ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> UNITED STATES FOOD AND DRUG ADMINISTRATION
>
> **ICH PUBLIC MEETING**
>
> Tuesday, June 24, 2003
>
> 10:00 a.m.
>
> 4630 Fishers Lane
>
> Room 1066
>
> Rockville, Maryland
>
> [C O N T E N T S]{.underline}
>
> Introductory Remarks: Janet Showalter 3
>
> ICH General Overview: Christelle Anquez 4
>
> GMPs: Janet Showalter 8
>
> CDT/eCTD IMPLEMENTATION STATUS
>
> CDER Perspective: Justina Molzon 28
>
> CBER Perspective: Bob Yetter 48
>
> Other Regional Perspectives: Christelle Anquez 54
>
> Presentation: Helle Gawrylewski 86
>
> PHARMACOVIGILANCE
>
> MedDRA: Patrick Revelle 90
>
> E2D: Post-Approval Safety Data Management:
>
> Susan Lu 101
>
> QT PROLONGATION
>
> E14: Clinical Part of Q-T Prolongation:
>
> Justina Molzon 108
>
> MORE PHARMACOVIGILANCE
>
> E2E: Pharmacovigilance Planning:
>
> Paul Seligman 119
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Introductory Remarks**
>
> MS. SHOWALTER: We are going to go ahead and get started. My name is
> Janet Showalter. I am the ICH Coordinator for FDA. We have a number of
> presentations to go through for you. This is a preparation meeting for
> the Brussels meeting. It is something we do prior to every ICH meeting
> as a matter of transparency and also to let you know exactly what we
> are planning to do once we get there so that we can get your input so
> that can use that as we negotiate in Brussels.
>
> The session is being recorded. There is going to be a transcript
> available. I believe that will be made available on the website
> following the meeting. Again, since there are not very many of us here
> this morning, I would like us to be informal. I think you are invited
> to ask questions as we go or you can hold them until the end for the
> presentations.
>
> One of the things that we do prior to starting this every time, and
> this may be old-hat for a lot of you, we do like to go through and
> give a brief overview of ICH and the process, what it is all about.
>
> This morning Christelle Anquez of my staff in the Office of
> International Programs is going to provide that presentation so I
> think we will try to sort of zip through some things so that we make
> sure we get to your questions.
>
> Christelle?
>
> **ICH General Overview**
>
> MS. ANQUEZ: Good morning, everyone. I will get started and then you
> will have the slides on the screen. I will go rapidly because I am
> sure you are very familiar with ICH and this is very basic.
>
> So ICH stands for International Conference on Harmonization of
> Technical Requirements for the Registration of Pharmaceuticals for
> Human Use. It is a unique approach. It comes from the agreement
> between the European Union, Japan and the USA to take action on
> Harmonization. It is a joint initiative involving regulators and
> industry as equal partners in technical discussions.
>
> ICH Guidelines are developed to harmonize the technology requirements
> that must be met for regulatory submissions in the EU, Japan and U.S.
> ICH was created in 1990 at a meeting hosted by the European Federation
> of Pharmaceutical Industries and Associations located in Brussels.
> Representatives from industry and regulatory authorities met to plan
> for the ICH conference. At the beginning, it was just to be one
> conference and it led to thirteen years of work. It also established
> the terms of reference and the method of working.
>
> The ICH objectives are the identification and elimination of the need
> to duplicate studies, to meet different regulatory requirements. This
> leads to a more efficient use of resources, human, animal, material,
> in the R&D process as a consequence. The bottom line is quicker access
> to patients of safe and effective new medicines.
>
> Since the focus of ICH has been on the ICH has been on the technical
> requirements for medicinal products containing new drugs and because
> the majority of these new drugs and medicines are developed in the
> Western European Union, in Western Europe, Japan and the U.S., when
> ICH was established, it was agreed that its scope would be confined to
> registration in these three regions.
>
> These are the six founding members of ICH. EU was this European
> Commission, EMEA; EFPIA, the Ministry of Health, Labor and Welfare,
> Japanese Pharmaceutical Manufacturers Association, the FDA and PhRMA.
>
> ICH is administered by the ICH Steering Committee which is supported
> by the ICH Secretariat. IFPMA is located in Geneva and provides the
> Secretariat to participate as a non-party member of this joint
> committee. The second part of ICH is the technical part where the
> science and technology occurs within the expert working group.
>
> On the steering committee, there are two members per party and a
> coordinator is the IFPMA, which is a non-voting member, and three
> observers, one for Canada, EFTA\--the European Free Trade Area\--and
> WHO. The role of the steering committee is to oversee and monitor the
> Harmonization process.
>
> The ICH topics are divided into four categories; safety that relates
> to preclinical studies. Efficacy relates to clinical studies. Quality
> and the last category is regulatory communications. That include
> MedDRA and other electronic items.
>
> The guidances are posted for each region and, for the U.S., it is
> posted on the CDER and CBER website. The steering committee has
> outlined the ICH for monitoring the process of harmonization work.
> Step 1 is the expert working group are building scientific consensus.
> The draft document, when it is agreed upon, it goes to the steering
> committee. The steering committee approves it by signing off on it and
> then it is released on the three regions for publication and comments.
>
> The comments are brought back by the regulatory authorities to the
> working group. They are discussed. The draft is revised if necessary,
> agreed upon and then, if the steering committee agrees with it, it is
> signed off. The regulators sign off on it. The last step, Step 5, the
> document, the guidance, is implemented in the three regions.
>
> ICH also organizes a final conference to present the work done for
> open and public discussion. The first conference was in Brussels in
> 1991. The second conference was in Orlando in 1993. The third
> conference was in Yokohama in 1995, then in Brussels in 1997. The
> fifth one was in San Diego in 2000 when the CTD got signed off. The
> sixth conference to come will be in Osaka in 2003.
>
> Thank you.
>
> MS. SHOWALTER: Thank you, Christelle.
>
> I am going to do the next presentation on the agenda which is one of
> the big items of discussion for the upcoming Brussels meeting is going
> to be the GMP Program for the 21st Century.
>
> **GMPs**
>
> MS. SHOWALTER: The way we are going to do the meeting today, we are
> going to go through some of the big topics for the Brussels meeting.
> One of the big items on the agenda is actually the ICH portion of the
> GMP Program, the Drug Product Quality, or GMP, Program for the 21st
> Century.
>
> What I want to do today is give you some idea of the work that we have
> done to prepare for this meeting and give you an idea of the kinds of
> things that we are going to be talking about in Brussels.
>
> First of all, I want to let you know the people that are on this
> committee, this is the International Working Group for the GMP
> Initiative. It probably helps to put this in context a little if you
> understand that that there are more than fourteen groups. I say more
> than fourteen because it grows kind of by leaps and bounds all time
> and I think several have been added.
>
> When we started this, there were fourteen working groups. The
> international group is one of those fourteen. This just gives you some
> idea of the magnitude of the initiative because you look at the long
> list of names that are participating in the international section. On
> all of the various committees, there is a list equally as long and, in
> fact, some people are participating on more than one.
>
> So I think it gives you some idea of the priority and the extent to
> which this is going to make a huge change in FDA.
>
> When we decided to take the GMP Initiative up in ICH, we had some
> concerns about whether ICH would be an appropriate venue for this. As
> we went, we reflected on some of the kinds of topics that we had taken
> in the past to ICH and we realized that there were some similarities
> with other topics in terms of the process that we might use for this
> one.
>
> So we are doing kind of a \"lessons learned\" from what we have done
> with gene therapy and also with pharmacovigilance. The process we used
> for those was to really get a discussion going of the technical
> experts that we had already within the ICH framework and then pull in
> some opportunities for outside expertise as well, and to also make
> sure that, before we embarked upon a single topic, that we really had
> a good understanding of the lay of the land in the area.
>
> So I really want to give you concept today that we are not really
> jumping very smartly on this but we are taking our time to stop and
> reflect and deliberate so that we can end up with a good and timely
> product.
>
> Another topic that we also reflected on was the work that we had done
> with a previous GMP topic and that was on the Q7A topic, GMPs for
> APIs. We though there would also be a number of lessons learned from
> this as well. In fact, we were looking at this topic because this is
> one where we had a great deal of success in accommodating our domestic
> time line even while making some serious steps forward
> internationally.
>
> The way that we did this, we realized, was to have a concrete idea of
> exactly what we wanted to do and then start marching down a very
> well-specified pathway.
>
> So, in working with my GMP international group, what we set out to do
> was to identify two major areas where we thought we would play an
> important role. The desired outcome or the goal for this initiative
> was firstly to have harmonized international scientific standards.
> This would be done under the auspices of ICH.
>
> When we looked at this topic, we really set our sites on standards for
> drug-product quality or GMPs that would promote technological
> innovation. Then we realized that that would not exactly get the
> entire job done but there would also need to be an additional goal.
> This was a more long-term plan for international regulatory
> cooperation and the end product for that would actually be an FDA
> concept paper that would outline the long-term plan for regulatory
> collaboration.
>
> This has actually a much longer time line associated with it. That FDA
> concept paper will probably not be ready for another, I would say,
> eighteen months or so or at the moment when we actually revisit the
> GMP initiative.
>
> So, in getting ready for this talk today, one of the things that I
> wanted to do, and I want to go through these fairly quickly, was to
> give you an idea of the buildup and how we are getting to this point,
> this sort of critical moment in time that we are going to come to at
> the Brussels meeting.
>
> As you can see from the next few slides that I put together, the
> international working group has actually met a about once a month. We
> have had some very good discussions, a lot of very important exchange,
> not with just the folks at CDER but also with our colleagues in vet
> medicine, in Biologics and ORA and the Office of Regulatory Affairs.
>
> We started this process in August of last year. We had our first
> meeting. That is when we realized we would need to do an ICH concept
> paper, that we would need to have Janet Woodcock actually address the
> steering committee in September of that year at the Washington ICH
> meeting.
>
> Following that, we did some additional brain storming in September
> after the meeting and realized that the first track would be a
> short-term deliverable. Basically, what we were told at the ICH
> meeting in Washington was that, if we wanted this topic to go forward
> in ICH, we would need to have something to our ICH partners by the end
> of November. I can tell you, this was no easy task trying to get a
> single concept paper that everybody across many centers and ORA could
> agree on.
>
> But we did meet our time line. Then we had some additional meetings to
> talk about what kind of document might accompany the concept paper.
> The concept paper is actually something that ICH requires before it
> takes up a topic. We realize that it was pretty sketchy at best in
> terms of what we knew last August or last September in trying to put
> this together.
>
> We realized, at our October meeting on October 22, the need to put
> together what we call a white paper. The white paper actually is
> something that lays out the lay of the land, the current situation in
> FDA and what we wanted to get out of the overall GMP initiative and
> how this would relate to ICH.
>
> Then we had a number of other meetings at the same time that we were
> proceeding down this track of doing the concept paper, the white paper
> and so forth. Also, the agency was trying to move forward with a
> number of contracts and getting those finalized.
>
> At the early stage of that, we thought that there could be an
> international component to those contracts but, as time wore on, we
> realized that probably wouldn\'t pan out. So our task became sort of
> in the fall through the winter to put together the white paper, to get
> that reviewed and vetted within the agency.
>
> You will see we had meetings in November, more meetings on that in
> December, culminating in a February finalization of the white paper
> and also this dovetailed very nicely\--some of you may have attended
> the April GMP workshop here in Washington. One of the things that we
> were trying to do is to get all of this great load of information that
> the various working groups have and figure out how we can coalesce
> that into sort of a unified program.
>
> This did come together at the April workshop. We heard a lot about
> what the international component of the GMP programs should be. There
> were many, many references to harmonization. This made us very happy
> the fact that we had early on decided to, at a minimum, take this to
> ICH and, perhaps, later on to other venues.
>
> One of the other venues that you will find repeatedly gets mentioned,
> and we had a discussion of this at our February meeting, is the PIC/s.
> That is something that we are currently investigating as a venue for
> further regulatory collaboration on this topic.
>
> We had additional meetings in March of this year. We also, at that
> point, got an update from our folks in FDA that we are working on the
> contract process. This is when the international component was
> actually deleted. However, there is still interest in soliciting some
> information from other countries. Some of those that we have set our
> sites upon for various reasons are Japan, because we work closely with
> them and they are a market leader in the pharmaceutical area. Also,
> there seems to be some potential for lessons learned with Switzerland,
> Canada and Australia. We understand that Australia has recently made
> some changes to more or less align themselves with the PIC/s scheme.
>
> There have been some additional meetings and discussion in May. At
> this point, we were finalizing our action plan and I believe that the
> long-term deliverable of investigating other venues was also approved
> by the GMP steering committee.
>
> So now, as we are really sort of on the brink of Brussels meeting,
> what we have been doing is meeting with the international working
> group and also with team that is going to ICH to negotiate this topic.
> We have really refined our thinking a lot since when we embarked upon
> this last August. I think it is worth noting that some of the topics
> that repeatedly come up as contenders for some sort of harmonization
> are things like general definitions for risk and quality, process
> capability, pharmaceutical development and also variations and
> changes.
>
> One of the things that also we set our sites on in June was the fact
> that an overall goal for this workshop should be development of a
> strategic plan. One of the reasons for this, I think, is also, as part
> of our lessons learned and the process of some level of introspection
> is that most of you have followed ICH know that we developed a series
> of guidelines for the drug-review pharmaceutical-development phase.
>
> Then, at the end, we kind of realized, well, gee, there is an
> opportunity for the CTD now because we have all these guidelines. This
> is a case where we are trying to do it the other way, something that
> ICH hasn\'t exactly done in the past, and really put together the
> strategic plan and what all the various pieces are. So we are starting
> broadly and then we will, from that process, figure out which of those
> discrete topic areas we may want to take up, and kind of the rationale
> for why we take them up when we do.
>
> Again, ICH has not done this kind of planning and so I think this will
> be a useful experiment to see how this shapes up at the Brussels
> meeting.
