Originally published Jan. 3.
By Turna Ray
In 2011, the US Food and Drug Administration made several organizational changes and issued key guidelines that will impact life sciences companies developing personalized drugs and diagnostics.
For example, the FDA released two draft guidelines in 2011: one on the development of companion diagnostics (PGx Reporter 7/13/2011) and another on the development and marketing of research-use-only and investigational-use-only in vitro diagnostics (PGx Reporter 6/8/2011). Both guidances stand to significantly impact how drug, diagnostic firms, and labs work together to develop and market personalized treatments.
In addition, FDA Commissioner Margaret Hamburg issued management changes in July as part of an ongoing effort to keep the agency in step with science and technology advances. One of her key appointments was Steven Spielberg, former dean of Dartmouth Medical School and director of the Center for Personalized Medicine and Therapeutic Innovation at the Children’s Mercy Hospital in Kansas City. Spielberg is now serving in the newly created position of Deputy Commissioner for Medical Products and Tobacco (PGx Reporter 7/20/2011).
The agency is also working to align its regulatory practices with advancing science through the practice of so-called "regulatory science." Personalized medicine is a key area of focus for the FDA under this initiative (PGx Reporter 10/6/2010).
Industry stakeholders in the personalized medicine space have been critical of these proposed changes and have asked the agency for greater clarity. In order to discuss some of the areas where the FDA needs to provide additional guidance, as well as identify areas of consensus and disagreement between the agency and industry players, some members of the Association of Medical Diagnostics Manufacturers have formed the so-called Companion Diagnostics Working Group.
So far, the working group includes pharma, diagnostic companies, labs, contract research organizations, and consulting firms. Although AMDM provides the working group members with a forum for discussion and opportunities to issue educational white papers, the association as a whole does not take a position on FDA regulation. However, members are free to submit comments to agency draft guidelines or communicate with the agency independently.
Eric Lawson, head of the regulatory and quality systems consulting company Critical Perspectives, chairs the Companion Diagnostics Working Group. Previously, Lawson worked for Voisin Consulting Life Sciences, as well as Metamark Genetics.
Lawson recently discussed with PGx Reporter the prevailing concerns among industry players on the regulatory changes affecting their businesses over the past year. He spoke as an expert in the field, reflecting the views and insights of companion diagnostics developers broadly; his comments do not reflect the opinions of AMDM.
Below is an edited transcript of the interview.
Can you detail how the Companion Diagnostics Working Group was formed?
The Companion Diagnostics Working Group was established by a group of diagnostic companies and was sponsored by the AMDM starting in mid-2009. As a working group we focus on the regulatory aspects, as well as the clinical trial and developmental relationship aspects, of companion diagnostics and their partnered pharmaceutical products.
Can you describe the membership of the working group?
The Companion Diagnostics Working Group was established by medical diagnostics manufacturers, both large and small [such as Roche Molecular, Abbott Molecular, Thermo Fisher Scientific, XDx, Celera, and GenProbe], as well as some laboratory test providers, [including the Laboratory Corporation of America and Caris Diagnostics]. The working group also includes CROs [ie. Docro], pharmaceutical companies [including a pharma division of Abbott, Millennium, Sanofi Aventis, and Eli Lilly], and consulting firms [such as Voisin].
There are several members from the FDA's [drug and device divisions] … to provide helpful clarification and the working group bounces ideas off them. But they don't provide advice, because this is an industry-driven working group.
The FDA issued two draft guidances this year – one on the development and marketing of RUO/IUO products and another one on companion diagnostics. Has the working group taken a stance on either document?
The AMDM does not position itself to provide commentary on FDA draft guidances. That's up to the individual membership of the working group to provide their own commentary and AMDM provides educational direction or clarification to help them do that.
We on the Companion Diagnostics Working Group are focused on companion diagnostics, and this RUO/IUO guidance and companion diagnostics guidance really impacted what we do and the broader field. We spent a lot of time discussing [these guidances] … A lot of the discussions we had informed what the members commented to the FDA [regarding these issues].
Have you come to any consensus in the working group on how FDA should regulate companion diagnostics?
