Executive Summary
FDA is close to announcing a new “Oncology Center of Excellence” to consolidate drug, biologic and device review functions in cancer. In the run up to the announcement, CBER has been stressing the need to preserve its culture and experience with novel manufacturing techniques.
FDA is moving forward with a “Center of Excellence” in oncology as part of the Vice President’s cancer “moonshot” initiative.
An announcement of the new center is coming “soon,” Commissioner Robert Califf promised during a June 16 Friends of Cancer Research/Alexandria Summit conference on real world evidence. While the integration of drug, device, diagnostic and biologic cancer review activities was not directly related to the topic of the conference, the idea was championed by FOCR as a logical next step in improving the regulation of cancer therapeutics. (“The Next Step In FDA Reform? Consolidated Drug/Device Groups Proposed By FOCR” — The RPM Report, December 2015)
Califf provided the update in the context of meeting he attended with the Vice President, and noted that he was accompanied by Office of Oncology & Hematology Director Richard Pazdur—in case there was any mystery about who is likely to have the lead role in an integrated oncology group. As was the case with the broader CDER/CBER therapeutic integration a decade ago, the goal of the “center” is to try to expand the regulatory reach of the drug center.
Which naturally begs the question of whether there are risks or downsides to shifting control from the other centers that oversee biologics and device/diagnostic reviews.
During the recent Food & Drug Law Institute annual meeting, Center for Biologics Evaluation & Research Director Peter Marks offered his views on what should be protected in the context of any integration.
In particular, he highlighted CBER’s existing expertise in complex biological manufacturing, flexibility in designing trials for biologics for small patient populations—and the center’s long history of regular, informal regulator-sponsor discussions on novel biologic therapies.
Marks framed his center’s role as “a boutique for complex biologics.” His public posture is not strongly against the creation of a new oncology center but urging caution in how tasks are reorganized around oncology reviews.
Marks is a good spokesperson for the current strengths of CBER’s role in new oncology technologies. He has an extensive personal background in hematology/oncology practice that gives weight to his arguments for looking carefully at some of the strengths of CBER activities. (“CBER’s New Director “Marks” A New Era For Biologics Regulation” — The RPM Report, January 2016)
The “CDER-ization” of CBER?
Marks told a session on CBER issues at the FDLI meeting on May 4 that the establishment of a new Center of Excellence needs to be “thought through” carefully. He portrayed CBER as being a center that specializes in technologies on the “cutting edge” without clear regulatory pathways.
The CBER director is politic about discussing the proposed consolidation and did not pick an open, public squabble with CDER and the Office of Hematology & Oncology Products. In fact, he refused the bait when a fellow FDLI panelist (Sheldon Bradshaw, King & Spalding and formerly FDA chief counsel under Bush II) asked about the threat of “CDER-ization” of the biologics center.
“There are complaints about difficulty of interaction with CDER,” Bradshaw noted. “From my perspective, I would hate to see some of these novel biologics that are being studied for oncology moved over to CDER and lose some of the flexibility that you are describing. I don’t think you would have the same flexibility at CDER.”
Marks focused on ways that the center could continue to provide close consultation to sponsors. He said his goal for closer coordination with the other centers would have “somebody in direct contact to the center for drugs or center for devices so that when you interact with them that you don’t see any difference in how we deal with issues.”
If FDA creates a Center of Excellence, Marks suggested, the agency should work to “keep the depth of what CBER has and potentially benefit. To the extent that it is great to have a dialogue with all of the oncology expertise in the organization, that’s to the benefit” of the approval process.
“If we can facilitate that while we don’t lose exactly what we were talking about …the ability to have the somewhat more intimate – for lack of a better word – dialogue that we [CBER] tend to have with sponsors, it can potentially be beneficial.”