>
> I just want to go back very briefly to give you some idea about the
> concept paper. I think all of this is in line with talk that
> Christelle previously gave on the procedures. One thing we just make
> sure we take note of is that the scope of the concept paper, which I
> do think is critical because we may be going forward to other venues
> for some of other aspects, we were very precise there and defined the
> scope, which was to assess the current state of and future directions
> for assuring drug-product quality.
>
> This really had to do with things that could promote or encourage
> innovation as sort of our reason for being NICH.
>
> Just a few words about the white paper. It was drafted by Brian
> Hasselbalch at FDA. We went through a very elaborate process of
> organizational vetting to make sure that it really did represent the
> agency\'s best thinking. One of the things that you will also notice
> is that our goal here was to have all of the ICH partners come into
> the Brussels meeting with sort of the same amount of information so
> that that could be basically a level playing field.
>
> If you attended the April workshop, you would have noticed that EFPIA
> did put forward their paper already. They presented that in April. In
> addition to that, we understand that we are going to be getting a
> paper, which is the European white paper, perhaps sometime this week
> or next, that they are about to finish theirs. I know the Japanese are
> working on something very similar as well.
>
> So the goal would be to start the workshop with some fundamental
> background from all of the sponsors which would be shared and used as
> the basis for those discussions.
>
> The time line, just to go over for you the time line for ICH, again,
> starting with that Brussels meeting, really, that will be a two-day
> discussion meeting talking about the current state of play and the
> identification of potential topics. It is very unlikely that there
> could be a expert working meeting. Probably that will not happen until
> Spring of 2004. I think it is likelier that we will have some level of
> additional discussion at the meeting not in Tokyo but in Osaka in
> November just prior to ICH-6. I think probably that will be a
> concept-paper drafting session.
>
> So when you look at the extended time line, you will notice that we
> are really not talking about having any sort of the Step-2 document
> until, at the earliest, the Fall of 2004. It probably won\'t happen
> then. It probably will actually be maybe in the Spring of 2005 or
> sometime that year, depending on how many extra meetings they might
> want to have and how many would be agreeable to the steering committee
> to fund.
>
> Back to the April GMP workshop summary and the international
> implications of that workshop, just to give you some idea of the kinds
> of things, again, that were mentioned that would have some sort of
> international component, I think. You see that we are sort of
> coalescing repeatedly along the same topic lines, but these would be
> things like how do you assess process capability, what are the general
> principles to assess new measuring technologies, again general
> principles for different new manufacturing technologies, general
> principles about a quality-system approach. Always, we end up talking
> about risk assessment and risk management.
>
> The other thing that repeatedly comes up internationally and also it
> is important here at FDA is how we link the review side with the
> inspection side. We are spending a great deal of time trying to work
> that out and what that means in terms of an overall quality-system
> approach.
>
> The Brussels meeting, the snapshot; again, it is a two-day meeting. It
> will be co-chaired by the EU and by FDA. Those chairs are Gordon
> Monroe and Ajaz Hussain from FDA, Monroe for Europe. Again, what we
> are really trying to do is keep the discussion fairly broad, on the
> broad themes that are important for developing the strategic plan.
>
> There will be a report to the steering committee that probably will
> come up on Friday morning. The meeting, itself, probably will start
> Wednesday afternoon and go all day Thursday. I think it is very
> likely, and this is just a forecast, but we are hoping that maybe two
> to three ICH topics could be selected. These would be the things we
> would write the concept papers for in the fall.
>
> Also, it is important to note that it is very likely at this meeting
> that pharmaceutical development will be agreed as an ICH topic. That
> is being folded under the GMP drug-product quality umbrella. It
> probably will also go down a very specific and discrete quality
> pathway within the ICH framework since there already was a lot of
> consensus about taking this up as a topic previously.
>
> Again, just to reiterate, and I don\'t think there are any surprises
> here is you get used to seeing the same things crop up, the themes for
> discussion will be the team approach for assessment and inspection,
> knowledge sharing and transfer models as a basis for postapproval,
> variations, changes, management, mechanisms for collaborating or
> cooperating in other venues.
>
> So, again, even though the meeting, itself, is being done as part of
> an ICH meeting, it is being done that way with the recognition that we
> are putting together a strategic plan. Some of the topics that get
> thrown out as important elements for that plan may not really be
> appropriate topics for ICH.
>
> One of the concerns that we also have is the ICH process really
> hasn\'t allowed for very much academic input so one of the things we
> will also be interested in is how do we get that kind of expertise
> into the program or what other venues are available where we might
> also benefit from that kind of expertise.
>
> Then the other items that we will be talking about; again, quality by
> design, product process knowledge and risk-mitigation strategies, more
> on principles for how you introduce and how you regulate and assess
> new technologies and always we come back to risk-based concepts so
> system-based inspections.
>
> So I think that really gives you a pretty good flavor or the kinds of
> topics\--these are not new. They were pretty well discussed at the
> April workshop. I think the real challenge for us is going to be how
> do we put them together into a strategic plan and then prioritize them
> and figure out what makes sense to work on and when.
>
> I want to turn now, for just a moment, to a part of this that really
> is not very well developed but is in the thinking stages. We have a
> time line for regulatory cooperation in other venues beyond ICH. What
> we are proposing right now is in September to report to the GMP\--and
> this is the GMP steering committee\--a plan for inviting some
> regulatory speakers in so we can get information about their
> experiences. I have listed out who those might be.
>
> In November of 2003, we would report again to the GMP steering
> committee on what the various activities that we would need to
> undertake as a long-range plan for how we would collaborate
> internationally on the regulatory aspects. I think what is important
> here is to keep in mind that the ICH part is really about science,
> innovation, new technology. But there is another piece of this that
> really is of great interest to the regulators. So we are going to be
> looking at those other venues in terms of how we can deal with that
> regulatory piece.
>
> Again, it seems that PIC/s might be one of the organizations that
> would allow that to happen. However, we do have to note, right now FDA
> is not a member of PIC/s so one of the things that my committee is
> looking into is what are the implications of membership. Do we have
> the resources to become a member? What would sort of the cost-benefit
> analysis of that be?
>
> In the Fall and Spring of 2004, we would want to meet with
> stakeholders, get outside input and then we would probably need to
> meet with the FDA staff on the drug-product-quality systems, its
> experiences with PIC/s and possible ways for regulatory authorities to
> collaborate.
>
> The overall plan is in May of 2004 to develop this long-term plan that
> gets presented. That wouldn\'t happen until June of 2004. That would
> be a concept paper to the GMP steering committee. This is the group
> that Janet Woodcock chairs. We would present our plan to that group
> and then I think it is quite likely that, from there, it would have to
> be vetted further within the agency, maybe at the executive council
> and so forth.
>
> But our big deliverable is to have this detailed plan by June of 2004
> so that some cuts can be made on how we are going to take the other
> piece of this\--that is the regulatory cooperation piece\--beyond what
> is happening in the ICH program.
>
> I thank you. I will be happy to take questions if there are any. Yes.
>
> AUDIENCE: Could you tell us what PIC/s stands for?
>
> MS. SHOWALTER: It stands for the Pharmaceutical Inspection
> Convention/Scheme. The Scheme was added later. It originally was the
> Convention. But then there were some legal difficulties associated
> with whether the European countries could participate in a convention
> because specific regulatory authorities were members.
>
> At that point, they changed it to the Scheme, and it is a much more
> voluntary organized group of people. Previously, it had been by
> treaty. So that is the difference. Also, it is regulatory authority
> with some observership status for industry and others. Currently, FDA
> is one of those observers. We are not a full member.
>
> MR. JERUSSI: Robert Jerussi, Jerussi Consulting. The question I have,
> listening to your presentation today, Janet; it seems to me ICH has
> developed almost a life of its own. It is in an expanding mode. I
> recall when it was going to be over after the third or fourth ICH. I
> wonder if there is any end in sight.
>
> I ask this question specifically because I believe, I firmly believe,
> ICH has escalated drug requirements in the United States and it has
> slowed and raised the cost of drug introduction.
>
> MS. SHOWALTER: So, as I understand your question, it is is there an
> end in sight. I suppose I am going to have to be a little flip here
> and I would have to say, based upon what I have seen, no. I think the
> short answer is no.
>
> Any other questions?
>
> MR. POSKA: Rich Poska from Abbott Labs. I was wondering if you can
> clarify; on one of your slides you mentioned transfer models as a
> basis for postapproval changes. What do you mean by transfer models?
>
> MS. SHOWALTER: That is a good question. We spent a lot of time talking
> around that. Basically, what we are trying to identify, and,
> certainly, I am not the GMP expert so I am just going to give you my
> two-cents worth, but what we are really talking about how information
> that comes in in an application, really, what we should be talking
> about what we think is knowledge transfer, how you transfer, in a
> reasonable way, what you get to the other components, stakeholders,
> that have a part to play in that.
>
> So I will tell you that one of the best documents that I have seen on
> that, and I don\'t know if you have access to it or not, is the ISPE
> document that they put together fairly recently that sort of goes
> through the various models for the kind of tech transfer, knowledge
> transfer, information transfer, that we are talking about as part of a
> quality system.
>
> That is one of the best explanations that I have seen. In fact, I
> think that it is possible that we may ask that group to make some sort
> of presentation about that at the upcoming meeting in Brussels.
>
> AUDIENCE: Which group are you talking about?
>
> MS. SHOWALTER: It is ISPE.
>
> MR. POSKA: International Society of Pharmaceutical Engineers,
> ispe.org.
>
> MS. SHOWALTER: I don\'t recall the date of the document but it is a
> fairly recent document.
>
> POSKA: I was on the steering committee and we published it last year.
>
> Any other questions? Thank you. This is going to conclude, then, the
> GMP section of this. I think, in summarizing, I would just like to say
> \"Stay tuned.\" There is a lot still being talked about and worked
> out.
>
> Now we are going to go into the CTD-eCTD implementation status. We
> have a number of speakers for that. The first speaker is going to be
> Justina Molzon. She is going to give CDER\'s perspective. Following
> that, Bob Yetter will give CBER\'s perspective. Then Christelle Anquez
> will talk about what is happening the other regions followed by the
> eCTD discussion.
>
> Justina?
>
> **CTD/eCTD Implementation Status**
>
> **CDER Perspective**
>
> MS. MOLZON: Thanks, Janet. I am just going to be giving a quick
> update. I know some of you have heard this presentation at DIA last
> week, but we have actually had an additional submission for CTD so I
> have updated my statistics. I think my statistics on the applications
> into the Center for Drugs and how it is broken down by division is
> basically going to be the main thrust of this discussion.
>
> Christelle has already given you background information on ICH. I will
> have a couple of comments focusing ICH initiatives on its CTD efforts.
> I will give you an update on what we have been doing in CDER and then,
> as I have already mentioned, a discussion of some of the statistics
> related to CDER\'s CTD experience.
>
> Christelle has already mentioned how ICH works. There is a series of
> expert working groups, safety, efficacy, quality and regulatory
> communications. Regulatory communications is a catch-all category and
> includes the CTD efforts. These working groups work on their various
> documents, present them to the steering committee and the steering
> committee then monitors and facilitates the work of the expert working
> group.
>
> Christelle already showed you this slide. It basically covers the
> conferences that ICH has put on in an effort to be transparent. At the
> fifth conference, which was in San Diego in the Year 2000, the main
> focus of that conference was the Common Technical Document.
>
> So what happened the few days before that major conference was that
> the expert working groups on the Common Technical Documents had to
> work in a frenzy to finalize those documents so they could be
> presented at the end of the week. So you literally had groups working
> around the clock. CDs were being burned the Wednesday night before the
> Thursday meetings. There were disclaimers on these PDF documents that
> they still had to be edited for consistency.
>
> After this frenzy was over, we realized that these three groups were
> actually working on isolation to finish these documents for
> distribution. Then, after ICH-5, these documents had to be edited for
> consistency, numbering system, style and format.
>
> Janet has already mentioned how, in the GMP efforts, we are trying to
> have more of a strategic plan. I dare say that the CTD was created in
> this flurry of activity and, later on, we had to figure out how to
> provide consistency for the various documents that had been developed
> by the expert working groups.
>
> So the reality of implementation is that, once the regulators start
> preparing these documents for publication, in our case, the Federal
> Register, or posting it on our web, we realized how complicated they
> were and we were faced with the enormous task of making them
> consistent.
>
> This, along with the fact that regulators have different systems for
> implementations meant that, no matter how closely we worked together,
> there were still going to be some minor inconsistencies. But these
> minor inconsistencies do not tract from the enormous work that has
> been done on the Common Technical Document, and the Common Technical
> Document should be as clear as possible.
>
> So we have been devoting, along with Europe and Japan, much effort to
> do away with these ambiguities and inconsistencies at our ICH
> meetings. This is a continuous process and I believe that CTD has
> evolved and improved over time.
>
> Many of you have seen this very simple diagram. This is how the CTD
> was initially presented. It has now evolved in a more complicated
> presentation based on discussions we have had at various meetings such
> as DIA raps or these open public hearings. We understood that people
> did not understand whether documents needed to be layered or stacked.
> So we added a numeric numbering system to indicate how we wanted these
> documents to be assembled. So outreach programs and discussions with
> our stakeholders have led us to clarify some of these issues.
>
> The truth is we really need experience with the documents and
> submissions will help industry and regulators to gain familiarity with
> the new CTD format. As I have already mentioned, meetings and
> discussions are helpful in improving these documents.
>
> But because you needed experience with the documents to help implement
> them, the voluntary-submission phase was extended from July of 2002 to
> July 2003. So we added an extra year so there could be more experience
> on the regulator side and also on the industry side with these
> documents.
>
> One thing that comes up at all of these public meetings is, someone
> asked, \"Well, I thought the CTD was supposed to be same and now we
> have to do these differences.\" I need to point out that the Common
> Technical Document is not a global dossier, so a very common
> misunderstanding by those not involved in the ICH process.
