Skip to content

Pink Sheet – FDA 'Intercenter Institutes' Legislation Headed for Senate Mark-Up

Pink Sheet – FDA 'Intercenter Institutes' Legislation Headed for Senate Mark-Up

The Senate Health Committee has unveiled formal legislative language to direct FDA to test consolidated medical product reviews in at least one disease area.

The legislation would direct FDA to create “Intercenter Institutes” focused on specific disease areas. Each Institute would “develop and implement processes for coordination of activities, as applicable to such major disease area or areas, between the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health.” (See box for the full legislative text of the proposal.)

The “centers of excellence” idea was first proposed by Friends of Cancer Research last year as a possible add-on to the “21st Century Cures” legislative process, but the new Senate bill is the first time it has appeared as a formal legislative proposal (“The Next Step In FDA Reform? Consolidated Drug/Device Groups Proposed By FOCR” — The RPM Report, December 2015).

The review pilot is part of a list of FDA and NIH provisions (PDF) expected to be considered at the final Senate Health Committee mark-up on innovation measures in April. Most of those other elements concentrate on hiring at the agencies and are already part of the House-passed “Cures” bill.

The legislative language leaves the focus, scope and details of the project to FDA’s discretion. The bill does not dictate any specific disease areas for FDA to choose, and it presents a menu of ideas for ways the Institutes could work but not specific prescriptions for organizational or policy changes. It would leave all those decisions to FDA.

That very much fits with FOCR’s approach to the initiative. The advocacy group wants legislation to push the idea forward, but also wants FDA to take the lead on determining where the greatest impact can happen with the least disruption.

Thus, the only explicit obligation in the bill is a deadline for FDA to publish an implementation plan (within one year of enactment), and then establish at least one Institute within a year of the close of the 60-day comment period on the implementation plan. FDA could decline to create a center following a formal, published determination that the idea “would not be feasible or would not benefit the public health.”

That said, oncology is all but certain to be a starting point – and the test may begin regardless of the outcome of the legislation. The Obama Administration has already proposed an Oncology “center of excellence” as part of the Vice President’s cancer “moonshot” initiative (“Cancer Moonshot Initiative: FDA To Form Virtual Oncology Center of Excellence” — “The Pink Sheet” DAILY, Feb. 1, 2016).

FOCR has suggested pilots could be done in other areas like cardiology, neurology and infectious diseases, with the goal of making certain that the proposal isn’t treated as “just” for oncology – but rather as a broader new approach to medical product regulation.

Companion Diagnostics May Be Starting Point

But how, exactly would a pilot program begin?

That was the subject of a Capitol Hill briefing on the “Centers of Excellence” concept hosted by Friends of Cancer research at the end of February. One point of consensus among stakeholders at the briefing is that drug/diagnostic combination product reviews may be an obvious place to start.

Former FDA Commissioner Mark McClellan (now director of the new Duke-Margolis Center for Health Policy at Duke University) pointed to companion diagnostics as a logical starting point to test the concept of greater integration of medical product reviews.

McClellan, who at times played the part of devil’s advocate among the panelists, favored a more informal realignment, at least initially, that would enhance communication between the different centers. McClellan’s concern, which he repeated several times during the hour-long panel, is that the cash-strapped agency does not have the resources to fund an organizational overhaul (“Don’t Rush To Reorganize FDA, McClellan Says” — “The Pink Sheet,” Feb. 29, 2016).

“Given the limited resources at FDA, making them go as far as possible means it may not be the most efficient thing to reorganize all the way around diseases of treatment areas,” he said. “There are a range of options that can be used that have a more progressively effect on structure and organization at the agency.” McClellan suggested first identifying the priority list of challenges, and then see where a new structure might “help more than hurt.”

McClellan’s cautious tone carries added weight, as he was the FDA commissioner who oversaw the last major reorganization of product reviews in the consolidation of therapeutic biologic reviews under CDER.

However, McClellan made clear that he agreed with the rest of the panel that it is time to consider next steps to reflect the evolvoing science, particularly in the field of oncology where companion diagnostics and new cellular or gene therapies are emerging quickly.