Marks pointed out that CBER (at 1,138 FTEs) is now the smallest of the three FDA medical product centers. “We’re just lucky to be smaller because we do not have the volume,” he observed. “It is not a knock on Center for Drugs; they have a lot more volume” of applications to deal with. “It is kind of nice,” Marks said, “to have a boutique for complex biologics and also allows us to give the manufacturing considerations the attention that is needed.”
Marks noted the October 2015 approval of Amgen Inc.’s Imlygic (talimogene laherparepvec) oncolytic immunotherapy and said that CBER expects to see more similar therapies in the future in its purview.
He pointed out that CBER is looking at new endpoints in relation to immunotherapy, including reduced toxicity, and less impairment associated with treatments. In an apparent reference to the Imlygic review, he pointed out “if you have melanoma and you have a large limb that is unusable because of a big melanoma lesion and you can check that, that is a big event. I think we want to be flexible as we think about these things.”
The CBER summary basis of approval for the Amgen drug notes an internal debate within CBER as to whether the 6-month durable response rate (DRR) was sufficient for approval and clinically meaningful. The CBER reviewers showed flexibility in the resolution of that argument.
FDA notes that some members of the CBER review team recommended that the DRR be treated as a surrogate endpoint and that the drug be considered for Accelerated Approval. “However, other members of the review team accepted DRR as clinically meaningful, particularly in consideration of statements during the Advisory Committee meeting.” (“Does Imlygic Make The Case For FDA Oncology Center Of Excellence?” — “The Pink Sheet,” Apr. 25, 2016)
Comfort With Alternative Analyses
As part of its flexibility, CBER is willing to work with sponsors on different statistical approaches to analyzing new products, Marks told FDLI. “We need to be aware,” Marks said that some sponsors have products “for small populations and might want to use novel trial designs based on Bayesian or other statistical methods.”
CBER has “experts in this area,” Marks said, “and they are very willing to work with sponsors to help them with trial design, to try to help minimize the size to get statistical significance and develop trial designs that reduce the number of participants and thereby help move things along. We are very amenable to a new statistical or novel statistical design. Also to novel ideas of crafting and pooling data from different design trials: not the perfect solution but we want to work in that direction.”
That flexibility on statistical approaches is shared across both CBER and CDER, and primarily as trials relate to oncology and hematology products. CDER’s Director of Biostatistics Lisa LaVange has recently noted that a snapshot of CDER in 2013 showed 8 trials using Bayesian methods (three Phase 3 trials and fifteen Phase 1 and 2 trials). A 2006-2013 survey within CBER showed four Bayesian trials (two Phase 3 and 4 and two Phase 2).
CBER’s intense focus on manufacturing as an inseparable and intrinsic part of biologic finished products is one key reasons why the center’s review process is ideal for new technologies, Marks contends.
In a lot of the products reviewed by CBER, Marks observed to FDLI, “manufacturing is crucial to the ultimate product. Quality has to be engineered in by design; you can’t fix it at the end. What I mean by that is for a small molecule product, at the end of the day, you can terminally sterilize it, you can figure out what it is by putting it through an HPLC reading. On the other hand, if you have a live organism, you cannot bake it at the end – because you would kill it. Manufacturing becomes a very important part of the content.”
Manufacturing processes are a particular challenge to some of the therapies currently under CBER’s purview, such as the CAR-T (chimeric antigen receptor-modified T cells), which is a personalized immunotherapy that shares some features with a previous technology approved by CBER for the prostate cancer product Provenge (sipuleucel-T).
CBER’s “intimate relationships” with sponsors help the regulatory work on technologies without a clear, established pathway, Marks argued. The relationships allow reviewers to interact closely with sponsors as they “get to be closer to the technology. Some of these things are really amazing: 3-D printing for organs; for modifying cells so that we can take out a gene or more than one gene and put in a different gene.”
Uncertainty Around Regnerative Medicine
CBER also faces uncertainties regarding its role on other significant new technologies: gene therapies, tissues and stem cells (regenerative medicine). In fact, CBER appears to feel under pressure on multiple fronts regarding its regulatory mandate.