>
> The submissions contents is different for the U.S., EU and Japan. This
> is because there are still individual regulations in those countries
> that have never been discussed in ICH. They were either too
> contentious or industry, who generally proposes concept papers for
> topics, they just were not proposed or they weren\'t taken up.
>
> So the Common Technical Document is an agreed-upon format for the
> modular presentation of summaries, reports and data. It incorporates
> the relevant ICH guidelines as building blocks and puts them in the
> same order for submission to ICH regions. So we have had over fifty
> ICH guidelines. All the Common Technical Document does is stack them
> in the same order so they are in the same order for Europe, Japan and
> the U.S.
>
> This question was also addressed in the Q&A process that has developed
> to help clarify some of the issues related to the Common Technical
> Document. So the very first question under the CTD general questions
> was, \"Will a dossier using the CTD format, Modules 2 to 5, be
> identical for all regions?\"
>
> The answer was, \"Not necessarily.\" The CTD provides a common format
> for the submission of information to the regulator authorities in the
> three ICH regions. However, the CTD does not address the content of
> submissions. This is in terms of regional requirements and sometimes
> applicants have different preferences for indications, dosage forms or
> whatever so there could be a difference.
>
> To help those submitting NDAs, BLAs, ANDAs, et cetera, to the FDA, we
> created a draft general considerations guidance called Submitting
> Marketing Applications According to the ICH CTD Format. This was
> posted in September of 2001. Originally, there was a comment period
> until November of 2001. Only twelve sets of comments were submitted.
> This was generally based on people just reading the documents after
> they were posted on our web.
>
> I point out that comments are always welcome but to encourage comments
> from companies that have experience assembling these documents, I
> reopened the document until June 16 of 2003. That was just last week.
> So we are going to be collecting any additional comments. However, I
> just note that two weeks ago, I went to the docket and looked and
> there still were not any additional comments.
>
> But we will incorporate comments from the steering committee, expert
> working groups and meetings such as this into our final draft of the
> general considerations document. So, please, send us your comments.
>
> We also have established a web for electronic submissions called
> esub@cder.fda.gov and also cdt@cder.fda.gov. So you can send comments
> directly in to the FDA. We are trying to consolidate those comments.
> If you have very specific questions about your applications, they come
> in to either the esub or the CTD e-mail address. They are reviewed by
> basically the same person and then we come up with a consensus
> response.
>
> Questions that would help the overall CTD process are taking to the
> ICH steering committee and expert working group meetings. So we have a
> few that we can take to Brussels in a couple of weeks.
>
> What I really wanted to focus on during this presentation is exactly
> what is the experience that CDER has had with applications. So far, we
> have had twenty-five submissions. We received one when I was at DIA. I
> gave a presentation at DIA, a cohort of twenty-four. But now I can say
> twenty-five.
>
> I have broken these submissions down by Office of Drug Evaluations I
> through V. So you can see that ODE I, Neuropharm, has had two.
> Oncology has had three. The asterisks here indicate that there were
> three NME submissions to Oncology. Two to Cardiorenal. In ODE II,
> Metabolic and Endocrine had three. This is where there was a change.
> Originally, just last week, there were two. We just received one a
> couple of days ago.
>
> So that provided for an additional NME so there are two NMEs. In
> Pulmonary, there are four. There are none in Anesthetic, Critical Care
> and Addiction Drug Products, none in Gastrointestinal and Coagulation
> Drug Products, three in Repro and Urological Drug Products, none in
> Medical Imaging, one in Antiinfective, two in Antiviral, two in
> Special Pathogens, and there are two NMEs in Ode V. There are three in
> Analgesic and Ophthalmic, none in Derm and Dental and none in OTC.
>
> I just read those out for the transcript, so I\'m sorry. I am sure you
> could have read all this yourself but I am trying to document the
> submissions.
>
> If you look at distribution between the Offices of Drug Evaluation, it
> is really not that much different. There is just a scattering with ODE
> I and II having seven each.
>
> If you look at the time frames, considering that the CTD was accepted
> by regulators as of July 2001, I have broken these down into half
> years since then. So, from July to December of 2001, there were five
> CTD submissions; January 2002 to June 2002, three; July 2002 to
> December 2002, nine; and then January 2003 to June 2003, eight, with a
> total of twenty-five.
>
> So, if you plot this out, you will see that the second half of the
> year 2001 to the second half of the year 2002, there has been an
> increase. The same from January to June of 2002 to January to June
> 2003. So there has been an increase. We then broke these out by months
> so you could get an idea of how these are submitted. We will get one.
> Then we won\'t get any. Then we will get one, skip a month. So it is
> just a scattering.
>
> It was sort of predictable that, in December of 2002, we had more
> because people gear submissions toward the end of the year.
>
> So, so far, there have been twenty-five submissions in CTD format
> submitted to ten different review divisions. All five offices, ODE I
> through V, have had experience and that experience is in terms of
> hybrids which is either just the safety module submitted in CTD
> format\--that is the pharm-tox information\--or the quality modules
> just submitted in the CTD format. Then the rest of the application
> would be an NDA or a BLA in Bob\'s case.
>
> New dosage forms was another CTD type of submission, new indications.
> and then NMEs or complete CTDs. So what I did to further delineate on
> experience, I looked at a typical NDA review team which is project
> manager, the medical officer, chemist, statistician, pharmacologist,
> pharmacokineticist, clinical microbiologist and a microbiologist.
>
> I just tried to plot the exposure for each of these types of
> submissions. So, for a pharm-tox hybrid, the project manager and the
> pharmacologist would have experience. For a quality hybrid\--that is
> just the CMC section in CTD format, project manager, chemist and a
> microbiologist, perhaps. For a new dosage form, once again, project
> manager, chemist, but a pharmacokineticist might be involved if it
> from a tablet to a capsule or vice versa and then a microbiologist for
> sterility issues.
>
> For a new indication, project manager. You would be involving the
> medical officer and, perhaps, a statistician, the pharmacokineticist
> and possibly the clinical microbiologist if it had to do with an
> antiinfective or antibacterial product.
>
> Then, for a new combination, you have included more and then, finally,
> for an NME, the entire review team would be exposed to the common
> technical document.
>
> So the good news about these submissions are that there were no
> \"refuse-to-file\'s\". These were not perfect submissions but they
> could be reviewed. I should note that CDER has been flexible during
> this voluntary submission phase because we wanted to encourage
> submission of these documents so we could gain experience.
>
> In terms of the number of companies submitting these documents, there
> have been nineteen different companies. Several of them have submitted
> two or three submission in CTD format. Breaking the companies down,
> there were nine large PhRMA companies, six mid-size companies, four
> small companies that had just one or two application overall and then
> the World Health Organization also submitted an application.
>
> On July 1 of 2003, the Common Technical Document will become mandatory
> in the European Union and Japan. It will be highly recommended by the
> FDA. The reason it is highly recommended instead of mandatory is that
> ICH documents have always been considered guidance by the FDA. Good
> guidance practices, or GGPs, require that the CTD not be mandatory.
>
> So this is not an indication of lack of commitment. It is just that
> our good guidance practices indication that these documents have to be
> guidance and not mandatory. So, presubmission meetings indicate that
> many companies are following this recommendation.
>
> In terms of presubmission meetings, this is an indication of the next
> wave of CTDs that will be submitted. I have been invited to twenty-one
> presubmission meetings for CTD-formatted NDAs. I generally go to a
> presubmission meeting with staff from Dr. Randy Levin\'s group, the
> Office of Information Management, so that we are available to the
> Review Division just to answer questions on the Common Technical
> Document because, if the reviewers have not received one to that date,
> we have a basis of experience that can help them.
>
> We are also available to help sponsors with questions on how the
> documents should be formatted. As I have already mentioned, with the
> esub and ctd e-mail addresses, we are trying to collect areas of
> concern and issues that require clarification.
>
> At the presubmission meetings, the sponsors were advised to follow the
> updated information on the ICH web which is www.ich.org. Because of
> our good guidance practices, it takes a while for our editors to
> convert the ICH-harmonized documents into the GGP-prescribed format. I
> also tell the sponsors that they should look at the ICH website just
> to check up on the Q&As that have been updated after each of the ICH
> meetings because these are helpful in assembling the CTD-formatted
> submissions because, often, another company has had the same issue
> that you are concerned about and there has been a coordinated
> consensus response in terms of the CTD disciplines. The Q&As are set
> out in terms of safety questions, efficacy questions, quality
> questions and then just general questions.
>
> Basically, the specific information that is relayed at these
> presubmission meetings are; do not modify the CTD table of contents,
> submissions should exactly match the CTD, provide all information
> under CTD-ICH-negotiated headings and numbers, do not create new
> headings or numbers.
>
> I have basically tried to say the same thing four different ways so
> people realize that you really should not modify the headers and
> numbers in the CTD format because that is what it is. You can\'t
> change or modify the numbers or headers in any way.
>
> Additionally, if a company does not have information for the section,
> provide the ICH CTD number and header and then put \"non applicable,\"
> or some other language. Don\'t skip or delete sections and never
> renumber sections. I have actually seen applications where someone
> just left something out and then went on with different numbers. So
> they had to redo their numbering system because that just wouldn\'t
> help them in the process because the numbers have to be the same and
> the headers have to be the same as the ICH CTD documents.
>
> At the ICH meetings last February in Chiba, Japan, additional sets of
> Q&As were endorsed by the steering committee and were posted on the
> ICH website. Some of these were related to general matters but some
> were also very specific. There was a very lengthy discussion of the
> ISS and the ISE and the need to include it in the CTD in some manner.
>
> But the meetings also focused on the eCTD which you are going to
> hearing about later from Tim or Randy. I always recommend that
> companies check the ich.org website after ICH meetings for the most
> recent information. So we are going to be going through the same
> process in Brussels. We will go over Q&As that have been proposed. We
> will try and finish up any problems that are still remaining in terms
> of confusion or clarification with the CTD.
>
> So the next steps for CDER are we are going to continue to meet with
> project managers for feedback on CTD submissions. Increased
> submissions will help determine the effects on the review process, if
> any. This may help organizes reviews and reviewers a little bit more.
>
> Presubmission meetings indicate more CTDs are on the way. CDER is
> looking forward to receiving submissions so that both industry and
> regulators can experience the CTD format. So we have a nice cumulative
> curve developed and I would just like to see many more submissions.
>
> Thank you very much for your attention.
>
> Are there any questions?
>
> MR. MILLER: Loren Miller, PPD. The question I had as, of the
> submissions you have had, how many were electronic and, secondly, of
> the full submissions, how many required a separate ISS or ISE that was
> taken out of the context of the\--
>
> MS. MOLZON: In terms of electronic, there has been a mixture. Some of
> the applications would come in according to the eNDA procedure but
> then the CTD portion would be in paper. So, depending on the company
> and the approach, there was a nice mixture. So we are going to be
> looking into those statistics. I haven\'t broken things down to that
> extent.
>
> In terms of the ISS-ISE, there has been a variety of approaches. Dr.
> Temple did a very nice presentation at DIA which will be posted. All
> of the DIA presentations from CDER will be posted on the website. It
> is just depending on the type of application you have and it is
> basically if the documents you have put together for ISS-ISE
> requirement can fit into the overview and the summary, then you do
> that. If not, you are going to have to put some of the narrative in
> those sections and then the data in Module 5.
>
> So it is really a case-by-case situation based on the size of the
> submission and the type of documentation you are providing.
>
> MR. POSKA: Rich Poska, again, from Abbott. You mentioned that, and I
> recognize that the CTD is only intended to provide a common format,
> but in your presentation you mention that it does not address the
> content of the submission because of regional requirements and
> regulations.
>
> However, the previous presentation that we had did talk about some
> initiatives that the FDA is working on towards trying to harmonize
> certain things. You talked about the concept paper on specifications.
> I think one of the largest benefits we can get out of CTD is, at least
> from an industry standpoint, to try to get harmonized requirements and
> specifications.
>
> So my question is, should we expect to see the long-awaited stability
> guidance from the FDA to be incorporating more ICH and less regional
> type requirements that will be more or less transparent or will it
> still contain inconsistencies with the ICH and require us to have
> separate sections for global applications.
>
> MS. MOLZON: I have a major disclaimer. I am not in the Office of New
> Drugs and I haven\'t seen the stability guidance. As I said, this is
> the beginning and things are evolving. It is hard to imagine exactly
> what is going to go on in GMPs. All these things are up for
> discussion. So you have started the framework. So now you have some
> additional topics to talk about.
>
> This is where we are right now. It would be nice to move towards more
> harmonized, but I can\'t predict that.
>
> MS. SHOWALTER: One comment about that is that, at every ICH meeting,
> there is now a section where we talk about implementation issues. For
> things like stability, and there is actually a mechanism for getting
> this aired internationally\--and I think it is an important component
> of the program, as we move more into an implementation phase.
>
> So what I would do\--and the vehicle for making all of that happen is
> really through PhRMA. So I would encourage, for those kinds of issues
> to be taken up within PhRMA and then they should be put on the table.
>
> There is a time line involved in this. It is too late for the Brussels
> meeting. Basically, the way you want it come up is you want it to be
> very well defined and described in a paper that PhRMA, then, could
> float hopefully, if it is with FDA, to FDA first or if it is with
> Europe, to Europe first.
>
> But then, if the issue can\'t be resolved or is not resolvable, then
> it really should be taken up as an ICH implementation issue. We
> actually encourage that. So there is a procedure put in place pretty
> much heretofore that has been empty. That section hasn\'t been
> discussed because nobody floats anything.
>
> It is sort of interesting to me. Prior to us taking that one, there
> seem to be all kinds of implementation issues. But, once we put it on
> the program as a specific agenda item, they just went away. But I
> would encourage steps to be taken to make that happen because we
> really should be taking about implementation issues.