Yes. There is much consensus on what FDA's regulatory stance should be regarding companion diagnostics. There are certain areas, for example issues around [laboratory-developed test] regulation, where there isn't consensus in the working group. The providers of the LDTs clearly have a different perspective than most of the diagnostics providers … But in most areas we are definitely right on target about what best practices should be in terms of improving and clarifying regulations as they stand.
Can you provide some examples of areas where there is consensus among members and where they diverge?
Some of the main areas involve labeling and classification of these products. We have discussed the miscategorization of [companion diagnostics], and [there were those that] felt that all companion diagnostics would easily fit into the category of combination products. People outside our group felt that way and even people at the FDA seemed to feel that way early on in 2009 and 2010.
We explained otherwise. I think everyone in the Companion Diagnostics Working Group felt that this would create great difficulty if you routinely categorize a CDx as a combination product. And we explained why and presented this at different roundtables and at public forums. I think the FDA realized this was the best way to go — that in 99 percent of the cases it is not a combination product. [It] may exist [as such] in the future for particular cases, but it would not be the norm.
Also, [regarding] the formalization of meetings [with the FDA], we discussed how there is a disconnect between how meetings between sponsors and the agency are handled on the therapeutic side, with [the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research] with the drug sponsor versus the way meetings are handled with the diagnostics sponsor at [the Center for Devices and Radiological Health's Office of In Vitro Diagnostic Device Evaluation and Safety]. There doesn't seem to be a way to link them up together.
The agency [says] that usually it invites [both the drug and test sponsor.] Well that's nice, but we feel that if we had some sort of formalized way to … [ensure] that when FDA holds meetings that all four parties — [FDA's drug and diagnostics divisions, the drug developer, and the diagnostics maker] — are present. They have to be there. Prior to Phase III or prior to submission [of regulatory approval] there should be some sort of formalized four-party meeting to establish how this will be handled and the agency can say we're moving in the right direction and the sponsors can be on the same page as the FDA.
The vast majority of my colleagues also feel it is important … that in most cases in the labeling for the drug, the diagnostics product should be named. We find a little bit of pushback from some of the drug companies and somewhat from the FDA, too. They feel hesitant to say that the drug label should name exactly the diagnostic that should be used. They are hesitant to go that far. Even though in the regulations it can be interpreted that it says this is the way it should be done. [ Editor's Note: Lawson is referring to 21 CFR 201.57(c)(2)(i)(C), which states that if "specific tests are necessary for selection or monitoring of the patients who need the drug," then "the identity of such tests," be mentioned in the label.]
Why do you think there is pushback from pharma and the agency to not name the specific, FDA-cleared test on the drug label?
Historically, drug companies feel that their label has to be very rigidly held and cannot ever change. [Some may feel that] if they have one diagnostic named in the first [version] of their drug label, and then they have a second diagnostic developed … six months, a year, or two years later, that it would be a nightmare to change the label.
That wouldn't be the case in the modern world. Quite often, the FDA asks drug companies to put a 'black box' warning on the top of labels and they have to change the label immediately … Sometimes drug companies have new data that benefits them and they add that to the label. So, the label does change more frequently than the current traditional perspective is.
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It would be very easy to name [in the drug label] the first current diagnostic product that is cleared or approved and have some language that would cover future diagnostics that would be cleared or approved by the FDA that would be similar in indication for use as the first one.
The pharmaceutical companies … want to have complete control over their own labels. I believe the FDA's Center for Drug Evaluation and Research supports that. The OIVD [under the CDRH] has a hesitancy to push back to CDER or the therapeutic sponsors to make a statement that the exact name of the diagnostic test has to be in the drug label.
How is the RUO/IUO draft guidance viewed among the workgroup members? Are any of the proposals in that guidance important in the way that companion diagnostics would be marketed or developed?
Many of the diagnostic manufacturers and many of the non-diagnostics manufacturers produce research-use-only types of products, and label them RUO as such. The FDA [in the guidance] has informed us of the restriction of the RUO label and said that [manufacturers] need to be more strict and compliant in enforcing how our RUO-labeled products are being used by our customers.
