Providing an oral explanation to the European Medicines Agency’s drug evaluation committee, the CHMP, or presenting before a US Food and Drug Administration advisory panel has to count as one of the most important and possibly most stressful tasks that drug companies might face.
These meetings are where drug sponsors get a final chance to address questions and concerns regulators have about their marketing authorization applications. Whether it’s at the CHMP or the FDA, each meeting brings with it specific challenges, according to regulatory consultant Kate Dion.
During a CHMP oral explanation, for example, sponsors have only an hour to make their case. After this, they are dismissed from the room and have limited ability to influence the committee’s ensuing debate and vote that will likely determine the fate of their product, said Dion, communications lead at regulatory consultancy firm 3D Communications.
Sponsors at an FDA advisory committee (AdCom) meeting are given more time to speak and spend all day in the room. That said, they “don’t have much opportunity to respond or react to” what the regulator says because they deliver their presentation before the FDA does.
It may not feel like it, but there is a lot companies can do to exert control, said Dion, who gave a presentation on how companies can optimize their preparation for both meetings at the recent Regulatory Affairs Professionals Society (RAPS) 2019 Europe conference.
There are similarities and differences between the two meetings that “really do matter in terms of how to prepare and how likely you are to succeed.”
“A high-stakes regulatory meeting is the wrong time for an original thought," Kate Dion, 3D Communications
In both cases, companies should prepare thoroughly, have a clear presentation and know how to answer questions and use back-up slides. “You really need to understand who your audience is and what it is that is bothering them, because they have legitimate concerns.” Dodging questions “is just going to alienate people.”
Most importantly, Dion warned, “a high-stakes regulatory meeting is the wrong time for an original thought. You do all the thinking before you get in the room. It’s not a time for improvisation.”
A Brief Background
CHMP oral explanations and AdCom meetings are only convened for certain marketing authorization applications that have reached the end of the regulatory review cycle.
Companies usually get called to an oral explanation when one or both of the CHMP rapporteurs want to settle major objections they might still have about an application. AdCom meetings are normally required if the drug under review is a new chemical entity or if the FDA has concerns over a product relating to such things as trial conduct, endpoints or missing data that warrant independent, outside input. Both the EMA and the FDA usually follow the recommendation of their respective committee.
Sponsors are usually notified around two to three months in advance of an oral explanation, and four to six months before an AdCom meeting. "In both cases that’s really not very much time to prepare,” cautioned Dion.
CHMP oral explanation meetings tend to comprise around 40-50 members (who are mainly pharmacologists and therapeutic area experts), of which 28 (one CHMP member – or their alternate where applicable – from each of the EU member states) cast a vote. Sponsors submit their draft presentation slides to the agency a week in advance but are not required to submit briefing materials. They can have around one or two presenters and a maximum of 10 people from their organization in the room. They are allowed 20 minutes to make their presentation and 40 minutes for Q&As, after which they are dismissed while the rapporteurs deliver their presentation and the committee discusses and votes on the product. In some cases, the committee might not vote until much later on at a subsequent CHMP meeting.
At an AdCom meeting, the FDA convenes a panel of 15 or so independent experts, who are the ones who vote, and there is also an open public hearing before their votes are cast. Sponsors send their briefing book to the FDA two weeks in advance. They normally have around five to six presenters, and another 15 responders and/or triage leads who help locate the necessary slides. They remain in the room for the entire day and have 60-90 minutes to present, followed by 15 minutes to answer questions. There is a raft of different AdCom panels, and companies present to the one that aligns most closely with the FDA review division for their product.
How You Tell Your Story Is Critical
A similarity between the two meetings is “that the people who are voting on your product, which has taken you many years to get to this stage, may not know very much about it,” Dion said.
CHMP members are likely to be familiar with a product, having spent the best part of a year reviewing it. However, there is no guarantee that all of the “people who have been really thinking about it are going to be in the room on the day of your meeting,” Dion explained.
Similarly, with an AdCom meeting, the product will be familiar to the FDA members at the meeting but not necessarily the independent experts sitting on the advisory committee.
“So, it’s really critical how you tell your story. It matters how you put your information together, how you structure it and how much information you’re delivering to these people.”
Differences In Transparency
A big difference between the two meetings – before, during and after – is transparency.
“CHMP oral explanations are private, all done behind closed doors,” Dion said. There is no public transcript and only a brief summary of the meeting is posted online afterwards. It is therefore “really difficult to know how other companies have solved issues in the past.”