>
> If we want to preserve what we have already achieved, we have to do
> that as well. And we understand that. So we would encourage that.
>
> I just have a quick question. Is the flexibility going to remain the
> same or will it change as of the first of July?
>
> MS. MOLZON: No; we are always flexible, in my opinion. You are
> submitting these documents and good guidance practices are very
> helpful in this situation. Because these documents are not mandatory,
> we allow leeway for discussion between the sponsor and the Review
> Division as to how they want things put together.
>
> But the headers and the numbering systems, there is no negotiating on
> that. That is not flexible. We were flexible in just discussing with
> the sponsors on how the documents were put together and we are going
> to be less flexible in terms of numbers and headers.
>
> We were just trying to get the sponsors used to these formats. But now
> they have to adhere to the numbers and the headers.
>
> MS. SHOWALTER: Thank you.
>
> The next speaker will Bob Yetter and he will provide CBER\'s
> perspective on the Common Technical Document.
>
> **CBER Perspective**
>
> MR. YETTER: Good morning. It is a pleasure to be here. I hope you will
> bear with me a little bit. I am not quite as recovered from a sinus
> infection as I had hoped I would be by now.
>
> Justina told you about CDER\'s CTD implementation plan and, to a great
> extent, it reflects the FDA\'s implementation plan. You have seen this
> consensus diagram of what the CTD is all about. The process that we
> have undergone in CBER looks very much like CDER\'s. It involves
> publishing and revising guidances as needed, addressing certain
> administrative issues, training staff and outreach to the industry.
>
> The primary guidance involved is the one that Justina mentioned
> earlier, the general guidance on submitting marketing application in
> ICH CTD format. That one has an introduction and background, talks
> about the CTD format, itself, provides considerable information on
> Module 1 and general issues for submissions. All of that is very
> important for people being able to use that.
>
> We have extended the comment period. It has again closed but we
> extended the comment period until June 16 to get further comment once
> people got some experience with working with the CTD so that we could
> find out where the problems were, where the issues were.
>
> We will use those comments that we got in and revise the guidance and
> get out a final guidance. In CBER, we instituted what would be called
> an administrative issues subgroup to address certain problems or to
> make sure that there were not certain problems. What it was intended
> to address was concerns surrounding receiving, reviewing, processing
> and archiving applications in the CTD format.
>
> They were supposed to look at needs for a smooth transition and
> predict potential difficulties and identify any remedies for the
> difficulties and identify training needs.
>
> Applicability and scope; I am going to mention this because recently,
> with other initiatives, these questions have come up. ICH was
> originally intended to address pharmaceutical products and specified
> biotechnology products. CBER has a variety of products including
> specified biotechnology products that fit within the ICH definition.
> But, as of the end of this week, the majority of those specified
> biotech products will be transferred to the Center for Drugs.
>
> That has raised the question of where is the Center for Biologics in
> terms of implementation? What is going to happen with the CTD for CBER
> if most of the products that this was intended, originally intended,
> to be applied to, will transfer?
>
> I am going to go back to what that administrative issues subgroup
> found out. They went off to work with their respective offices and
> really identified no major issues for the implementation of the common
> technical document. There were no serious concerns about receiving
> them. There were no serious concerns about reviewing them and
> certainly no concerns about archiving them.
>
> They looked at the potential benefits of the CTD for CBER. Increased
> harmonization between the NDA and BLA; now, that is something we have
> been directed to do since FDAMA in 1997. Increased consistency between
> applications; one of the biggest problems that we have is that every
> BLA that comes in, because there is no real prescribed format in
> regulation for a BLA, every BLA that comes in is unique.
>
> This provides us more consistency in what will be coming in. It will
> facilitate communication within the FDA and between CBER and the
> sponsors, we believe. So it is a more predictable format which would
> allow for more consistent reviews and easier analysis across
> applications, something that we frequently do to try and predict
> trends and develop guidance documents to provide industry more
> information on what we expect. In other words, we go back and look
> across applications to see where things are not clear to industry.
> This is going to make that effort easier.
>
> So where does that leave CBER with respect to the CTD? We intend to
> continue to implement the CTD for our products, all of our products
> that are licensed. We will apply it to vaccines. We will apply it to
> the biotech products that are not transferring and we will apply it to
> the licensed products that remain in CBER, the traditional biologics.
>
> We have to date, and I haven\'t got all of the wonderful statistics
> that Justina had on what we have received, but we have received, in
> complete CTD format, fewer than ten new applications or supplements. I
> don\'t have any numbers on how many partial CTD submissions we have
> gotten.
>
> One of the difficulties in assessing this is that we have not actually
> gotten a CTD in paper. All of these have been fitted into our current
> electronic BLA submission paradigm. They have all come in
> electronically. Had they been printed out, they would have been nice
> paper CTDs. But they don\'t actually take a true CTD format because
> they are fit into the current eBLA submission approach.
>
> Now, as the eCTD becomes available, we expect that those will be
> submitted in the proper eCTD format and we will begin to gain
> experience with that.
>
> So that is where we are with implementation of the CTD in the Center
> for Biologics. I would happy to entertain any questions.
>
> MS. GAWRYLEWSKI: Helle Gawrylewski, J&JPRD. You both mentioned that
> the comment period for the general considerations document was closed
> but Justina intimated that comments would still be accepted. Is that
> true both for CBER and CDER? What would be the window of opportunity
> to submit additional comments?
>
> YETTER: As a fact of the good guidance practices, you may comment on
> any guidance document at any time.
>
> MS. SHOWALTER: Thank you, Bob. Next on the agenda, Christelle is going
> to give you just a few brief comments about what we have learned that
> is happening in the other regions with respect to the Common Technical
> Document.
>
> **Other Regional Perspectives**
>
> MS. ANQUEZ: I will give you a brief update on the CTD implementation
> that we authorize in the three regions, Europe, Japan and Canada. I
> don\'t have slides for this. I\'m sorry.
>
> As you know, the three regions are getting ready for the July deadline
> which is the time when the CTD will be mandatory in Europe and Japan
> and strongly recommended in Canada.
>
> In Europe, they received twenty-six submissions using the CTD format
> of which sixteen are in full CTD format and six are in mixed CTD and
> old Europe dossier format.
>
> Among these twenty-six applications, there are six on biotech products
> and twenty-one on new chemical entities. Japan received sixteen
> submissions in CTD format, five for biologics and biotech products and
> eleven for chemical drugs. Among the submissions for chemical drugs,
> five were for already approved drugs, one for a combination process
> and five for new chemical entities, new drug applications.
>
> The Japanese have already had three meetings with JPMA, their
> pharmaceutical industry association, to explain how to compile CTD
> documents in April, 2003. Following this meeting, Matilda Bilieu is
> planning to publish within the next month a notification about the
> revised CTD guideline document as well as a Q&A document which
> contains Q&A agreed on in the ICH meeting in Tokyo in February.
>
> In Canada, they have been very actively preparing for the July 1
> deadline, as you will see. They received sixty submissions in CTD
> format, fifty for chemical entities of which thirteen were for new
> drug submissions, twelve for supplemental new drug submissions and
> twenty-three for abbreviated submissions.
>
> The ten remaining concerned biologics and radiopharmaceuticals. Health
> Canada had two sessions with industry in late April and, following
> these, they revised a number of guidances. They revised the general
> filing guidance to take into account the most recent ICH decisions and
> guidance. They also prepared a revised guidance on the filing of
> bioequivalence studies in the CTD format that includes a description
> of how such information should be filed within the E3 framework. They
> should permit the use of the clinical-study report for general
> application.
>
> Health Canada also prepares quality guidances to assist sponsors in
> the filing of applications for vaccines, conventional biologics and
> blood products. A similar guidance is also near completion for
> radiopharmaceuticals. They also revised the drug guidance on biotech
> products.
>
> All these guidances will remain as drafts until the fall. This will
> allow them to incorporate other amendments following up the
> discussions which will occur in Brussels.
>
> The notice and all these accompanying document guidances will be
> posted by next Friday on the Health Canada website. Lastly, the
> original Q&A will be published in conjunction with the ICH CTD Q&A
> after the Brussels meeting.
>
> Thank you.
>
> MS. SHOWALTER: Thank you, Christelle.
>
> The next presentation will be on the eCTD and Tim Mahoney is going to
> provide that.
>
> **eCTD**
>
> MR. MAHONEY: Good morning. Thank you for coming to sunny Washington,
> D.C. Every day is sunny here\--at least today is, anyway. I am here to
> talk about the eCTD. We have been pretty busy in the FDA and in the
> eCTD Implementation Working Group because we are now an implementation
> working group. We are not just an expert working group. So we are
> working on implementing the eCTD in the three regions.
>
> I am going to focus primarily on what we are doing in the FDA in the
> U.S. but let you know what we are going to talk about in a few weeks
> in Brussels.
>
> I am not sure of your background, what you know about the eCTD. Are
> you familiar with it? I started to become familiar with it in August
> and there are a lot of acronyms; eCTD, CTD, ICH, ETB, all those
> different things. I don\'t know what your background is. So I will
> explain the eCTD a little bit.
>
> There has been some mention of, and Justina mentioned, CTDs coming in
> with some electronic components. There is a very clear distinction
> between the ICH eCTD and an electronic eCTD. They are not the same.
> They are very, very different so we need a way to view eCTDs. I am
> going to tell you how we will do that and when as well as the next
> steps for both the FDA and ICH eCTD IWG and where you can get more
> infection.
>
> The eCTD is an ICH specification, obviously. This is an ICH public
> meeting. To be implemented in the U.S., EU, Japan as well as Health
> Canada has a very strong interest in implementing the eCTD and
> harmonizing with the FDA. It is not a content function. The eCTD IWG
> doesn\'t address content. We take the CTD and transfer it
> electronically from applicant to regulator so we are not a content
> group.
>
> But what it does for the FDA and for the other regions is it provides
> first and foremost a cumulative view, a table-of-contents view, rather
> than the folder-file structure that you may be familiar submitting in
> the U.S. This will be a cumulative view so, as your submissions come
> in for an overall market application, a cumulative view will be built.
> And it is consistent.
>
> That was addressed a little bit earlier, but it is the same table of
> contents and the eCTD is not flexible at all. There are rules to
> submitting an eCTD, not FDA rules but technology rules. So you have to
> follow what is called the document-type definition in order for this
> to work. But what it will also provide is a consistent table of
> contents for both you building it and our reviewers reviewing it for
> INDs, NDAs, BLAs, ANDAs, DDMAC promotional material and everything, if
> you have read the draft U.S. Module 1, all the different components in
> there.
>
> So you will be doing the same thing. Our reviewer will be looking for
> the same information across all these different types of marketing
> applications. Its components mirror the CTD. It is actually taken
> directly from it. Module 1 is defined in each region. The U.S. has a
> draft Module 1 ready to go. Modules 2 through 5, their content is
> defined in ICH. So, for those of you were not quite familiar with the
> eCTD, hopefully that helps a little bit. How is the FDA going to let
> you know what we are doing here? A lot of the eCTD specification
> leaves things open to regional guidance. It really wasn\'t that we
> were running out of time in the working group and said, \"We will just
> regional guidance.\" It was really that there are distinctions.
> Justina made a really good point. This is not a global submission but
> it is a common format for submitting in the three regions.
>
> Some of those things, especially when you take PDF files and use them
> in Japan, there are distinct differences. So there are going to be
> some differences across the regions but the technology is the same.
>
> The FDA has released eCTD specifications. They support a
> soon-to-be-published eCTD guidance. You may have recently seen an eCTD
> guidance and that was really just the local publication of the Step 4
> eCTD specification. But this week, as a matter of fact yesterday, on
> the website you see up there, www.fda.gov/cder/regulatory/ersr, we
> published a series of specifications that fill in the technical blanks
> for eCTD implementation in the U.S., particularly Module 1. It is not
> just a document-type definition file. It is a narrative.
>
> Modules 2 through 5, study reports, which is an interesting topic, one
> that we have sort of bounced around in ICH. The Step-4 eCTD
> specification was signed and then we received comments that it really
> doesn\'t provide the structure for study reports that the CTD
> references. So we have had some debates and some good conversations
> and some harmonization in the eCTD IWG.
>
> That has resulted so far in what is called the study tag-in file which
> is a way for you to follow the eCTD Step-4 specification as well as
> provide the granularity in the structure that we need for those study
> reports.
>
> XML is the technology you use to create and eCTD. If any of you here
> are not coders or developers, then you have absolutely no need to
> understand XML. You are not going to have to. But what they call it is
> human-readable XML. I don\'t know if that is really the case. If you
> have ever tried to read XML, you are still human but it is not as
> readable.
>
> So we have a real human readable overall FDA eCTD table of contents
> published on there as well. And we welcome comments. Now, the draft
> guidance is making its way, per our good guidance practices, through
> the different centers affected. This is a combined CBER-CDER project,
> as Dr. Yetter mentioned. But these specifications can help
> particularly the technical folks that are going to help you prepare an
> eCTD.
>
> These are all posed on a website that gives suggestions for the steps
> to submit in an eCTD. Step 1 is to read all of that. Then, when you
> are done in October reading all that, get back to us and let us know
> when you are planning an eCTD. The technology is new. It is new for
> you. It is new for the FDA so we want to make sure that there is a
> good dialogue going.
>
> The esub e-mail that Justina mentioned is the place to go. Let them
> know exactly when so we can prepare on our end getting the training in
> place for reviewers and also getting ready to test your sample and
> make sure that it will display the way you want for the reviewers.
>
> It won\'t be a real labor-intensive process. It will be just
> exchanging small files for any of the quick tests and getting back to
> you saying, \"Hey; everything looks okay,\" when we are finally done.
> Then you will be ready to submit.
>
> I will leave this up for a moment so you can write that down. This is
> part of the U.S. Module 1 DTD, document type definition. It is pretty
> clear with the leaf content in there. Up to this point, a lot of
> concentration has been on the XML. That really shouldn\'t be the case.
