The promise of an expedited development pathway for “breakthrough therapies” is potentially one of the biggest game-changers to come out of the FDA Safety and Innovation Act, and it has certainly generated excitement among FDA, industry and patient groups. But the promise of speeding innovative medicines to market could be blunted unless issues related to manufacturing, companion diagnostics and international harmonization are adequately addressed.

That was the message from a multi-stakeholder panel discussion at the Nov. 14 Conference on Clinical Cancer Research, co-sponsored by the Friends of Cancer Research and the Engelberg Center for Health Care Reform at Brookings.

Stakeholders envision earlier discussions between FDA and sponsors to prevent manufacturing issues from becoming an obstacle to commercialization.

If a drug is ushered through the development process, the hold-up may come from other areas, panelists and FDA representatives agreed. Discussions surrounding chemistry, manufacturing and control issues for new drugs and biologics will need to take place much earlier in the clinical development process than currently happens to avoid a situation where a breakthrough therapy is approved but the manufacturing processes are not in place to support commercial marketing.

Breakthrough treatments that require companion diagnostics also could be potentially problematic, as the development, validation and approval of the diagnostic may not be able to keep pace with the drug’s abbreviated clinical development program.

Finally, the breakthrough designation may have little practical effect in shortening development time if sponsors must still conduct the full complement of clinical trials necessary to satisfy regulators across the globe.

The First Breakthrough Therapy Designee Is …?

The breakthrough therapy provision in FDASIA is aimed at shortening the development time for drugs intended to treat serious or life-threatening conditions and for which preliminary clinical evidence suggests a substantial improvement over existing therapies.

The designation was, in part, an outgrowth of discussion at the Friends of Cancer Research/Brookings cancer conference in November 2011, when a panel of agency representatives and stakeholders collectively proposed an expedited development pathway model for drugs with early evidence of large treatment effects Also see "Expedited Approval Pathway Concept Draws Strong Support But Different Proposals" - Pink Sheet, 5 December, 2011..

Under FDASIA, sponsors must request that their product be designated as a breakthrough therapy, and FDA must respond within 60 days. For drugs receiving the designation, the agency must work in a variety of ways to expedite the products’ development and review, including providing timely advice to the sponsor to ensure the development program is as efficient as possible and involving senior managers and experienced review staff in a collaborative cross-disciplinary review.

Under the law, FDA must issue draft guidance by January 2014 on the process and criteria for making designations and actions the agency will take to expedite development and review.

However, sponsors are not awaiting formal guidance before testing the waters. FDA has established some basic guidelines for submitting a designation request and Office of New Drugs Director John Jenkins told a recent rare diseases conference that three or four such requests had already been filed Also see "Industry Wants A Breakthrough Therapy, Even Without All The Standards" - Pink Sheet, 29 October, 2012..

At least one of those requests has been approved, although the identity of the recipient and the product have not been publicly disclosed.

“We have recently sent out a breakthrough designation, but I can’t tell you who,” Center for Drug Evaluation and Research Director Janet Woodcock said at the Nov. 14 conference. “That’s up to the company to say what company it was or what drug it was for.”

Criteria For Breakthrough Designations

Although FDA has yet to lay out the criteria it will use for designating products as breakthroughs, a panel comprising representatives from academia, industry, the National Cancer Institute and patients has developed its own proposal, in the form of an issue brief presented and discussed at the FOCR/Brookings event.

“We all think that this pathway should actually be reserved for exceptional new drugs that have the potential to profoundly change how a disease is being treated,” said panelist Percy Ivy, associate chief of NCI’s investigational drug branch.

The brief proposes three qualitative criteria for making breakthrough designations. The disease under study should be either debilitating or life-threatening with no established standard of care, or with a currently accepted standard of care that results in poor clinical outcomes. The designation should be based on compelling early evidence suggesting major clinically meaningful improvement over existing therapies in a defined disease setting. Finally, the therapy will typically have a compelling scientific rationale and promising mechanism of action, such as targeting a molecular driver of a biologically characterized disease.

