A town hall meeting held last week at DIA 2010 in Washington, D.C. featured seven of CDER’s key personnel, but it was clear from the start of the meeting who the star of the show would be. Grande Starbucks cup in hand, CDER director Janet Woodcock kicked off the session by providing an overview of hot topics currently on CDER’s plate, and presided over an ensuing Q&A session in which she spoke with candor, passion, and humor about issues critical to CDER’s work. Woodcock’s colleagues played off her lead and, for those used to droll or technical dialogue from the Agency, this session was a breath of fresh air.
First, a review of those hot topics, and then a summary of the Q&A:
I. Hot Topics
Biosimilars: Flying the Plane While Building It: Woodcock discussed the impact that new healthcare legislation in the U.S. would have on creating a pathway for biosimilars. “This is somewhere between generics and a new drug approval,” Woodcock noted, “but functionally, it remains to be seen” how the new laws will be administered. Woodcock noted that FDA has formed a policy working group (cochaired by her and CBER’s Karen Midthun) to manage its approach to biosimilars, to ensure that the Agency’s response is seamless across CBER and CDER. Separate CBER and CDER biosimilar review committees have been established to handle “product-specific issues and issues related to scientific methodology.”
FDA will hold public meetings in order to solicit comments from stakeholders, Woodcock noted. “We’re trying to provide clarification” on policies, she noted, “but of course we have to devise those policies first . . . we’re flying the airplane while we’re assembling the airplane.”
“The Avandia Issue”: FDA has reiterated its mission of ensuring the safety of drugs for the duration of their time on the market, said Woodcock. The Agency has slated a July 17-18 joint committee meeting to look at all existing safety data on Avandia, and whether there are cardiovascular risks that outweigh its benefits. “Scientists don’t always agree and they may in fact passionately disagree with each other . . . and this is in fact what’s happening with this issue.” Woodcock also noted that Commissioner Margaret Hamburg has asked the Institute of Medicine to study the ethics of doing randomized safety studies when there’s a “signal” of health concern to patients, and how to manage safety data coming from disparate sources.
QbD: An Evolving Success: “There have been some striking success stories on how Quality by Design can reduce defects and variability,” she noted. QbD itself is “a success story that is evolving . . . at the same time, we’re dealing with globalization, so we really need to push on quality and supply chain issues . . . we should use the highest quality science and technology to ensure that, and we should continue to move away from our traditional methods.”
CDER’s Quality System: “My single goal for CDER is to implement a Quality System . . . which enables us to reproduce a reliable quality,” Woodcock stated. “We are taking the first steps down that path and this will really pay off for us in terms of efficiency and quality, and for those who work with us.”
II. Questions and Answers
A summary of some of the questions posed to CDER:
Audience Question: Does FDA plan to better monitor clinical trial investigators and censure those who act inappropriately?
Woodcock: “I have very violent opinions on this.” [laughter] “We don’t have a clinical trial infrastructure in the United States . . . it isn’t just clinicians, but it’s study personnel who are needed to ensure a trial as well.” Woodcock went on to elaborate on these comments, speaking emotionally and urging that the current U.S. trial system be reviewed and overhauled.
Audience Question: Have FDA’s recent rule changes loosened the requirements of reporting misconduct among clinical trial regulators?
Woodcock: If I understand correctly, you are referring to our rule on data falsification, and it doesn’t loosen requirements . . . what’s happening is that there are people I call the “serial killers of clinical trials” and they would [regularly] falsify data. In many cases, drug companies would simply drop the investigators, who would just move on to another company and take their money. . . .
We had people who had worked in dozens of clinical trials and falsified data . . . we understand that companies don’t want to tell us about this because [they’ll likely be] involved in a legal case . . . but they could be the next company rooked by one of these people.
Deborah Autor, JD, Director, Office of Compliance: We’ve also streamlined our processes for investigator disqualifications . . .
Audience Question: What is happening with the computational science effort at CDER? What’s the real mission, long and short term?
ShaAvhree Y. Buckman, MD, PhD, Director, Office of Translational Sciences: We’re very excited about this effort . . . We use a lot of paper currently [and it’s] hard to look across trials and do comparative studies. . . . [We’ve got to] develop more modernized analytical tools to be able to assess data in real time . . . we’re really focusing on data domains . . . what we’ve got, what we need, and making sure we have a feedback loop . . . to help us bridge that gap between our reviewers and sponsors to make sure we understand what they need.
Woodcock: Our informatics folks are the ones doing the procedural part of this, and they’re partnering with ShaAvhree’s folks who are doing the standards work.
Buckman: This is a major effort, and not one that one office can do alone . . . and we want and need to be successful in this.
Audience Question: The Sentinel initiative aims to look for public health issues that unexpectedly go wrong, but once you build this source of data will you also look for things that “unexpectedly go right”?
Woodcock: A lot of drugs give us some humility, because a lot of times we find [unanticipated] benefits, like with penicillin . . . Data is often structured about what goes wrong with a person . . . and it’s hard to find data about unexpected benefits . . . but we’re not opposed to it. It would be great!”
Audience Question: Is ICH making any efforts to incorporate regulatory bodies of other regions beyond the U.S., EU, and Japan?
Justina Molzon, JD, MPharm, CAPT, USPHS, Assoc. Director for Intl. Programs, Office of the Center of the Director: ICH is 20 years old, and in the beginning it was mainly the US, EU, and Japan . . . we have done a lot to include additional countries . . . we have over 60 guidelines which we think contain this common regulatory language [of the common technical document, CTD].