> That should be left to the technical folks. It is, what does the XML
> do. Here is more of that U.S. Module 1.
>
> Building that cumulative table-of-contents view, giving us the ability
> for life-cycle management to reference across different submissions.
> That is what you need to know about the XML. You don\'t need to know
> what an href or what a leaf\--well, a leaf, you may. But you don\'t
> have to know XML, just the ability it gives both you and us. That is
> why this is important to you.
>
> This isn\'t just going to help our reviewers, but if you can archive
> and store and generate your information standard across many different
> application types and then across many different regions, that initial
> up-front investment will return pretty quickly to you.
>
> A little bit better, a little more human readable description of the
> U.S. Module 1 for the eCTD contains this information. I won\'t run
> through the entire list because the information is up on the web and
> you can take your time and disseminate it.
>
> But there is a good bit of information. And it does allow for
> submitting electronic INDs. Particularly CBER has had an electronic
> IND guidance out there but CDER has been waiting for the eCTD. And it
> is finally here.
>
> So how are we going to view these, all that gobbledegook you saw on
> the U.S. Module 1 there? What we are using to start off with is an
> internally developed system called the eCTD Viewer System. It is a
> combined CDER-CBER project. If you remember Dr. Levin, particularly
> John Clark, Nike Ya, several years ago presented the Cumulative Table
> of Contents Viewer. It was really a few chemists were trying to solve
> a need, that cumulative view need.
>
> That is the prototype that we built the system on so it looks a lot
> like it but it is meant for production across the two centers. It is
> built by reviewers. I work in an IT shop and content is something I
> don\'t know much about when it comes to the science of what we do at
> the FDA. How they want to view it, also, I wouldn\'t know much about.
> So reviewers build the system. They define the prototype and the
> production system. We just take care of the technical end.
>
> They approve all change requests or a configuration-control board. So
> they are actively involved. They are also part of our outreach plan,
> so we are going around to the particular divisions right now from
> those CCB members presenting the viewer.
>
> The initial functions we are going to have in the FDA, all of the
> things I mentioned about the eCTD that it will let us do, we would
> develop over time. Some of them we need to gain more experience on,
> but view, navigate and download. The system is in production. It
> works. It is in both CDER and CBER. If an eCTD were to be submitted
> today, and it was created correctly, we could process it and view it
> in each center. Technically, we are ready.
>
> We spend a lot of time going through requirements gathering, doing use
> cases and all these other different methodologies you may not be
> familiar with. We also identified additional requirements that really
> we need a little more time with the eCTD to develop, particularly,
> preferences, quick access to an area of an eCTD, searching and book
> marking.
>
> A lot of that is going to be CTD as well as eCTD education, so as we
> get experience with them, we will add that functionality. So what do
> we need? We need guidance and we need specifications. The draft
> guidance is ready for internal sign-off and the specifications are
> posted. So we can almost check that one off.
>
> We need a system. That one is installed and being configured. We can
> check that off. And we need outreach. We need to let everyone know how
> to do this. We are in the middle of that. We are supporting internally
> our reviewers, those that support the reviewers and the technical
> staff. We are working with Dr. Levin\'s Office of Information
> Management to provide just-in-time training.
>
> So, when you let us know you are submitting an eCTD, we will guarantee
> that the reviewers are trained. If you don\'t let us know, we can\'t
> guarantee that. So training is a big part of the internal and external
> as well. And then maintaining the system.
>
> So what we are doing now; we have a couple of small change requests on
> the system but we are doing a lot of outreach. Presentations to
> divisions\--and they have been very positive. Even those reviewers
> that really hold on to paper and don\'t want to let it go see the
> power that the eCTD provides them with that first cumulative
> table-of-contents view. It is really a tradeoff, and it is a good
> tradeoff to the eCTD.
>
> We are preparing for eCTD. I already went over these steps. We are
> going to watch this. We are going to maintain both the eCTD
> specification in ICH and our system internally at the FDA. Part of
> that is the next meeting in a few weeks. The agenda in change control.
> Technology cannot remain static.
>
> You may be familiar with a word called \"shelfware.\" So you spend a
> lot of time and they spent years developing the ICH. If there is no
> process in place to control change, it become obsolete. Really, none
> of that existed in ICH. So, after Step 4, the first thing we did was
> develop a change-control process.
>
> A lot of technology is guessing until you start implementing. Then it
> is going to change. So we need a way to prioritize, first accept, then
> prioritize and address change requests. One of the first one is that
> study report. That will be one of the first things we talk about,
> showing our examples in the U.S. with the study tag-in file.
>
> There may be a different future down the line for study reports in the
> eCTD but, for now, the study tag-in file is the way the FDA is going.
> We are releasing a comment style sheet for those that don\'t have
> eCTD-viewing software. It is very similar to a web browser. It
> provides the content and will give you a common view between the
> regulator and applicant.
>
> So the FDA has created it. We took the burden on ourselves to create
> it and will present it with our partners\' approval to the steering
> committee next month.
>
> Another thing we need to think about are DTT releases. Those of you
> here from software developers, this is of particular importance to
> you. One thing that our PhRMA partners that we work on, they get
> nervous with every meeting because they don\'t quite know what is
> going to happen. If there is an industry out there building eCTD
> software, we can\'t do that, too. So we are going to talk about
> scheduled releases of DTT changes as they reflect changes in content
> to the CTD or changes in technology.
>
> We are also the M2 expert working group. As that, we have been tasked
> to look at technology. Recommendations we have made in the past, which
> are outdated, include media types. Then we need to confirm our ICH-6
> topics and speakers.
>
> So what we are going to do at the FDA, we are going to be future
> versions of the eCTD viewer. We are not a software development company
> in the FDA. So, if someone else is out there doing it better, cheaper,
> faster, we will take a look at it. So part of that is doing
> alternatives analysis on those commercial products that can be used to
> meet our needs for viewing and processing eCTDs.
>
> For those of you who would like to see what we are doing, we are going
> to put it out there this summer. We will post our eCTD viewer and
> related documentation and you can do whatever you want with it, except
> complain about the way it was developed over and over again. So, we
> won\'t be able to trouble shoot if you want to install it in your own
> environment, but we have pretty good documentation. It is all CMM
> Level-3 documentation. So you should be able to do it.
>
> More information; esub@cder.fda.gov. That is a great place to go.
> Really, if you send me an e-mail, I am about 348 behind so get in
> line. But esub always responds. Part of our change-control process in
> ICH is filling out change-request forms. If you notice something wrong
> with the eCTD specification, something is missing or even if you have
> a general question, in the CTD page, along with the eCTD
> specification, is a change-request form as well as those change
> requests that we have already identified.
>
> So, if you see something up there already, we are working on it and we
> will get to it as soon as we can. If you have any from the U.S. that
> you want to send, you can send them directly to me at that e-mail. I
> will do them quickly if you are trying to make the July meeting, as
> within the next hour.
>
> So thank you for your time. Can I ask are there questions? What are
> your questions before I step down?
>
> MS. GAWRYLEWSKI: Helle Gawrylewski, J&JPRD. I have a question about
> the study-tagging files. So FDA has a proposal and you are taking it
> to the M2 expert working group. I understand there will be some
> discussing and arguing about that specific element of the eCTD
> proposal. What is the mechanism to propose alternative ways of doing
> this study-tagging at this point, realistic mechanisms?
>
> My second question is when did you post all of this at the website
> because I looked yesterday and I didn\'t see anything new. Was it
> late?
>
> MR. MAHONEY: It was late.
>
> MS. GAWRYLEWSKI: It was late?
>
> MR. MAHONEY: Late for us in the government. It was about 3:30. That is
> a good question. The study-tagging file, the good thing about our
> change-control process that I mentioned is we don\'t argue. We do
> discuss, though. Arguments really go nowhere so we needed a process to
> disseminate information.
>
> There was a fact. The FDA needed a level structure. There is a sample
> up there now. Our original proposal has been up there for a while for
> study reports. It has been up on the ICH website next to the eCTD
> specification. Including that in the backbone, we couldn\'t get
> consensus in February, or even before February and we did a lot of
> work.
>
> So the options were limited. It was the FDA will either bring
> this\--is this an ICH topic or is it regional? If it is regional, we
> will go off and we will figure out the best way to do it without
> breaking the specification we agreed to.
>
> But we wanted to keep it in ICH because we understand, the technology
> has a ripple effect and you can\'t just go off and do whatever you
> want. So we keep bringing it to ICH. What we found in February was
> that the JPMA folks had a solution that worked. We had consensus from
> the group as part of our change-request process. I wish I had brought
> the diagram, but it shows there are two different ways that a change
> request is deferred. One is just because we didn\'t have the time. The
> other is because we need more information.
>
> The study-tagging file is one of those where we need more information
> about it. So the FDA is implementing this study-tagging file solution
> in the U.S. As far as the ICH goes, we will report at each meeting but
> if someone wants to bring up the request, which they have, of
> including this information in the eCTD backbone, we will listen but I
> don\'t know if it is going to be our argument anymore because we have
> gone down that path already.
>
> So when the other five partners are ready, then we will move to put it
> into the backbone. But we have given them about all the information
> they need. But, if you have alternative recommendations, we would love
> to hear them. The last thing you want to do in technology is be
> closed. So you can feel free to send those directly to me. And it is
> never too late.
>
> Thank you.
>
> MR. JERUSSI: Robert Jerussi from Jerussi Consulting. I have a general
> question, not just on the eCTD but any CTD. Since it is a voluntary
> submission in the United States, do you really see a lot of companies
> submitting it? I mean, as a consultant, the question I get, should we
> submit an application in a CTD format. And I say, \"Well, it is not
> required.\"
>
> The other thing I say is it requires you to submit more information,
> and a lot more. A pharmaceutical development report for both the drug
> substance and for the drug product, a summary section which allows
> importation from other sections of Module 3. So those are a couple of
> things that are required; in other words, it is more information.
>
> Why would a firm voluntarily submit that? To give you an example,
> there is a drug-product guidance out now. I think the comments are due
> by the end of this week, seven-and-a-half pages of it. 14 percent is
> devoted to pharmaceutical development documents.
>
> Why would a firm want to submit that and expose themselves to any
> number of questions? So I ask, am I all wet? Have I missed the boat?
> Is the CTD easier or does it really require more information, require
> companies to subject themselves to a greater scrutiny at the
> headquarters because development documents were always required, but
> they were at the plant and the investigators would look at them.
>
> So it is not just for you. It is for anybody.
>
> MR. MAHONEY: I can, I think, tackle all of that. No; I can tackle the
> eCTD part of it. You haven\'t missed the boat but the horn is sounding
> on the eCTD. That is a great question; why would you do it.
>
> My question is why wouldn\'t you? Why would you take the time to have
> an infrastructure that supports three different technologies in three
> different regions or spend the time in investing, on building a
> submission in an electronic format that is not consistent?
>
> So, for the electronic part of the eCTD, you can develop your
> infrastructure. I know the FDA has pretty good IT costs. They are not
> skyrocketing but I know, from talking to my counterparts in PhRMA,
> that their IT costs are astronomical. They want the eCTD because then
> they build one infrastructure that supports one way to submit for
> INDS, ANDAs, NDAs, BLAs and the FDA as well as the other regions. So
> it is consistency.
>
> Everything is called this, this, this and this every time. So that is
> the benefit electronically. I will pass off the scientific contents to
> some of the other experts here for the answer on that one.
>
> YETTER: Do we expect the industry to submit in CTD format? Yes; I
> think that the industry is going to. I think there are benefits to the
> industry. The benefits that we perceive for CBER, I think, are
> benefits that also pertain to the industry as well. Does the CTD
> actually require more information than would be required in an NDA or
> a BLA? Not really.
>
> One of the things that you are seeing is the evolution of regulatory
> process. There is not more information being requested. It may be
> organized differently. It may not look like what you are used to
> seeing. But I don\'t believe it is really requesting more information,
> to a great extent.
>
> We would be happy to entertain comments to that extent on any of the
> guidance documents that you see or even in fora like this. But, right
> now, we are in the process of revising some of our CMC documents to
> conform to CTD. We don\'t see ourselves increasing the amount of
> information we are asking for.
>
> We are asking you to put it in a particular place, but we are not
> asking you to duplicate things. In fact, if anything, this will allow
> us to decrease needless duplication much the way we achieved when we
> eliminated the establishment license application.
>
> MS. MOLZON: Just to repeat what Bob said. All we are asking to be
> submitted is an NDA in CTD format. Dr. Jerussi knows that ICH is a
> joint initiative between regulators and industry and the working
> groups involve industry as well as regulators. Industry proposed the
> common technical document and had to go through a number of
> feasibility studies before the regulator would even take the topic up.
>
> In the discussions, there is a consensus on these topics so industry
> is at the table negotiating these. Then, when consensus is reached,
> the document is published for comment and it goes through the ICH
> process. So industry helped develop these documents, Dr. Jerussi, so I
> am having a difficult time understanding why you are saying why would
> industry do this when they are the ones that proposed this to begin
> with.
>
> MR. JERUSSI: I was not present at that meeting, the mid-May DIA
> meeting, which spoke about this business of the pharmaceutical
> development report. But, according to the trade press, a number of
> company representatives, and I don\'t know whether they were generic
> or PhRMA companies, got up and voiced strong objection to submitting
> that kind of information in a document.
>
> So it is not just my thought. There are people in the industry who are
> saying, \"Why does FDA want a pharmaceutical development report for
> the API for the drug product, which is new\--this was never required
> in an NDA. I don\'t know about BLAs. Not only that, there is even more
> to it than that. It is the whole business of how did you develop this?
> What difference does it make how a company develops something as long
> as they developed it.
>
> It has to be the drug that meets the requirements of the agency, is
> efficacious, is safe. It doesn\'t really make any difference how they
> developed it.
