issues
Teleconference Date: December 17, 2008 Meeting Time: 10:00 AM
Memo Date: January 5, 2009
Lew Markoff, Dick Daemer, Jeff Roberts, Rose Tiernan, Manette Niu, and Daryll Miller
Paul Wilson, Oliver Mutschlechner, Christoph Klade, Katrin Dubischar-Kastner, and Elisabeth Schuller
The meeting was requested by Paul Wilson and colleagues to discuss the most recent draft package insert (PI) that was sent to Paul Wilson on December 16, 2008, as well as to discuss post-marketing commitments after the vaccine would be licensed. The sponsor agreed to send us their understanding of the discussion points as minutes to the meeting. The Sponsor’s meeting minutes are reproduced below with our comments added.
1. Package Insert (PI) Draft 3 Comments to the Sponsor:
Discussion of PI draft provided by FDA on Dec 16:
Sponsor: All comments from the Agency but one will be considered for the final draft of PI. As suggested by the Agency, numbers of adverse events will be inserted where applicable instead of adverse reactions throughout the PI. All other numbers i.e. for Study IC51-304 will be checked for accuracy.
The comments that could not be addressed as suggested by the Agency was regarding new calculations for geriatric data.
From study IC51-301, immunogenicity was analysed in 24 subjects aged 65 and above, and 95% CI have not been calculated for GMT and SCR. Intercell had considered them of limited usefulness in this small subgroup of subjects, since such a low sample size would yield extremely wide confidence intervals. Intercell has initiated the calculations but will not be in a position to provide the data, probably before early next year, as we are dependent on external resources here. The Agency agreed to consider this and provide feedback.
In study IC51-302, the numbers of subjects aged> 65a and older is limited and in terms of statistical analyses has not been considered as a separate stratum. Intercell did analyse safety by age group in the pooled analysis, which provides a larger dataset. Hence Intercell has proposed to use these data in the PI. The Agency indicated that analyses from pivotal studies are preferred. However analysis in a bigger dataset with a substantial number of subjects aged> 65a and older would derive meaningful results and would allow to draw firm conclusion.
Safety data of IXIARO and placebo in the elderly subpopulation from the pooled safety data is acceptable for use in the PI. Intercell will suggest a wording. Calculation of 95 % confidence intervals for SCR and GMT shall be initiated, but the Agency will consider the need for 95%CIs and provide feedback.
2. Data of Patient Information Draft 3, Study information 304.
The results of the study IC51-304 are inserted in the PI, a separate table is showing seroconversion rates and GMT.
A different design of the table will be considered by the Sponsor. The reference of the study IC51-304 will be inserted by the Sponsor.
3. Post-licensure Commitments- Elderly
The Agency would like to see a formal plan to have a set of at least 200 subjects aged> 65 and older investigated.
Sponsor: The assumptions on a subpopulation of subjects aged> 65 and older in the enhanced surveillance is less than 50 persons per year. Also, in ongoing phase 3 trials, inclusion of subjects aged> 65 and older could be focused on. However, the Agencies in Europe and Australia have not required further analyses in this population.
To yield the required number of elderly subjects, the Sponsor suggested to evaluate this in a separate protocol. The Agency found this acceptable and prefers a separate investigation in elderly including assessment of immunogenicity. It is agreed on that this study may be performed in Europe only.
Other than that, the Agency did not have any comments about the revised post-marketing plan Intercell had submitted.
Synopsis of an immunogenicity study in subjects aged> 65a and older will be provided by the Sponsor, to have a written commitment before licensure. Details on the study would be agreed on post licensure. Apart from that, the post-marketing program is acceptable to the Agency.
At this time we view favorably the remaining elements of the post-marketing program as proposed by Intercell. However, final program details are still under discussion and thus the post-marketing commitment section of the approval letter will reflect what is acceptable to the Agency.
4. Post-licensure Commitments- Pediatric Population
The Agency does encourage the inclusion of individuals younger than 1 year of age in the clinical pediatric development program for IXIARO. Given different constraints in developing and in developed countries, no particular number of subjects below one year of age is required. The Sponsor needs to demonstrate a good faith effort that recruitment in this age group is encouraged.
It was confirmed by the Agency that the number of subjects in each clinical study and overall will be acceptable for licensure.
It was discussed whether the Agency would in principle accept data from an open label trial, to overcome ethical discussion on placebo injection in children which would be needed to blind study IC51-321 (Day 7 injection in the IC51 group when compared to the three-dose comparator Jencevac). The Agency will consider this for discussion after licensure.
The Sponsor is going to remove the exclusion criterion younger than 1 year of age; instead inclusion of individuals younger than 1 year of age is part of the study protocol.
Overall the proposed numbers of study participants are accepted by the Agency.
Decision on open label trial (IC51-321) is to be discussed upon submission of the final protocols post-licensure.
We expect to reach agreement on this point pre-licensure (see points for further discussion below).
Points for further discussion and clarification:
- You mentioned that there may be ethical issues recruiting subjects <1 year of age for the study, IC51-322, which will be conducted in non-endemic areas ( U.S. and Europe). Please confirm that the plan for the study is to recruit pediatric subjects expected to travel to endemic areas, for whom there would be prospect of benefit. Please comment on any ethical issues specific to <1 year old subjects.
- Because of the issues involved with administering an intramuscular injection of placebo to children in the IC51 group on Day 7, you requested that Studies IC51-321 and -323 be conducted as an open-label format. We would accept this approach.
- Data generated using non-U.S. licensed vaccines as comparators generally cannot be used to support labeling claims. This applies to your decision to use JenceVac as the active comparator in the studies to be conducted in endemic areas (IC51-321 and IC51-323). Given these facts, we ask that you consider the following proposal for changes to your pediatric development program:
- Conduct Study IC51-321 open-label and non-randomized, vaccinating all 400 subjects with IXIARO.
- Conduct Study IC51-323 open-label and non-randomized, vaccinating all 1150 subjects with IXIARO.
- If a) and b) are acceptable, you could fold IC51-321 and -323 into one trial, with immunogenicity follow-up on a subset of 400 subjects.
- On page 4 of your letter to us dated August 25, 2008, you stated that it may be easier to recruit subjects <1 year of age in Asia. Please provide an estimate of the number of such subjects you would be able to enroll under study protocols IC51-321 and IC51-323 (or a single trial, as outlined above) if the lower age limit of the inclusion criteria were changed from 1 year of age to 6 months of age. Please include in your estimate the following stratification: 6 months to ≤1 year; >1 -≤3 years; >3 -≤17 years.