We have tried to incorporate them into our discussions, they send representatives to sit in on our expert working groups . . . recently we’ve created the regulator’s forum . . . which is specifically for regulators who are interested in implementing ICH guidelines . . . we share experiences on how we’ve implemented ICH guidance. [Molzon cited China, Korea, Singapore, Australia, and Brazil as examples of countries that have been actively engaged in these forums.]
Audience Question: It seems like there have been many more drug recalls in last few years? Why?
Autor: There have actually been more drugs recalled, but about a steady number of recall events. Last year we had a spike in recalls (around 2,000), but when you look at that it’s the same number of companies—for example, KV pharma recalled some 1,300 products.
Audience Question: What is the impact of FDAAA (Food and Drug Administration Amendments Act of 2007) on the FDA’s ability to meet the goals of PDUFA?
John Jenkins, MD, Director, Office of New Drugs: FDAAA came out three years ago and we were transparent that that would impact on our ability to meet some of our user-fee goals. That trend has recently been reversing . . . in recent months it’s pretty much gone back to where it was before FDAAA, so that’s good news on application review . . . but we’ve never lost our focus . . . the wheels didn’t come off the wagon. We continued to meet those goals in the 80% range, but not in the 90% range . . . In some cases your companies were happy with this . . . applications were under review . . . we didn’t think it was fair to start all over again [reviewing applications] . . . we ate those goals and went overdue and got those products approved . . . but generally we’ve gotten back to that 90% level.”
Woodcock: I’m the one at CDER who has to manage the budget . . . so I kind of have a long view of this. Since the user-fee agreement originally passed . . . to my understanding the PDUFA budget has not been increased . . . and we’ve gotten additional work . . . and now we have the biosimilars, and we don’t have any additional resources to put against that. It’s very difficult for me from a budget standpoint to manage all these additional requirements that have been put upon the drug review process.
Audience Question: REMS is very “med guide heavy,” but what we’re hearing from stakeholders outside industry that they find this burdensome and not sure what REMS is supposed to do. Is there a better way to use and implement REMS?
Woodcock: We feel we should go to a single-patient leaflet for prescription drugs, and it would have benefits as well as risks . . . The FDA proposed this in the early 70’s or early 80’s and we got slapped down because of paper burden . . . as a result you get info stapled to your prescription bag in pharmacy [which is not good]. We’re going to have to harness the electronic media and access to electronic data . . . with [the advent of] e-prescribing . . . we could use that as a vehicle to provide information that is patient-friendly . . . we know people have problems with med guides and that they’re not actually getting to the patients in some cases.
Jenkins: We recognize that it’s not only a large administrative and review burden for us to go through the FDAAA procedures [ie, medication guides are listed as one component of a REMS] . . . it’s an impact on pharmacies, companies, and the whole society . . . stay tuned to see if we’re able to find some creative ways around this.
Audience Question: Can there be better collaboration between FDA and EU in regards to review pediatric drugs in development?
Sandra L. Kweder, M.D.. Deputy Director, Office of New Drugs: Requirements for reviewing data on pediatrics come much earlier in the EU than with us . . . the information often comes to us long after these discussions have been held in the EU . . . then it’s put on our doorstep and we’re asked to comment long after these discussions have been held . . . We’re working to provide comments much earlier in the review process even if it is not required [Kweder’s emphasis] . . . we’re already seeing the benefits of doing that because it facilitates that harmonization.
Woodcock: And if a company starts engaging with other authorities [about pediatric studies] . . . they should call it to our attention. We should know that those conversations are being initiated.
Molzon: Because of our working relationship with EMA, we have clusters of activities in which we discuss topics like this . . . we have a better understanding of the possible way forward in both [regions] . . . those discussions take place under our confidentiality arrangements [and are thus not made public].
Audience Question: Can FDA do a better job of indicating which drugs are likely to be approved and which are not?
Jenkins: My advice is to develop drugs that are highly effective and safe . . . that will make it much easier for us to evaluate that drug . . . than if you come in and show us you had a 1% change from placebo . . . we didn’t pull the rug out from under you, your drug just didn’t meet expectations . . . the more effective the drug is, and the safer it is, the easier it is for us to do a benefit-risk balancing.
Kweder: As you’re developing your drug, it’s very easy to see if it’s good. You’ve got to be brutally honest with yourself, and step back from the process and look at what’s happening in society [regarding the need, or lack of need, for certain drugs] . . . For example, we have seen a really big shift in expectations of diabetes drugs, and that landscape is shifting in the development of those drugs now . . . Be brutally honest with yourself about your product.
Woodcock: The world is changing . . . new products on the market are going to have to have major value against alternative therapies for those conditions. That’s the direction that reimbursement is heading . . . it’s a question of value in the eyes of the payer whoever that payer is . . . payers are playing more in this area and they’re deciding what the value is.
Jenkins: Trials are analyzed based on the average response, but often there’s a wide distribution of response of the people enrolled in the trial. That’s another area you need to look at . . . If you get information about those [extreme] subgroups [at data extremes] . . . then that’s another way to shift your benefit-risk distribution . . . that’s another place you can use the new science. . . “
Woodcock: And if we don’t approve these, we get bitter letters from that subgroup . . . if you can show tremendous value for your drug, even in a small patient population, the payers will pay for it, and I believe that’s the future.
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