Therefore, we have to be the policeman of our customers to a large degree. Many of the diagnostic companies do have a concept of compliance and things of that nature, and so they have a capability of understanding what this means. Many of the non-diagnostic, non-FDA-regulated companies that make RUO products have no prior experience in doing this kind of vigilance for their products. When they put an RUO product out on the market, the customer can use it as they please, in their opinion. Now, the FDA is saying, 'No. You, who may not previously have been regulated by the FDA but are producing RUO products, you have to have some level of vigilance over your RUO products. You need to ensure that your customer is not using them for clinically reported patient results.'
So, this is a difficulty and … a greater burden for the previously non-diagnostic product companies than it is for the diagnostic companies. But it is still a burden for us, the IVD manufacturers, because now you have to police and it's not clear exactly how you need to police. The FDA is saying, 'Oh, you shouldn't sell [RUO IVDs] to a clinical lab if you feel it's going to be used for a clinical purpose.' That's difficult to control. Many of the RUO products are sold not just to universities or research laboratories; they are often sold to hospitals, they are often sold for research use in those hospitals. Maybe a portion of that clinical lab will adopt a portion of those assays and develop a lab-developed test using an RUO product. Thereby, the RUO product flips into an LDT format and therefore the clinical results are being reported.
[Due to the agency's practice of 'enforcement discretion' over LDTs] when RUO products are used as LDTs, this is happening under the radar of the FDA. Therefore, it seems like the FDA is expecting industry to step in as the policeman to put their thumb on that LDT.
Have your members individually made these concerns known to the FDA, and if so, what has the agency's reaction been?
We had an FDA roundtable [meeting] at the agency's campus almost immediately after the release of the draft RUO/IUO guidance. Many of these concerns were brought up there and then at several of the other roundtables I've attended in the past several months, including one just a few weeks ago … We didn't get back clear, crisp details [from FDA] as exactly how to [ensure customer compliance with RUO labeling].
For example, [at these meetings] someone said, 'Can we get a contract that our customer signs [saying] they won't use RUO products for clinical purposes? Is that good enough?' To that, the FDA seemed to say, 'That's a nice start but it's not really good enough, because the customer may change and they might start using it for reporting of clinical results.' Somehow, the IVD manufacturer has the burden of needing to ensure that the customer doesn't change their position and switch from research mode into clinical mode.
In terms of some of the issues that companion diagnostic developers might be facing in 2012, has the workgroup pinpointed any that need to be addressed with the FDA?
We touch on several [regulatory] issues in a white paper that we've been constructing and many of the presentations we've made at conferences and seminars. With regard to the labeling issue, we want to … get better control and consistency on how the drug and diagnostic labels are handled. We want to see greater detail in the [companion diagnostic] guidance and on future guidances on how co-development and co-submission will best be handled.
The review process and the timing of review processes for a diagnostic and a therapeutic are dramatically different. The FDA has said that [industry] should time this and make this work so you can co-submit and make it so it's a co-approval. That isn't going to work out if you follow the rules [under the Medical Device User Fee and Modernization Act] in terms of timing. You can potentially have some serious timing issues and you may have to withdraw purely for timing issues … It's a great burden to have to bend over backwards and try to foresee what the timing of the therapeutic review process will be and then fit your submission and expected approval of your diagnostic [into that timeline].
We have proposed in the white paper and in our presentations that we have some sort of understanding that [if there is a] clinical diagnostic linked up to the therapeutic, then we have some review process prioritization … where you can have an early approval [for the companion test] pending the release of the drug. So, you can conclude for the diagnostic partner that everything is wrapped up and the product is approvable and will be good to go as soon as the drug is [approved].
Diagnostic companies have a different business model and don't have the depths of resources to handle a long, extended review process. They need to move on to other projects right away. If this product is not done, they're left in limbo for six months or up to a year or beyond. So, we need incentives in the timing of the review process.
There were several examples in the past year of Rx/Dx simultaneous review and approval, such as in the case of Pfizer's non-small cell lung cancer drug Xalkori and Roche/Plexxikon's melanoma treatment Zelboraf. Do you think these examples are the exception or will such cases be the norm in the future?
