By NANCI BOMPEY

FDA recently made its first breakthrough drug designation but is still grappling with how sponsors will utilize the expedited development pathway

that was created as part of the recently enacted FDA Safety and Innovation Act, agency officials revealed this week. The revelation came as stakeholders this week proposed qualitative criteria the agency could use to evaluate eligibility for the new designation and categories of drugs that could qualify for the expedited development pathway.

Janet Woodcock, head of FDA’s drug center, said Wednesday (Nov. 14) at the Friends of Cancer Research Annual Conference on Clinical Cancer Research that the agency has designated one product as a breakthrough therapy but declined to say which company or product received the designation. The breakthrough designation is intended to expedite the drug development timeline for treatments of life-threatening diseases showing early clinical activity.

“We have recently sent out a breakthrough designation,” Woodcock said, adding that divulging information about the product and company is up to the sponsor. She added that FDA is also evaluating other requests for breakthrough designation and working on guidance for requesting the designation as well as defining the criteria for a breakthrough product.

“The real issue is not the designation, it’s what do we do after we get it designated: How do you work on making sure the trials are the most parsimonious trials you could do and still get you the information you need in a timely manner and that is going to be challenging,” Woodcock said. “But the key is that we are all going to work on it together because it is challenging instead of just waiting until it becomes an urgent problem that we haven’t solved for any given treatment.”

Bob Temple, deputy director for clinical science in FDA’s drug center, said the breakthrough concept is not entirely new and contains similar elements to other expedited pathways the agency employs, but FDA now has an obligation, under guidance from Congress, to pay particular attention to the idea and “get its house together,” including instituting similar behavior among all review divisions. “This is a much more clear message that we need to have a systematic and organized approach,” Temple said.

FDA could look to suggestions from a panel convened as part of the conference as it develops the new pathway, with the breakthrough concept developed during a similar panel last year. This year’s panel sought to identify criteria for designating a product as breakthrough, categories of drugs that could fall under the new designation and the designation process itself.

The panel proposed using qualitative criteria for evaluating if a product qualifies as a breakthrough therapy, with an ultimate determination done on a case-by-case basis. These criteria include that the disease will be serious with no standard of care or a standard of care with 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, including substantial clinical efficacy or a superior clinical therapeutic index compared to the standard of care in a similarly defined population; and the therapy should typically have a compelling scientific rationale and promising mechanism of action.

“This pathway should not be viewed as a default pathway for all oncology drugs,” the panel said in an issue brief. “Defining a threshold of evidence required to obtain Breakthrough designation is necessary to provide some degree of consistency and predictability to the process.”

Further, the panel proposed five categories of breakthrough therapies, including drugs that address conditions with poor outcomes for which no established standard of care or available concurrent control exist, including drugs that demonstrate efficacy in previously untreatable diseases or refractory populations; drugs that provide substantial therapeutic improvement over existing, established standards of care for conditions with poor outcomes, including novel agents that act through a different mechanism than the existing treatment 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; and drugs that previously demonstrated efficacy in a tumor type driven by an identified mutation that show substantial clinical efficacy in an additional tumor type with the same mutation.

The panel also proposed that a sponsor be allowed to initiate discussion for consideration of a potential breakthrough therapy designation at the time of an Investigational New Drug submission or anytime thereafter prior to receiving marketing approval, with the pre-IND meeting an opportunity to discuss and agree on evidence needed to meet the breakthrough therapy criteria and the contents of a designation request, the potential timeline of a request and the content of the IND.

The request for designation should describe the category the therapy would fit into, expected outcomes for that population, any existing therapies that are available, the scientific rationale and mechanism of action that enable the drug to meet the designation, early phase clinical study results, and a potential clinical development plan and steps to streamline manufacturing and development of a companion diagnostic, if necessary. In the event of a non-designation, FDA should issue a letter explaining its rationale and recommendations for what criteria would need to be met for the designation.

Sandra Horning, senior vice president and global head of clinical development for hematology/oncology at Genentech and a member of the panel, said it will be up to FDA to determine the criteria. “(M)y assumption is that we will want to be judicious about these early candidates for breakthrough and be sure that they really do meet the threshold that we’ve outlined and fit into the categories and so forth,” she added.

Horning said not only will these drugs have to show substantial levels of efficacy but those levels will need to be observed early, with those cases likely based on a strong understanding of the science and mechanism of action in molecularly defined subsets, which could aid in selecting candidates for breakthrough designation.

Temple said FDA and sponsors will need to think about how effects seen in small populations could make a convincing case for utilizing the pathway.

Further, he said drugs that show a major improvement in quality of life or fewer side effects compared to other therapies could be a basis for a breakthrough designation, along with drugs that show more durable responses or a drug that works in sub-populations.

Temple said he expects many of the designations could come from therapies that show a response rate for populations that have been unresponsive to other treatments.

“It is very tempting because you expect the response rate to standard therapy to be essentially zero,” Temple said. “Even a relative modest effect size is pretty convincing that you’ve got something special so I think a lot of them are going to be for that.”

Richard Pazdur, director of the Office of Hematology and Oncology Products at FDA, warned that there also needs to be an understanding that some breakthrough therapy designations could be revoked if the initial results are not borne out in further clinical experiences.

Temple noted that a similar process exists for fast track designation and said that process could apply for breakthrough therapies too. Further, he said while the safety database may be reduced for breakthrough drugs, sponsors will be expected to conduct trials where safety issues could be detected and FDA also plans to utilize registries or other surveillance tools to watch for adverse events.