With AdCom meetings, everything is public. The meetings end with an open public hearing, where patients, physicians, advocacy groups and anyone else who wants to talk about the product in question – either for or against it – can speak up at this stage of the proceedings.
The FDA also posts the sponsor’s and the agency’s briefing books online 48 hours before the meeting takes place. And a full transcript of everything that is said during the meeting is published afterwards.
When it comes to tactical execution, there are differences again.
The focus for sponsors at a CHMP oral explanations should be on “message retention,” Dion said, while at an AdCom “it’s all about controlling the microphone.”
Because companies speaking at an oral explanation only have an hour in the room, they really need to make their “message stick.” It is not clear how much of what they have said is retained by the people who discuss and vote on their product after they have left the room.
With an AdCom meeting, companies can engage with the advisory committee during the discussion period, and “should think of themselves as a member of the conversation that’s going on,” Dion advised. “You have every right if you feel they are going off track or it’s not going in a particularly helpful direction to break into that conversation and take control of where it’s going and make sure that you’re bringing people back on to the path that you think they need to be focusing on.”
The room set-up for each meeting is something else that companies should bear in mind.
Both set-ups are daunting, according to Dion, but an AdCom meeting is even more so, partly because “you’re going to be presenting to people [of whom a] half to two-thirds have their back to you.” While this is “not really conducive to effective communications,” these things can be overcome “as long as you think about it first.”
Saying it Like You Mean It
When it comes to choosing their presenters and responders, companies need to be selective. “You want to make sure that you’ve got somebody who has both a command of the data and the ability to communicate clearly, confidently and politely. We don’t want anybody getting into arguments. This person should be able to answer questions credibly and take control of the message.”
Before going into a meeting, sponsors must ensure they understand and are able to address the issues that the regulators are concerned about.
Presenters should make sure they answer the questions asked of them during a meeting, “because it’s amazing how many people go straight to bridging,” moving from a difficult question to a prepared key message.
Presenters should “say it like [they] mean it” and take care not to “break into jail” by bringing up information or data during the Q&A that might make the meeting members ask more challenging questions.
In addition, Dion recommends that the people who present the data and proposed risk management plan should be from the company itself. This task should not be given to the external key opinion leaders (KOLs) that sponsors sometimes hire to speak during these meetings.
The consultant said that KOLs should focus on clinically relevant content such as why the product is necessary and how it is going to be used in clinical practice. Doing so helps a company build credibility, especially since the CHMP and the FDA are aware that they have paid their KOLs for their services and there may be a risk for bias.
“Again, try to make sure that even if this is the most highly esteemed KOL in a given space, don’t let him or her get into an argument with the people they are talking to. That’s not going to end well for anyone. They need to be very respectful, very polite and keep themselves in check.”
As a rule of thumb, Dion advises sponsors to use American KOLs in America and European KOLs in Europe. “There will be exceptions, but that is a good guiding principle.”
Regarding company team size, she said that this would be slightly different according to whether it was an AdCom or CHMP meeting. “For both you’re going to need a regulatory liaison, a moderator, presenters, subject matter experts/responders, triage support to help with slide, medical writers and statisticians.”
For AdCom meetings, companies also need people to staff the “backroom,” which is another room at the FDA where the sponsor has two members listening to the proceedings by video conference who can prepare new analyses, data or new slides that the company can show, as necessary.
Meaningful And Memorable Content
Creating meaningful and memorable content for both meetings is critical. But even here there are nuances, Dion said.
Discussions at CHMP oral hearings, she explained, focus on issues, whereas the vote itself is on the benefit-risk profile of the product.
When dealing with these issues, Dion advised sponsors to put the CHMP’s concerns and objections into perspective “with some clear and concise messages and credible data” that establish the favorable benefit-risk profile for their product.
“You have to address the rapporteurs’ major objections. It’s not about convincing them that they’re wrong and you’re right. At this stage in the game it’s about coming forward with sensible, innovative, effective strategies to make sure that you’re addressing their concerns.”
With an AdCom, the focus is on benefit-risk, Dion said. Companies that bear this in mind when they prepare their presentation are much more likely to keep benefit-risk “in the front and center” of the people they are speaking to “even though the discussion may end up going onto very specific issues.”
Avoid Data Dumping
When it comes to framing and delivering the message, the rules are the same for both AdCom and CHMP meetings.
“Don’t data dump,” Dion said. “People are not going to remember anything you’ve said if you give them way too much information and they do not know what the context is or how to put it in context. They are just going to be lost.”
She described a simple, four-level pyramid format that companies can use to pull their messages together.