>
> Now, the industry may find this but I don\'t know\--when I was
> involved with ICH, the generic-drug industry was left out. They got
> saddled with a number of requirements. Now, I know they are observers,
> I believe, now. But I don\'t know if they are really in on this. But I
> do get these questions.
>
> MS. SHOWALTER: Actually, I think we are sort of moving from the strict
> CTD response to we are now sort of getting into the area that I talked
> about at the beginning with respect to the GMP, the drug
> product-quality program. So we are kind of blurring the lines a little
> bit here, which is okay because I think this is sort of how the
> discussion is evolving. But we are getting into some uncharted
> territory a little bit.
>
> I think what Justina and Bob correctly are referring to is the fact
> that\--and they have correctly characterized what we have done with
> the CTD and how it came to pass and so forth. When you start talking
> about pharmaceutical development, one of the things I mentioned is
> that is probably going to be endorsed as an ICH topic at the meeting
> in Brussels.
>
> It really relates back to the GMP part of the ICH program. I think
> that the discussion is going to emerge probably along the lines that,
> if we are talking about implementing a quality-systems approach to GMP
> and product quality oversight, then I think the tendency is going to
> be that we are going to have to have additional data going into that
> to understand that a quality-system approach is in place.
>
> So now you are sort of moving into this other conversation about
> assurance. It really doesn\'t have much to do with the CTD except if
> we make some changes in terms of taking on the pharmaceutical
> development and what the different requirements are in the various
> regions. That, of course, will impact, potentially, the CTD down the
> road. So it could be that there will be other additional requirements.
> There will be other ICH topics that may have to be reopened and looked
> at.
>
> So things will be potentially revisited. Will this lead to some
> additional requirements? Perhaps, but I think a part of it is a little
> bit of a balancing act. If we are looking more in terms of information
> transfer and what we see, a lot of that reassurance that is going to
> come front-end versus what we do on the inspection side and how the
> two relate together, all of that has to be worked out.
>
> I don\'t think anybody can predict right now what that is going to do
> overall to whatever requirements, whatever guidelines, et cetera, may
> well be in place. We would all just be speculating at that point.
>
> In terms of the narrow scope of the question and what is in the CTD, I
> think that part has been answered very accurately and correctly. Then
> you segue into things that are somewhat unknown at this point that
> have a lot to do with pharmaceutical development, with what additional
> things might be required in support of a GMP drug-product-quality
> approach that really is more of a quality-systems, risk-management,
> risk-assessment type of approach.
>
> That is sort of the long answer, but you are right on target with
> where the thinking is tending to evolve. Of course, comments are very
> welcome in that area.
>
> MR. MILLER: Loren Miller, PPD. I was interested in one slide that was
> presented where it was stated that the Common Technical Document was
> not considered a global dossier. I am not so sure industry didn\'t
> expect that, though, at the beginning when all this started out, that
> potentially a global dossier was possible.
>
> In fact, I remember when all this started that, in fact, many people
> in regulatory affairs had that expectation. I seems to me, though,
> that with all the different modules and all the add-ons required by
> different countries, and a good example is the ISE-ISS controversy
> within FDA relative to what the document outlines now.
>
> If you have ever had to write up one of these things and then you have
> to write it up two or three different ways for different countries, it
> is complicated. It is about as complicated as filing independent
> applications. So I think industry is hopeful that there would be some
> advantage on the harmonization side so that wouldn\'t need to be done.
>
> MS. SHOWALTER: I am not sure there really is a response to that, but
> the only thing that I would say is that when the initiative was
> undertaken, I think that the regulatory authorities realized the
> challenges that would be involved, and that is why we did spend a
> number of years in the feasibility phase because it is a little more
> complicated than to just say it is strictly a format because we also
> understood that the way that the format got constructed has an impact
> on the content as well and the way that the application is separated
> and reviewed within a regulatory authority, et cetera.
>
> So I think we do understand that it is more complicated than that. I
> think we also understand the goal, ultimately, might be to have
> something that is more akin to a global dossier. But we have got to
> start somewhere. All the comments that I have heard, basically, are
> that this is a pretty good starting point.
>
> With a little ability to undertake those challenges, you can, at
> least, submit a package that works in each of the regions. Part of the
> feasibility study at the beginning was that we knew companies were
> already doing this as well. There have been some test cases where they
> didn\'t say they were doing that, but, at various DIA meetings and so
> forth, companies would get up and report on the fact that they had
> achieved success already in doing this.
>
> So I think all we can say right now is that it is a reasonable
> starting point. It is a good thing, conceivably, for the industry,
> also for the regulatory authority, to have some sort of standard
> format to look at. It kind of takes you into the next wave of doing
> templates for reviewers and things where I think everybody agrees
> there is a lot more consistency.
>
> So it is an evolving art form, I think it is fair to say.
>
> Thank you, Tim. In order to get us back on schedule a little bit for
> some of the people who are here from the outside, I think what I would
> like to do, Justina, with your permission, is move the QT prolongation
> to the end so we could pick up, after Helle Gawrylewski\'s
> presentation, with the pharmacovigilance section.
>
> The meeting allows the opportunity for outside speakers. We did have a
> request for an outside talk. This will be provided by a representative
> of a DIA committee that looks at the work that is being done on the
> CTD. I will let them introduce themselves and provide the
> presentation.
>
> **Presentation**
>
> MS. GAWRYLEWSKI: Good morning. My name is Helle Gawrylewski. I am
> Co-Chairman of the Drug Information Association\'s Medical Writing
> Special Interest Community, SIAC, Standards Subcommittee. With me is
> Barbara Kamm and also Sandy Heckler. Barbara is Medical Writing
> Projects Manager at Allogen, but our comments do not reflect any
> official opinion of our respective companies or affiliates.
>
> We are here on behalf of the DIA Medical Writing SIAC Standards
> Subcommittee and our basing these comments on several surveys, a
> roundtable discussion and several other team meetings within our
> group. We discovered that there are some misunderstandings about the
> ICH E3 Guidance on the format and content of clinical-study reports.
> So we recommend that the ICH Steering Committee consider reopening the
> guidance for some clarification and refinement.
>
> Since its inception in 1990, various ICH working groups have
> successfully harmonized over 50 guidances that have measurably
> instituted time-saving and cost-saving effects on drug development.
>
> The ICH E3 Guidance was one of the first major efforts to harmonize
> the very building block of a drug submission or marketing application
> in U.S., Europe and Japan. This particular working group should be
> commended for completing this difficult task because the spirit of
> global harmonization is a commitment we see widely supported today but
> that was not the case at the time this guidance was developed.
>
> We are not requesting major changes or revisions but recent
> developments motivate the request for refinements. Specifically
> good-guidance practices are in place now and we request that the E3
> guidance be evaluated for consistency and clarity and also because of
> the eCTD standards that DTT and the study report tagging system
> proposed by the FDA has caused some confusion, although I have not
> seen the details specifically on the website, we have heard some of
> the details.
>
> So, in our surveys and questioning, we found that the writers in the
> pharmaceutical industry, whether working for large or small PhRMA or
> independent for CROs can interpret the guidance section numbering in
> two very different ways. Some consider the numbering to be a template
> to be followed exactly while others consider the numbering system to
> be simply that of the guidance and not applicable to the CSR, which is
> the clinical study report.
>
> Internal QA auditors are also interpreting the guidance numbering and
> section content literally and they interpret it almost carrying to
> weight of law even though the level of flexibility is clearly
> discussed in the introduction of the E3. The message really isn\'t
> getting through.
>
> Thus, we recommend a clarifying statement be issued about the extent
> to which these numbers should be followed and we recommend flexibility
> in the numbering scheme as long as the elements are present.
>
> According to the ECD-CTD study report granularity document, apparently
> the appendix numbers are recommended to be exactly the numbers used in
> the E3 guidance as file names; for example, 16.1, 16.1.1 and 16.1.2.
> We recommend a simpler system of sequential numbering, 1, 2, 3, 4, 5,
> 6. There is really no need to consider the appendices as part of the
> report document. The separate granules that are recommended now are
> the synopsis, the report body and we are also recommending a separate
> granule for the study-supporting documents, the summary tables and the
> listing because these are generated by SAS. Then each appendix has a
> separate file, a separate tagging file after that.
>
> Also some optional appendices should be allowed for unforeseen special
> reports. I know that the numbering, once it becomes specified in the
> eCTD, will be unchangeable so we are concerned about that being the
> case.
>
> Other issues to address with the E3 guidance is the need to include
> some explanatory information about the contents of the recommended
> appendices and the inclusion of a location for data not mentioned
> specifically in the guidance at this time; for example,
> pharmacoeconomics, health outcomes and pharmacogenetics and genomics.
> These are new and increasingly included as endpoints in studies, yet
> they do not have a specific location in the CSRs.
>
> Some types of information are mentioned in several sections and this
> could lead to some duplication, so we would recommend, for example,
> that statistical methods and statistical issues be placed together in
> a single section. Right now, they are spread in multiple sections.
>
> For signatures and approvals, it should be possible to incorporate the
> sponsor\'s medical officer signature in a report appendix and
> hyperlink to signatures required regionally in Module 1 or place all
> signatures in Module 1 with just a placeholder in CRSs. More clarity
> on this issue and in the CTD recommendations would be welcome.
>
> the final point is that if essential documents are maintained in the
> trial masterfile according to GCP recommendations and are available at
> all times for reference if requested, what would be the streamlined
> list of documents essential for review and interpretation of study
> data.
>
> For example, one appendix requires documentation of interlaboratory
> standardization methods and quality-assurance procedures. Some
> companies have interpreted this to mean inclusion of all laboratory
> manuals for routine laboratory tests.
>
> For accredited laboratories, this represents an extra cost in
> resources, both human and paper, in scanning the voluminous documents
> that this would entail, documents that a reviewer might not need and
> might not even want. So, in an effort to supply what the reviewers do
> need and to avoid the extra costs in time for industry, could more
> explanatory texts be added to the required appendices and some
> appendices actually deleted altogether if the data have not proven
> useful.
>
> This would be an ideal time to review that because, once these eCTD
> specifications go into effect, these appendices are there forever and
> if there is unclarity about the content of these appendices, it will
> lead to some difficulties later on.
>
> According to Commissioner McClellan\'s recent statements at the DIA
> conference, we need to perform efficient global risk management,
> provide clear guidances and use the best science available for
> creating a standard set of rules to reach our policy goals in the
> least burdensome way. Large PhRMA has had the experience to use this
> least-burdensome approach but smaller companies are struggling.
>
> So the details of some minor issues that might add to the clarity of
> this valuable document will be provided for the record as a starting
> point for consideration. I have some details but I don\'t want to read
> all of that into the record now.
>
> In conclusion, our recommendations for reevaluation of the ICH E3
> guidance include the structure and numbering of sections, specific
> guidance on the contents of the key appendices, duplication of
> information in more than one section, eliminating that and adding some
> missing locations for other types of information, and clarity on
> signatures and placement options for signatures.
>
> A Q&A area on the ICH website with harmonized responses and
> clarifications similar to the CTD Q&A area would work well for some of
> the more minor areas.
>
> Respectfully, Helle Gawrylewski and Barbara Kamm. Thanks very much for
> listening.
>
> MS. SHOWALTER: Thank you.
>
> We are quite a ways behind schedule, I understand. If we could do a
> little bit of a shifting of the agenda and take up the
> pharmacovigilance topics next. The first speaker under that section
> would be to talk about MedDRA MSSO and then we will proceed with E2D
> after that, E2E, and then we will come back to E14, a Q-T prolongation
> topic.
>
> **Pharmacovigilance**
>
> **MedDRA**
>
> MR. REVELLE: First I would like to thank the FDA for inviting us here
> to speak. It is a good opportunity, I think, for us to at least give a
> little update on MedDRA and about some of the activities that we are
> going forward with.
>
> I will give a little bit of an intro about MedDRA so you will get a
> sense of what I am talking about but I think MedDRA actually
> represents a ICH success story. It has come through the whole ICH
> process out of the M1 Expert Working Group and is now actually in wide
> use in the pharmaceutical industry. I will talk a little more about
> some of the other related sort of issues.
>
> So what are the objectives of MedDRA? It is to provide an
> international multilingual medical terminology really to be used
> across the full spectrum, from clinical-trial drug development through
> postmarket reporting. The real goal, I think, or one of the several
> goals is to have standardized communication not only just from
> industry to regulators but between industry, themselves. They have
> actually found it to be very useful tool, especially during this
> consolidation period within industry, itself.
>
> MedDRA has a pretty wide scope and it is fairly different than some of
> the terminologies that we are replacing. It goes, obviously, across
> adverse events, but medical history, physician examinations, medical
> and surgical procedures, laboratory tests, just to give you the sense
> of the spectrum.
>
> In fact, I think this next slide is the listing of all of the
> top-level what we call system-organ classes in MedDRA to give a sense
> of the scope of the areas covered within the medical terminology.
>
> I work for an organization called the MedDRA Maintenance and Support
> Services Organization which is really tasked to do a couple of
> different things, the first of which is to maintain and continue the
> development of MedDRA through an international change-request process.
> So, as you subscribe to MedDRA, you have the rights to be able to
> submit change requests and then you receive MedDRA on a twice-a-year
> basis at this point.
>
> Our other goal is, obviously, to foster MedDRA use worldwide through
> communication, education and some services that we provide.
>
> That is a very quick introduction to MedDRA and, hopefully, it filled
> in a little bit of gaps for you if you have those. I am going to talk
> about a couple of different issues that are significant, at least in
> the MedDRA world right now. We started a process called a MedDRA
> blue-ribbon panel. As you may be aware, MedDRA, or the MSSO, started
> the maintenance of MedDRA in November of 1998.
>
> Initially, the process of maintenance was relatively simple because,
> while MedDRA was very well-developed by the time we got it, there were
> still some areas that needed some work. So, to fill those holes, at
> that point in time, was relatively simple.