McClellan pointed to companion diagnostic reviews as a good place to start, given the rapid growth in the development of targeted treatments, and how well that area of R&D fits with the Obama Administration’s Cancer “Moonshot” and Precision Medicine Initiative. But he shied away from a full-on bricks and mortar restructuring, specifically mentioning the cross-Center consults as a model to be explored in the short term while larger structural issues are addressed.

“Not to defend the status quo, but there are some good efficiency reasons for having the same expert regulatory staff dealing with products across a number of areas,” McClellan said. “Looking at where the biggest bang for the buck is going to be in terms of a more integrated structure is very important.”

Complete The CBER/CDER Merger?

Another option might be to focus on completing the integration of CBER and CDER when it comes to therapeutics for oncology. That was the starting point for remarks by former Center for Drug Evaluation & Research Director Steve Galson (now head of global regulatory affairs and safety at Amgen Inc.) during the panel.

Galson was particularly enthusiastic about FOCR’s proposal, arguing that FDA’s siloed drug-device-biologics structure no longer fits with the modern world of drug development. Targeted drug development and precision medicine, advances in genomics and an evolution in drug delivery systems should prompt another look at how the agency that regulates those areas is structured, he said. “I see this even more now than I did when I was at FDA.”

Galson pointed specifically to the development of immunotherapies for melanoma as an example of why a realignment of the Center-specific structure is needed. Amgen’s cancer vaccine Imlygic, he noted, was “reviewed fast” by the Center for Biologics Evaluation & Research and approved last October; the vaccine is a herpes simplex-1 virus that is injected directly into cancer tumors and therefore fell under the CBER’s jurisdiction (“Amgen’s Imlygic Approval A Milestone For Oncolytic Cancer Vaccines” — “The Pink Sheet” DAILY, Oct. 27, 2015).

However, other immunotherapies have been reviewed by the Center for Drug Evaluation & Research’s Office of Hematology & Oncology Products. And that, Galson says, raises two issues: One, it would be most preferable for oncologists – currently housed in CDER – to review oncology products. Not only do oncologists have the expertise required to balance the benefits and risks of a single application, they can also weigh that individual product against the spectrum of available treatments. That alone, Galson said, would argue for a “Centers of Excellence” model.

Looking further down the road, as Amgen explores the potential for improved efficacy with Imlygic in combination with other immunotherapies, it is unclear whether review teams from two different Centers would review a combination product.

That issue is likely to become more pressing as cell based therapies like CAR-Ts and eventually gene therapies or gene-editing approaches mature to the application stage.

Decisions ‘Have To Be Made By One Person’

Galson stressed the importance of FDA speaking with one voice: “The decisions that are most complicated have to be made by one person. You can’t have two people making one decision – it’s a formula for inefficiency.”

Galson was quick to acknowledge that FDA is already taking steps to address coordination across centers, and that the agency is well aware that sponsors face differences in communication and regulatory policy when Centers work together on the review of a combination product. Most recently, an internal assessment (PDF) of FDA’s inter-Center consultations identified key areas where the review system for combination products could be streamlined, many of which have been addressed (“FDA’s Combo Product Consultations To Be Streamlined” — “The Pink Sheet” DAILY, Oct. 15, 2015).

In many ways, a restructuring would clean up the missing pieces from the CDER/CBER merger from 2004, when regulatory oversight of therapeutic biologics moved into the Center for Drugs. Products like monoclonal antibodies, which were the rage a decade ago, were included in the transfer, but cancer vaccines and gene therapies – which seemed like science fiction but are now hot new areas for R&D – were left in CBER.

Career FDA officials (at least in the drug center) appear to be generally supportive of moving forward with some form of consolidated review model – though there are likely to be differences of opinion within the agency on what a new structure would look like and how far-reaching it would be.

Panelists at the briefing discussed a range of options that could be implemented:

  • Encouraging more informal conversations between the Centers;
  • Creating a formal process for the development and review of combination products
  • Greater use of Commissioner-led initiatives like the Biosimilars Implementation Commission, or
  • More significant bricks and mortar restructuring that would move offices and staff

While FOCR is interested in helping to shape the discussion around what that new organizational structure would look like, Founder and Executive Director Ellen Sigal, PhD, made it clear she would like more than a promise for better communication between Centers. “This integration has to be real. It can’t be ‘let’s all be friends and talk.’ At some point it has to have some teeth to it. It has to be thoughtful, and it has to be done in a way that is real.”…