Zelboraf clearly had an ideal case scenario. It worked out very smoothly. The drug was escalated in terms of how it was reviewed, the diagnostic was well thought out in terms of the development of the drug, and so they were capable of going forward at the same time … It's a nice case study. However, if we could get a better roadmap to solidify this process or to make it more of established methodology instead of people trying to reinvent the wheel and trying to reproduce how the development process went for Zelboraf, then that would be very helpful for co-development and co-submitted products.
I envision many scenarios where drugs will be developed and [the sponsors] won't recognize the type of companion diagnostic they will need. They might start off with one companion diagnostic candidate and realize that isn't the one that adequately differentiates their subpopulations of responders and non-responders or [identifies] safety issues as well. They might need a new companion diagnostic … to satisfy that issue, and [that] might come in Phase III. Then you'd have to work very quickly and the submission process would have to be staggered and then it wouldn't go as smoothly as Zelboraf did.
So, yes, this scenario [of simultaneous drug/test approval] may happen more often in the future, but at the same time, we need a more flexible, controllable roadmap of how it will be handled [so that] if it is going to take longer for the drug [to be developed], then the diagnostic will not be negatively impacted.
Also [with regard to] the meeting process … we should have some stake in the ground that all four parties, [the drug company, the diagnostic maker, FDA's drug and device division,] will meet together and we will ensure it happens this way.
Have you gotten any insights from the FDA on any new guidances that might be coming along the pipeline in 2012?
The FDA has said that they might modify this draft [companion diagnostics] guidance to include some of the newer perspectives. They have also said that they will put together a more detailed co-development process guidance. Also, I believe there will be several other companion diagnostic-related guidances coming from multiple centers besides OIVD.
Does the white paper you mentioned earlier have consensus among the working group? Beyond the issues we've already discussed, does that white paper highlight any issues we've not yet touched on?
The majority of the white paper does have consensus with the members of the Companion Diagnostics Working Group. It was assembled with input from all the members of the working group. In that paper, we have put in some perspectives about regulation of lab-developed tests, which are not exactly in alignment with some of the providers of lab-developed tests, who want to have more flexibility there. But all of the IVD manufacturers agree that since a therapeutic drug is an FDA-approved product, a diagnostic that relates to it in indication and labeling should also be an FDA-cleared or –approved product.
I've noticed anecdotally in the industry that many of the lab-developed test providers have a feeling that [regulation] is heading this way for almost all diagnostics. There are different industry organizations that remain firmly opposed to any FDA contact with LDTs. But a lot of the individual companies I've spoken to feel that the FDA is heading in that direction.
And when will the white paper be released?
The document is virtually done. Some of statements in the paper don't have or would not have 100 percent consensus with all AMDM members. So, the AMDM would like us to formulate the white paper into an educational document before the association releases it. The AMDM has said that a paper like it could be released by individual members of the industry [who] happen to also be members of the Companion Diagnostic Working Group. So, we may put together such a document and give it to [OIVD Director] Alberto Gutierrez or [Director of Personalized Medicine at OIVD] Elizabeth Mansfield to represent what we as regulatory professionals in the industry feel is valuable to our industry membership. In that way, AMDM would not be affiliated with the more sensitive aspects of the document.
I plan on presenting it that way first, after I get some other industry members to sign off on it. Later on, we can make a shorter, open-ended educational version that AMDM can use as its publication.
Are there any other issues that you'd like to highlight that industry stakeholders you've worked with are concerned about?
One of the issues the [diagnostics] industry has been discussing, outside the scope of the white paper, is that the OIVD is a rather large and complete office, and has much of the structure of a large FDA center, but it doesn't have the authority of a center. The OIVD has to deal with CDER and CBER, but it's only an office and not a center. Some of my colleagues have said that maybe diagnostics should have a center unto themselves.
A diagnostic is not really a device. So, in my opinion, [diagnostics] should be viewed as a separate category of medical product altogether, and there could be a separate center for diagnostics. If such a center had that authority, then it could have the manpower to review and regulate LDTs as well.
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