>
> More recently, the task of maintenance has been more complex and the
> number and the types of changes that we are getting are much more
> granular and much more fine in their distinction between existing
> terms. We are also trying to balance between the development and the
> growth of the terminology versus the value of that growth to the
> subscribers and users of the terminology.
>
> So, as a part of that, we are trying to implore the users to provide
> more rationale for changes so we don\'t just automatically include
> every change that we receive.
>
> To aid in this process, we have worked with our management board which
> consists of both regulators and industry to come up with this concept
> of the blue-ribbon panel to give us additional input for guidance and
> policy regarding the types of changes we should consider and continue
> to consider for MedDRA.
>
> So we talked about things regarding the general scope and specificity
> of MedDRA as well as to support the consistency of maintenance
> activities. Quite honestly, our biggest concern is to make sure that
> we are consistent in what we include or exclude through the life of
> the maintenance of MedDRA.
>
> The panelists reflected the makeup of the ICH so we had regulators as
> a part of the panel as well as industry representatives. We also
> included our subscribers as observers and, actually, they are really
> participants in the panel through questions and answers.
>
> The end result of this panel is for them to develop with really our
> assistance a series of recommendations that will provide to our
> management board before we will make them public, but the idea is,
> again, to refocus the efforts of the MSSO to make sure it is
> consistent with what the user community is looking for. After we get
> our management board approval about those recommendations, we will
> publish them on the MSSO website and, obviously, make it available to
> all of the users of MedDRA.
>
> We thought it was a great success, actually, for us to hold this
> blue-ribbon panel. We thought the format worked very well. So, as a
> result, we actually plan on continuing to have these blue-ribbon
> panels on other MedDRA-related topics and right now we are talking
> about about two per year.
>
> Another sort of an interest area in MedDRA is MedDRA is not only
> available, obviously, in English but part of our task is to maintain
> it in multiple languages. From the outset, MedDRA, from its earliest
> version that was delivered, Version 2.1, was available in English and
> in Japanese.
>
> Through the series of different releases, there have been other
> languages added including Spanish through the lowest level term level,
> which is the lowest level of detail in MedDRA. Other languages, like
> French, German, Portuguese have been translated but only through the
> preferred term level of MedDRA which is the next level up of detail,
> the lowest-level term, which I will get into, is somewhat problematic
> for some of the languages. Dutch is scheduled for release in September
> of 2003.
>
> One of the true values that we saw in even the developers of MedDRA
> and the M1 Expert Working Group saw was that each MedDRA term is
> assigned a unique MedDRA code so there is a possibility that you could
> code in one particular language and output in another based on the
> linkages of those codes. That works today. I will talk about some
> issues related to the translations next.
>
> Typically what it revolves around is the lowest-level term which tends
> to have some synonyms, some colloquial terms especially in English. I
> make an example here of edema, edema spelled both ways. MedDRA
> incorporates the English version, both the North American version of
> English that I speak as well as the British English that is spoken
> across the way.
>
> Obviously, that poses a question when you are performing translations,
> is how do you translate that to Spanish. How do you translate that to
> Japanese? Right now, unfortunately, some of the languages are handling
> that differently. So we are considering that as a potential next topic
> for a blue-ribbon panel because it could destroy some of the utility
> if we don\'t maintain a reasonable link of the translations between
> the different languages.
>
> One of the other major topics that we are working on is some efforts
> to coordinate our MedDRA maintenance with a CIOMS group that,
> interestingly enough, had independently come to the same conclusion
> that we had which MedDRA had gotten a wide acceptance and wide
> implementation for the codification of clinical-trial data or just
> clinical data in general.
>
> But, to extract data once it has been coded in MedDRA was starting to
> become somewhat of a more difficult task. So both the CIOMS group and
> the MSSO initiated two separate activities to try to address this. The
> CIOMS group started to develop a product called the standardized
> search queries and the MSSO was developing something called MedDRA
> Analytical Groupings.
>
> We started to notice that both of us were working on the same thing
> and thought it might be better if we combined our efforts. So what we
> have done is we now are working together on a single working group to
> develop what are\--of course, we had to come with a new acronym, our
> standardized MedDRA queries.
>
> During that process, we have held a series of different meetings to
> try to coordinate our efforts. They have developed a series of
> different SSQs. We developed a series of MAGs. We want to consolidate
> that effort.
>
> To give you a little bit more sense of what I might be talking about
> is an SMQ is a group of MedDRA terms that relate to a defined medical
> condition or area of interest. So it combines, say, the laboratory
> test, the diagnostic, the signs and symptoms all related to a very
> specific issue that you might be looking for.
>
> Then you could use that as kind of a stored query to go against your
> data to try to pull the cases of interest and make it a little more
> useful for you.
>
> Just to give you a sense of where we are going, you will see what are
> generally considered to be very interesting topics especially from the
> safety side, to be able to develop what are the terms in MedDRA that
> are relevant to these particular SMQs and then define that, distribute
> that to the users of MedDRA so they can start using that as a tool
> against their own database.
>
> They could also use it as a tool for communication against their own
> database. They could also use it as a tool for communication amongst
> themselves and we think eventually to regulators as well. I might make
> a note that a regulator is including the FDA, EMEA and others, who are
> all involved in the development of these SMQs and are very much
> interested in the outcome and the eventual product coming to fruition.
>
> You might notice that there are four of the SMQs that are asterisked.
> They will be coming out in the next version of MedDRA which is
> scheduled for release in September of this year.
>
> I will give you a little bit more of our plans for the SMQs. It is a
> two-year collaborative process that we have in mind right now with the
> CIOMS group. Obviously, MedDRA or the MSSO would continue to maintain
> these SMQs after that point, but at least this intensive effort with
> CIOMS would continue for the next two years.
>
> IFPMA would own the rights to these SMQs as they do with the rest of
> MedDRA. The MSSO will maintain and distribute with each MedDRA release
> so, as things change in MedDRA, we will either add new terms to an SMQ
> or, potentially, remove them. It is part of a standard MedDRA
> subscription so there is no additional cost associated with.
>
> Obviously, we need to develop additional documentation to make sure
> users of MedDRA will have some sense about what we are talking about.
>
> I mentioned before that the first set of SMQs will be scheduled for
> release this September. It will be part of the MSSOs change-request
> process so that the subscribers to MedDRA could also either identify
> additional SMQs to be developed or recommend changes for existing
> SMQs.
>
> With that, I will take any questions you have regarding MedDRA.
>
> MS. SHOWALTER: Thank you. Questions?
>
> MS. GAWRYLEWSKI: I have one quick question. Being part of industry,
> there is a heavy mention of industry involvement and regulator
> involvement. I am just assuming, and this is probably a really naive,
> stupid question, that practicing physicians in the private sector are
> also involved in developing this. It is not really mentioned very
> often or well-known. How are they involved, actually practicing
> physicians.
>
> MR. REVELLE: MedDRA is actually available through the GPRD which, I
> think, is a U.K.-based group that is trying to make terminologies
> available to regular practicing physicians. So we are looking at other
> groups to try to get MedDRA down to that level as well so they are not
> excluded from the process.
>
> The initial development, obviously, was for the pharmaceutical and
> biotechnology industry. But it is, I think, within our scope or at
> least in our intent to try to serve them as well.
>
> MS. SHOWALTER: Thank you.
>
> Now we will move on to the next talk which is Susan Lu is going to
> bring us up to date on E2D. That would be post-approval safety-data
> management.
>
> **E2D: Post Approval Safety Data Management**
>
> MS. LU: ICH E2D is a guideline of post-approval safety-data management
> and provides standard definitions and terms for key aspects of
> expedited reporting. This guidance is intended to help harmonize
> methods for gathering and evaluating safety data.
>
> This topic was adopted by ICH in February, 2002 and the working group
> has met previously three times since June of 2002. The former name for
> this guideline was V2, the second of three pharmacovigilance topics
> but, at the February meeting, the ICH Steering Committee renamed it
> E2D. The current status E2D is Step 1; that is, building consensus
> through discussions between regulators and industry for harmonization
> of concepts in postmarketing safety.
>
> E2D is an expansion of an existing E2A guidance which set standards
> for clinical-safety data management. E2D is similar in style and
> content to E2A and considers how those concepts can be applied to the
> postapproval phase. Relevant concepts and recommendations from the
> CIOMS-5 report on pharmacovigilance would be incorporated into this
> guideline.
>
> The title of the first three sections of the guideline are identical
> to those in E2A. There is a short introduction, a section on
> definitions and terminology associated with postapproval drug-safety
> experience and standards for expedited reporting.
>
> A fourth section on good case-management practice is a topic
> originating from CIOMS-5. The introduction section states the purpose
> of the guideline which is to establish an internationally standardized
> procedure in order to improve the quality of postapproval safety
> information, to harmonize the way to gather and report information.
> This guideline is based on concepts from E2A and although E2A
> standards and definitions have been applied by regulators and
> industry, there is a need to formalize this. Also, there is a need for
> definitions that are specific to the postapproval phase.
>
> The second section of the guideline is the definitions and terminology
> for postapproval drug-safety experience. This includes basic
> terminology, formally defined in E2A such as an adverse event, an
> adverse drug reaction. The criteria for seriousness and expectedness
> is also discussed. There are also new definitions that are not in E2A
> such as labelness, which refers to local product labeling, and
> listedness, which refers to the core-company datasheet.
>
> Class ADRs is also addressed in the premise that these are not
> automatically considered expected unless the labeling describes an
> event as occurring specifically with the product.
>
> Other definitions such as healthcare professionals and consumers, we
> really don\'t address these in U.S. regs but the working group felt
> that these are important to include because, outside of the U.S.,
> these reports are not considered valid unless there is confirmation by
> a healthcare professional.
>
> There is also an extensive section within the definitions and
> terminology that describes the sources of individual case reports.
> Most of these are described in the CIOMS-5 report.
>
> The third section of the guidance is standards for expedited reporting
> which addresses what should be reported. It states that single cases
> of serious unexpected adverse events is always subjected to expedited
> reporting. It also does describe some other cases such as lack of
> effect. These are generally not subject to expediting reporting except
> in certain circumstances where there is an exacerbation of disease or
> the product is used in the treatment of life-threatening disease.
>
> Drug-dependence type reports are also addressed and these are events
> that may qualify for expedited reporting of not associated with
> further adverse events unless it is described in the product labeling.
> In contrast, reports of overdose with no associated adverse outcome
> should not be reported as adverse drug reactions.
>
> Reporting time frames are also addressed in this section. The minimum
> criteria for reporting is the minimum dataset that consists of an
> identifiable patient, an identifiable reporter, a suspect product and
> an adverse event. The time clock start point is defined as the date
> when a company first receives a report that fulfills the minimum
> criteria for reporting.
>
> The last section of the guideline is good case-management practices
> which stresses the need for accurate and complete information to
> identify and assess adverse drug-reaction reports. The five topics in
> this section are assessing patient and reporter identifiability, the
> role of narratives, single case evaluation, follow-up information and
> how to report.
>
> Assessing patient and reporter identifiability is important to verify
> the existence of a real patient reported. Identifiers would include
> patients initials, code, sex, age, category, name and phone number of
> the reporter. Establishing identifiability minimizes case duplication
> and this facilitates a follow-up of individual cases.
>
> The role of narrative sections states that a narrative of a case
> report should summarize all the relevant clinical information
> including the patient characteristics, therapy details, medical
> history, clinical course of the event including outcome, laboratory
> data and any other information that would support or refute the
> evidence or diagnosis for an adverse drug reaction.
>
> It also states that an autopsy should be provided when available and
> ICH E2B establishes that company narratives are required for all
> reports of serious reactions.
>
> The single case evaluation section proposes review for correct
> interpretation of medical information and for quality and completeness
> of information. This also emphasizes the need for sound clinical
> review.
>
> The follow-up section stipulates that the highest priority for follow
> up is for cases of serious unexpected events. The use of a focused
> line of questioning such as a questionnaire is encouraged to capture
> clinically relevant and important information and follow up is
> suggested to be performed by healthcare professionals with
> pharmacovigilance training.
>
> Our goal in this working group is to ensure that the contents and
> concepts are consistent with current-use regs and guidances and with
> the safety-reporting proposed rule. As I mentioned earlier, the
> working group is in Step 1 which is consensus building and there may
> be further changes. There are still issues, particularly in the
> definitions and terminology section and, to a lesser extent, in the
> expedited reporting section which will require further discussion.
>
> Looking ahead, there may be additional topics to consider for
> incorporation into E2D. Some examples of these would include issues
> such as medication errors, the concept of requiring full datasets for
> all serious adverse drug reactions, always expedited reports and
> requiring full documentation for reports of death and hospitalization.
>
> Any questions? Thanks.
>
> MS. SHOWALTER: Thank you, Susan.
>
> The next-to-last topic that we have is E2E, pharmacovigilance
> planning. Paul Seligman is going to do that topic for us\--if he is
> here he will, anyway. But if he is not here, and he doesn\'t seem to
> be at the moment, Justina why don\'t you do QT prolongation and then
> we will come back to that one.
>
> **E14-Clinical Part of QT Prolongation**
>
> MS. MOLZON: I need to start this presentation with a disclaimer. I am
> here pinch-hitting for Dr. Douglas Throckmorton, the Division Director
> for Cardiorenal. He is actually the rapporteur for this group and this
> group is the newest expert working group, so we thought it would be a
> good idea just to fill you in on what has been going on and the plans
> for Brussels.
>
> The point of this whole topic which deals with the clinical evaluation
> of QT-interval prolongation and proarrhythmic potential for
> non-antiarrhythmic drugs is that that is a concern about drug-induced
> proarrhythmias. The goal of the documents that are being discussed in
> this expert working group is to provide recommendations to drug
> developers concerning the design, conduct and interpretation of
> clinical studies to assess the potential for delaying cardiac
> repolarization.