The tip of the pyramid is where you want to get to the point as soon as possible, so start with a headline or a summary statement, Dion said. The second level down should include the data and facts that support the statement. The third level is where you can visualize the importance of the data by establishing an emotional connection between yourselves and your audience. You might explain, for example, what the data mean to a child with cystic fibrosis, or to a mother of two with breast cancer. “That helps to really drive home the message,” Dion said.
The final level, or bottom line, is where you reinforce your headline so that the meeting members “are in no doubt as to what it is you are trying to get across. This is really important, especially for the CHMP meeting when you’re not in the room anymore.”
Regarding slides, Dion reminded companies that these visuals should support and not compete with the verbal messages. “People remember information a lot better when they see it and hear it at the same time. So again, this will dramatically increase the odds that they will remember what you said, and they will agree with it when it comes to the voting.”
Each slide should focus on one main idea, have a meaningful headline, and contain concise, bulleted text. Any graphs or charts should be bold and easy to understand.
Regarding briefing books, Dion noted that while the FDA requires these of companies, the CHMP does not. Nevertheless, she advised that sponsors submit a briefing book to the CHMP.
These books “are critical” as they provide your perspective ahead of the meeting, she explained, adding that they should be to the point and easy to navigate. “Make sure each section of the briefing book has a clear key message and you’re reinforcing what’s going to be in the content of your core presentation, so you’re not hearing it for the first time on the day of the meeting.”
Practice Makes Perfect
Once a company has pulled its messages and slides together, it needs to make sure these are going to work. For this, Dion advises that companies run realistic mock meetings and practice.
“This is a really fundamental part of your preparation and is going to give your team a lot more confidence as they go into these two quite tough meetings.”
Because the regulatory audiences are different, the mock membership should be as well, she said. “You really want to choose mock members who are going to best represent the voting members you are trying to persuade. Give them a specific identity and make sure you stay in role.”
Dion noted that a common frustration for sponsors with AdCom meeting is that the FDA provides short notice regarding who the sitting and temporary voting members are going to be.
Nevertheless, she said that “having to present and answer challenging questions to external people who have been hand selected to represent your CHMP or AdCom audience is a great way to focus the mind and improve the speaker’s credibility.”
The consultant also encouraged companies to practice Q&As several times a week.
“This really helps you to identify, prioritize and organize questions. It means it’s easier to create clear, memorable answers and back-up slides” and that “you are able to pull up the right slides at the right time.” This, Dion said, was particularly important for AdCom meetings “because you can be looking at 1,000 to 1,500 back-up slides that you need to pull up in an instance during the meeting.”
Similarly, for CHMP oral explanations, it is critical that during the Q&A you have the appropriate slides again “because your verbal message being supported by visual will help with message retention.”
On the topic of back-up slides, Dion noted that because the CHMP often uses a single PowerPoint file to present data, some companies have tended to answer questions without any stand-by slides because they do not want the committee to see them. “That’s OK, it’s not wrong, but it does lessen your ability to really make a message stick,” she cautioned.
Dion included in her presentation advice for companies that she had received from the regulatory community and industry.
The following is from former CHMP chair Thomas Salmonson:
make sure all slides are clear, transparent and credible – don’t jeopardize losing the trust of the CHMP members;
ask for clarification if you don’t understand a question – English isn’t most peoples’ first language; and
don’t speak too fast – be aware of potential language barriers.
Meanwhile, Alan Moses, a former chief medical officer at Novo Nordisk, said:
be ready for push back at both meetings – and when it comes, don’t take it personally;
for the FDA, be ready for that surprise question, or perspective or issue; and
for the CHMP be “extra” succinct, since you only have 20 minutes to present.
Stagger Preparation Timelines
Dion also had advice for companies that have to attend both meetings.
They should take control of the timelines, she said. “Try to either delay the FDA or the EMA submission, or at least stagger preparation timelines. You don’t want to be preparing for the two meetings at the same time, it’s just too much.”
Companies should focus on one goal at a time. “Your team will otherwise be completely overwhelmed with different information requests” from the two agencies.
To ensure continuity and consistency, the same individual should oversee all the documents for both the FDA and the EMA, and other agencies if necessary.
Sponsors should set realistic expectations with their senior management and their team. “Let them both know it’s going to take a lot of time and a lot of energy and resources to really excel.”
In addition, they should have enough statistical support and medical writers to help with all the requests for information they are going get.
Dion concluded her presentation for companies preparing for oral explanation and AdCom meetings with a quote from Albert Einstein: “If you can’t explain it simply, you just don’t understand it well enough.”