Panel member Sandra Horning, senior VP and global head of clinical development for hematology/oncology products at Genentech Inc., said it is likely that drug candidates will be designated as breakthroughs “based on a strong understanding of the underlying science, mechanism of action, and very likely in molecularly defined subsets.” It is expected the pathway will be used largely in situations where patient populations are refractory to standard therapies, she said.

The issue brief also describes five potential categories of breakthrough therapies (see box).

Five Potential Categories Of Breakthrough Therapies

Drugs that address conditions with poor outcomes, which may be defined by clinical or biologic subsets of disease, for which no established standard of care or available concurrent control exists. This includes drugs that demonstrate efficacy in previously untreatable diseases or in refractory populations.
Drugs that provide substantial therapeutic improvement over existing, established standard of care for conditions with poor outcomes. This includes novel agents that act through a different mechanism of action than the existing standard of care, and second-generation targeted drugs that address unmet needs not addressed by first-generation compounds.
Drugs that provide a substantial therapeutic index advantage over a standard of care with well characterized efficacy and safety in a similarly defined population.
Drugs that dramatically enhance the activity or tolerability of an existing regimen.
Drugs that have previously demonstrated efficacy in a tumor type driven by an identified mutation or pathway alteration and have shown substantial clinical efficacy in a different tumor type with the same mutation/alteration.

Although he was not a signatory on the issue brief, CDER Deputy Director for Clinical Science Robert Temple participated in the panel discussion and said one of the threshold questions surrounding breakthrough designations is when can early data make a sufficiently convincing case that a drug appears to be strongly efficacious.

One obvious case is when a drug makes the tumor go away, Temple said. “Are there other settings in other diseases where you might have a similarly dramatic effect? I think as we get more genetically oriented, we may be able to find places where drugs have very dramatic effects.”

“What it really calls for is a situation where looking at individual patients can be convincing,” Temple continued. “That’s not so common in most drug development settings, but there may be more of them than we know about.”

Manufacturing As A Rate-Limiting Hurdle

The issue brief includes proposals for steps FDA can take to expedite the development process once a designation request is granted, with a view toward an “all hands on deck” approach at the agency. This includes the need for regulatory flexibility in current requirements relevant to CMC issues and companion diagnostics so that approval of a breakthrough therapy is not delayed by other factors once the clinical evidence is gathered.

In a clinical development program, there are multiple CMC-related steps that follow their own timeline, Horning said. However, the amount of time needed to address and resolve CMC issues will be compressed if a breakthrough agent is ready for approval following an abbreviated development program.

The brief suggests that certain CMC-related processes, such as validation requirements that do not directly relate to patient safety, could be deferred until after drug approval. Leveraging regulatory acceptance of prior platform knowledge with respect to both process and products would allow for significant acceleration on the CMC side, the brief states. The use of comparability protocols also should be leveraged, because “this will enable the efficient execution of post-approval changes, technology transfer and scale up changes that will be required under such a program,” the brief states.

Commercial drug supply is also a critical factor. “The sponsor needs to be able to manufacture sufficient drug to supply a reasonable number of patients,” the brief states. “The ability to reliably manufacture ‘reasonable’ quantity should be a prerequisite for approval.”

Although Woodcock was not part of the panel discussion on breakthrough therapies, she spoke later in the meeting about how manufacturing issues could be the “rate-limiting” step to true acceleration in the development and commercialization of such treatments. “I think we’ll have drugs that tend to develop rapidly and will show their benefit very quickly,” she said. “The bad news is we’re going to have to figure out new ways to make them.”

When drugs enter clinical development, they are manufactured at a very limited scale “and it’s very difficult to scale them up and make them reliably,” she said. “I think when we get into these expedited programs, we’re going to have to have a separate meeting that starts very early in clinical drug development on manufacturing and what is the scale up plan and what’s that going to look like.”

Genentech’s Horning said there will need to be a lot of coordination between FDA and the sponsor with regard to CMC issues. She noted the issue brief recommends that when sponsors file their designation requests they include proposals for how manufacturing-related issues could be streamlined.