The Senate has discussed a conditional approval process for a broad group of CBER-regulated products under the rubric of regenerative medicine. There is a bill proposed (REGROW, S. 2689) for inclusion in the Senate companion bills to the House 21st Century Cures legislation.
Asked about the key considerations in anticipated applications for gene therapies, Marks focused on the need for extensive follow-up to assure the long-term safety and the duration of effect from gene therapies.
“Without speaking about specific products” in the gene therapy area, Marks said, “I think in terms of getting them to market, it is a matter of both having good evidence that you have efficacy and a good plan for follow-up to make sure that that efficacy and safety continue.”
Marks said it would be unwise to wait for premarket trials to understand long-term effects of gene therapies; that might mean waiting for a “whole generation” to make a decision. “You may not have durability at license,” Marks said. “You may just have to collect data over time to see how durable these effects are.”
He related the regulatory issues for gene therapies to another class of products under CBER’s purview, tissues. “As we go back to the tissue paradigm, some of the issues with tissues, it is really not a matter of whether the tissue is going to be efficacious or not, it is how durable it is.”
“Bumps In The Road” Ahead for Gene Therapies?
Marks warned that an emphasis of post-marketing experience for gene therapies is likely to lead to some rough spots in the future for the technology. Expanding from small initial efficacy studies to more post-market use and more post-market close monitoring is likely to turn up information about other effects of gene therapies.
“I am not trying to be pessimistic here,” Marks said. “You should be realistic that it won’t be surprising if there are some bumps in the road with gene therapies as they come on line. Remember they are going to be in small populations. Any drug, once you expand the population, the tendency is more adverse events.”
A clean safety record in a small number of people may be sufficient for initial licensure, but is not an assurance of the safety and efficacy profile after a longer, broader extent of use. “If you don’t have an adverse event in 100 people, that might be good enough to get something to a licensure. But after you treat 1,000 or 2,000 people, will you see something? It is possible. There is a benefit/risk calculation here.” Marks indicated that he favors being careful not to set the initial threshold too high. “Sometimes perfect may be the enemy of the good in this field.”
In fact, he ended his discussion of gene therapies at FDLI on a very positive note saying “if I look over the horizon, I would say one or another of these products is coming. It is going to come across the horizon.”
Marks expressed a “pet peeve” about the degree of caution expected by a segment of the population about genetically modified foods compared to an apparent predilection for more risks with gene therapies in humans. “We want our foods to be non-GMO, but we are willing to be pretty liberal with our genetic modifications of people. I think we have to be kind of consistent here.”
The gene therapy field encompasses a wide variety of approaches, Marks observed. “Gene therapies represent an incredibly complex array of different products – some of which you could imagine could be an off-the-shelf product much like almost any other drug – a vial or something to ingest. Or it could be a virus. Or it could be a cell in which there is a gene-based vector. It is really complicated across the spectrum of what gene therapies can be.”
The “entire spectrum” of gene therapy is regulated by CBER under Sec. 351, Marks pointed out. There are efforts, however, to move some products away from current controls. “Some have advocated that these therapies be regulated under a lower standard.”
CBER is feeling similar pressure in its regulation of cell, tissue and tissue-based products where its December 2014 minimal manipulation guidance attempted to draw a line on which products qualify for an exemption from biologic and drug regulatory approvals. Marks noted “it doesn’t take much to shift something from not needing premarket review to a full biological license application.”
To Marks, the primary issue for the cell and tissue products is “figuring out how to generate the data that will answer some of these questions from therapies that are done by practitioners across the country.” Collecting that data from separate physicians to form the foundation for regulatory decisions “is really one of our challenges,” Marks said. He maintained that there “has not been a wonderful systematic study of the effectiveness of these things.”
https://www.pharmamedtechbi.com/Publications/RPM-Report/12/7/CBERs-Bout…