>
> Currently, in ICH, we have a pharm-tox or safety topic called S7B
> which looks at the safety pharmacology studies for assessing the
> potential for delayed ventricular repolarization or QT-interval
> prolongation by human pharmaceuticals. So this is the pharm-tox or
> non-clinical aspect of the clinical document that is under way.
>
> This safety document was released for consultation under Step 2 of the
> ICH process in February of 2002. It was published in the Federal
> Register. Notice of its being released for consultation was in the
> Federal Register in June of 2002. Then we sort of held it at this
> point because we were waiting for the clinical document to develop so
> the two can proceed at the same time.
>
> So the safety pharmacology people are actually gathering information
> to help feed into the clinical document.
>
> Now, there is some additional background to this ICH topic. It started
> with a document that was drafted by Canada\'s Therapeutic Products
> Directorate. I believe that this was in response to a coroner\'s
> inquiry into some of the products that were causing QT prolongation
> which resulted in several deaths in Canada.
>
> CDER was working on a similar document because we had similar concerns
> and we recognized the value of a joint effort and, further, the effort
> of a harmonized ICH document. So we talked about introducing this
> topic into the ICH process which is unusual because, generally,
> industry proposes topics. But here this was a regulatory concern and
> the regulators wanted to introduce the topic. But the regulators
> recognized the need for expertise outside of the ICH process.
>
> Just to talk about some time lines; Health Canada came out with a
> draft guidance document on QT-interval prolongation in March of 2001.
> That document was combined with FDA efforts and a proposed concept
> paper was put together in November of 2002.
>
> We then developed a consultation workshop held here in Washington,
> D.C. in January of 2003. What we were trying to do with this
> consultation process was to sort of jump-start the ICH process by
> using a draft or final document that was being developed in one of the
> ICH regions that would provide a strong foundation for the development
> of an ICH guideline.
>
> So, instead of having a very brief concept paper being introduced into
> the ICH process, you have a fairly well-developed document to start
> the ICH process. This more developed document would ensure the
> inclusion of the necessary experts outside of the ICH process. So the
> idea here was to involve the people with necessary expertise that
> would not be necessarily part of the ICH working group.
>
> So, to develop or to enable inclusion of this specific medical
> expertise, the preliminary concept paper that the FDA and Canada\'s
> Therapeutic Products Directorate worked on was posted in the DIA, the
> ICH, the TPD and CDER websites on the same day, November 20 of 2002.
> This was so that everybody that was interested in the document could
> read it before we had discussions in a DIA meeting where we invited
> experts outside of the ICH process for a very scientific discussion.
>
> So we worked with the North American Society of Pacing and
> Electrophysiology to make sure the correct expertise was included in
> this discussion process. And the ICH working group for S7B plus this
> newly established group on QT prolongation was present for the
> discussion so they could listen to the scientific discussion and then
> take those thoughts back into the ICH process.
>
> This was a bit of a different approach for all of us because it is
> outside the norm for the regular guideline development within ICH,
> CDER and TPD. It was also a different venue and process for the Drug
> Information Association because this was very academic setting to
> provoke academic discussion. This was a meeting that took place at the
> University of Maryland at Shady Grove, so it wasn\'t a hotel. It was
> just an academic huge conference room.
>
> More than twice the number of panelists were on the program. We must
> have had twenty to thirty panelists so that we had a wide variety of
> expertise from a wide variety of settings; academia, hospitals,
> clinics, CROs, et cetera. It ended up being one of the largest
> programs outside of the Annual Meeting for DIA, with over 620 people
> attending.
>
> To capture all of the effort at this workshop, there was a transcript
> to capture the discussion and the resulting recommendations and
> conclusions were incorporated into the document that had been posted
> for consideration. The recommendations and conclusions from the
> workshop were incorporated into the document for ICH consideration.
>
> This document was fed into the ICH QT Prolongation Working Group
> during the meetings in Tokyo this past February. The result is,
> hopefully, going to be a harmonized approach to QT prolongation.
>
> Now, the following slides are from Dr. Doug Throckmorton and they
> represent his report to the ICH Steering Committee at the meetings in
> Chiba, Japan in February of 2002. Basically, he just provided an
> outline of the guideline. The guideline, I believe, has seven
> sections; background and scope, clinical-trial design\--that includes
> Phase I through evaluation, Phase II and III evaluation. Section 3 is
> a collection and analysis of QT-interval data. Section 4, analysis of
> QT interval and ECG wave-form data. Section 5, adverse-experience
> collection. Section 6, regulatory implications, labeling and risk
> management. So I mis-spoke. There are only six sections.
>
> Dr. Throckmorton talked about progress of the working group at those
> meetings in Japan. There was an initial discussion and revision of the
> document, so this is the document that came out of the workshop that
> was put on before the ICH meeting.
>
> There was an identification of items requiring additional data or
> discussions such as operating characteristics of nonclinical assay
> systems. So this is where the S7B group fits in, and the potential use
> of nonclinical data to inform design of a thorough clinical QT study.
>
> So, how can you use the nonclinical, preclinical or animal data to
> support what needs to be done or not be done in the clinical studies.
> Trial-design issues were also discussed and this included validation
> of Phase I study assay sensitivity, use of data from thorough Phase I
> assessment and to inform Phase II and III trials.
>
> The action items that were presented to the steering committee was
> there was, believe it or not, a huge controversy about what to call
> this topic. Logistically, it should have been E13 but, for some
> reason, in this very scientific forum, that was not acceptable. So it
> is now E14 skipping E13.
>
> Also the working group edited the version of the concept paper for
> presentation by the steering committee and they discussed the clinical
> research necessary to parallel the S7B research initiative. There was
> the possibility of an interim meeting or teleconference following the
> availability of nonclinical data from the S7B working group.
>
> I don\'t believe that actually took place because it wasn\'t
> necessary, but it had been proposed.
>
> Las month, in CDER, the Cardiovascular and Renal Drugs Advisory
> Committee held a two-day meeting on nonclinical studies and their
> sensitivity and specificity. The potential impact of nonclinical
> testing on the design of the thorough clinical QT evaluation will be
> discussed in Brussels. So we are also using some of the information
> from this recent advisory committee to feed into the Brussels
> discussion.
>
> The goal in Brussels is to reach a Step 2, so that would be a document
> that would be put out for comment. So, once again, the document will
> be available for anyone to comment on and I believe that this is a
> very short turnaround for an ICH document. So, by jumpstarting the ICH
> process and putting a lot of expertise or whatever into the document
> initially, you can actually speed up the ICH process.
>
> I think that is it. Any questions should go to Dr. Throckmorton but I
> would be pleased to pass them on. Does anyone have any questions?
>
> MR. PARKER: Ford Parker from Hoffman LaRoche. One thing we were
> surprised to see in the document was, at the DIA meeting, people were
> very opposed, including people that do a lot of these ECG studies like
> Joel Morganroth that the document included requiring detecting a mean
> QTC change of 5 milliseconds, which he said was nearly impossible and
> our calculations, from the standard deviations that you typically see
> in healthy volunteers, is about 12 to 14 milliseconds for QTC, would
> require upwards of 100 subjects per arm.
>
> In addition to that, you also recommend using moxifloxacin as a
> control which causes changes of 5 to 10 milliseconds which,
> supposedly, the agency thinks is inconsequential clinically. So the
> question is why would you expect people to detect 5 milliseconds in a
> 500-subject study where you don\'t believe these changes are even
> clinically meaningful.
>
> MS. MOLZON: First of all, I don\'t know if that information is
> actually still in the document because, as I said, recommendations
> from the DIA workshop were used to revise the document that went into
> the ICH process.
>
> MR. PARKER: It was in the February 6 document after the DIA meeting.
> It was still there, 5 to 6 milliseconds.
>
> MS. MOLZON: Okay. I am not the expert here. But I still don\'t know if
> that information was rediscussed in Chiba, Japan and is still in the
> document that will be posted at Step 2. So what you need to is, when
> that document is posted, if you have comments on that specific
> section, just make sure that you send them in to the docket for
> discussion at the next phase.
>
> MR. PARKER: Okay. A second general question is can outside persons
> attend the Brussels meeting? Is this a closed meeting or is it open to
> the public.
>
> MS. MOLZON: Your representative will be the PhRMA representatives on
> the committee. So, if you have concerns, you should work with your
> PhRMA representative. But it is a closed meeting. It is just open to
> the ICH partners, so it would be PhRMA\--Christelle showed the chart
> of who is involved, so it will be PhRMA and FDA for the U.S., EFPIA
> and the EU for Europe and then JPMA and MHLW for Japan.
>
> Your representative will be the PhRMA person on the committee. So, if
> you have concerns about this specific issue, you should get in touch
> with the PhRMA rep on the committee and then they can relay these
> concerns to the expert working group.
>
> MS. SHOWALTER: Let me just further comment on that. You actually have
> the possibility of conferring with the PhRMA, which is the U.S.
> industry rep, but also with the EFPIA representative as well, which
> would be the European industry rep, so you would have more than a
> single opportunity to talk to your industry representation.
>
> I think that the names of those representatives should be listed on
> the ICH website. I think we have a list of all of the experts for the
> various expert working groups. So you will see who that person is and
> you will be able to contact them that way.
>
> Thank you, Justina.
>
> Dr. Paul Seligman is with us now and he is going to provide the update
> on the other pharmacovigilance topic which is E2E, Pharmacovigilance
> Planning.
>
> **E2E: Pharmacovigilance Planning**
>
> MR. SELIGMAN: Good afternoon. The Pharmacovigilance Planning Group or
> E2E is one of the newest topics being considered by representatives at
> the ICH. The interest in and genesis of this topic comes primarily out
> of Japan\'s recent regulation requiring early postmarket
> pharmacovigilance, or EPPV, for newly marketed products in that
> country.
>
> Dr. Yusuki Tanagawara from KO University who represents the Japanese
> Ministry of Health, Labor and Welfare is the co-lead of this new
> working group along with Dr. Peter Arlette from what was formerly
> known as the British Medicine\'s Control Agency.
>
> Myself, along with Dr. Robert Ball and, most recently, Dr. Miles Braun
> from CBER have represented the FDA on this working group. The question
> basically before the E2E Working Group is that, beyond the current
> harmonized regulatory requirements for submitting reports of adverse
> drug events, should there be international agreement and a common
> understanding regarding additional surveillance data to be collected
> and/or studies to be conducted in the post-marketing period and, if
> so, should the sponsor of the product submit a plan to be reviewed by
> regulatory authorities prior to the approval or licensing of the
> product that describes essentially these additional studies or
> additional surveillance; hence pharmacovigilance planning.
>
> The basic premise of this planned pharmacovigilance approach is that
> it offers the opportunity to reduce risk and increase benefit of
> medicines to the public of marketed products. The scope of the
> guideline as it is currently outlined is essentially to provide
> guidance to industry in the preparation of a pharmacovigilance plan
> prior to the launch of a product.
>
> It focuses primarily on new drugs, biologics, new formulations and any
> new indications. It is essentially meant to lay out a
> pharmacovigilance specification which essentially is the risk basis or
> safety basis for developing the plan. It describes the initial content
> or elements of such a plan and it also talks about the types of
> postapproval studies that may be utilized to examine a particular
> safety question postmarket.
>
> This effort has many similarities to FDA\'s current effort to develop
> guidance on good pharmacovigilance practice and postmarketing risk
> assessment. Some of you may be familiar with the public meeting we had
> last April 9, 10 and 11 here in Washington and the concept paper which
> is currently on the website which is serving as the basis for the
> draft guidance that will be provided by the FDA in the fall as part of
> our PDUFA-3 agreement.
>
> As these two efforts more forward in tandem, the ICH thinking has been
> shared with the drafters of FDA guidance and vice versa, so we want to
> make sure that our guidance development is well harmonized with ICH.
> This ICH document, I think, is probably best described as in its
> earliest phases of development.
>
> That is really all I have to say. I am happy to field any questions
> about E2E or what this pharmacovigilance planning group is up to.
>
> MR. MILLER: Loren Miller, PPD. Is this guidance set up to establish a
> safety marketing plan prior to launch that is kind of sequential plan;
> that is, you are ready to evaluate safety in a very short period of
> time, let\'s say, after your product is launched. Are you required to
> collect data at earlier time points than you normally would by current
> regulations? What is the thrust of it? Is it just a planning document,
> per se?
>
> MR. SELIGMAN: Essentially, it is a planning document. In the PDUFA-3
> agreement and the goals letter, they talk about more either intense or
> concerted surveillance for the first two to three years postmarketing.
> I think this pharmacovigilance planning essentially is going to
> parallel that although, in the ICH document, they have not gotten down
> to that sort of level of specificity yet.
>
> I think it is primarily focused on that sort of early period of time
> following the introduction of new product.
>
> Any other comments or questions? I feel like I have just zoomed in and
> zoomed out.
>
> MS. SHOWALTER: There don\'t seem to be any. So, thank you.
>
> MR. SELIGMAN: As I say, there are PhRMA representatives on the
> committee; Linda Hoselly and Janice Bush and Waiju Dai. They are the
> three who have served to represent PhRMA\'s interest in the early
> development of this paper.
>
> MS. SHOWALTER: Thank you.
>
> I want to adjourn the meeting. I thank everyone for their
> participation and your indulgence with our bending the agenda a little
> bit to try to accommodate everybody. I know we have run long today but
> these meetings are very valuable to us and we will continue doing
> prior to each ICH meeting. So we really appreciate your participation.
>
> We also always welcome outside speakers. We are very thankful that we
> had one today and we would hope to more of that in the future.
>
> The transcript will be made available on the web. Again, I just want
> to thank everyone including our speakers for their time today. I know
> it is difficult getting ready for this meeting to take time out of the
> schedules, but, again, we think it is very valuable.
>
> So thank you and we adjourn the meeting.
>
> \[Whereupon, at 12:50 p.m., the meeting was adjourned.\]
>
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