Flexibility In Dx Development Timeline

Issues surrounding development of companion diagnostics also require early attention and regulatory flexibility so that breakthrough drug approvals are not delayed, the issue brief states. As with manufacturing, the time in which sponsors have to develop and validate a companion diagnostic would be compressed with an abbreviated development program for a breakthrough therapy.

Under a 2011 draft guidance, FDA typically requires contemporaneous approval of a targeted therapy and its companion diagnostic. However, the guidance allows for approval of a therapy intended to treat a serious or life-threatening condition absent an approved companion diagnostic.

“This flexibility could be utilized to enable approval of the breakthrough drug without concurrent approval of the co-Dx,” the brief states. “This may enable minimal development of the assay for the registration trial … in order to support expedited clinical studies for breakthrough drugs.” This could lead to registration of a companion diagnostic on the basis of a bridging study or to conditional approval pending further studies.

It would be irresponsible for the agency not to approve a breakthrough therapy that showed strong efficacy with an off-the-shelf laboratory test, FDA’s Temple said.

Temple sought to tamp down concerns that approval of breakthrough therapies would necessarily be delayed by the absence of a companion diagnostic that passes regulatory muster with the Center for Devices and Radiological Health.

“Suppose someone uses a locally available diagnostic agent off the shelf and does a trial and shows just a fantastic response in people who have that marker. Well what are we going do? Are we going to say, ‘No, you can’t have that approval even though it saves lives just because CDRH hasn’t gotten to it?’ We’re not going to do that,” Temple said.

“We’re going to urge that the test be brought through the system, that it be refined,” he said. “But if you have a dramatic effect on something with a shelf test … we would probably approve it because it would be irresponsible not to.”

An Eye Toward Harmonization

The issue brief also cites the need for harmonization with other regulatory agencies, particularly the European Medicines Agency, on data requirements for treatments designated by FDA as breakthroughs.

Absent an equivalent development pathway in the EU, “drugs that receive breakthrough designation in the U.S. may still be required to go through the traditional drug development pathway for EMA approval. These differing requirements may make the breakthrough pathway an unattractive option for drug sponsors,” the brief states.

The paper suggests that EMA may be able adapt its own expedited development pathways, such as the “exceptional circumstances” program that allows for limited clinical development in situations where comprehensive efficacy and safety data are not feasible, to be compatible with the breakthrough therapy pathway.

During the development of the FDASIA legislation, Woodcock cited the need for FDA and EMA to “be on the same page” about abbreviated development programs for breakthrough therapies Also see "“Breakthrough” Designation Another Harmonization Opportunity, Woodcock Says" - Pink Sheet, 9 April, 2012..

Speaking from the audience at the FOCR/Brookings meeting, FDA Office of Hematology and Oncology Products Director Richard Pazdur echoed those concerns. The breakthrough therapy provision in FDASIA “may not be as promising if sponsors have to do large randomized trials for European regulators. There really has to be a consensus here with the EMA and the FDA on what they … will accept,” he said.

Watching The Designation Disappear

Pazdur said there also needs to be thought given as to what happens when subsequent studies of a breakthrough-designated product fail to confirm the encouraging efficacy signal seen early in development.

“We have to have an understanding that when we designate something as a breakthrough therapy that there may be some of these products that this designation may be taken away from,” Pazdur said. “That’s the reality of the world and I think we have to come to terms with that.”

Temple suggested the agency’s guidance on breakthrough designations would account for such a scenario. “The concept clearly includes the possibility that it looked really good at first and then now it doesn’t and so it’s designation could go away,” he said. “I’m sure there will be a provision for that.”

Proposals for improving and expanding the use of accelerated approval under FDASIA were discussed by a separate panel at the FOCR/Brookings conference (see related story, Also see "Redefining Accelerated Approval Criteria Would Expand Pathway’s Use, Panel Says" - Pink Sheet, 26 November, 2012.).

“Breakthrough Therapy” Development Speed May Be Tempered By Manufacturing Hurdles

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