Meeting News

FDA commissioner: Greater efficiencies can unlock opportunities created by better science

Scott Gottlieb
Scott Gottlieb

CHICAGO — FDA officials are taking several steps designed to make the drug development review process more efficient while reducing costs and creating more opportunities for innovation, according to agency Commissioner Scott Gottlieb, MD.

Those strategies — which Gottlieb outlined during remarks at ASCO Annual Meeting — relate to all aspects of the continuum, including clinical trial recruitment, application submission and evaluation, and postmarket data collection.

“There are more reasons than ever for [patients with cancer] to expect to live longer lives, and to have a greater shot at long-term remission or even a cure,” Gottlieb told ASCO attendees. “To harness these opportunities, we need to make sure our regulatory processes are as sophisticated as the drugs we’re being asked to evaluate. ... That means building a dynamic regulatory environment across the entire lifecycle of product development.”

The success of this effort will hinge on establishment of a framework that breaks down artificial silos between clinical research and clinical practice, harnesses real-world data at the point of care, and enabling greater access to experimental therapies under evaluation in clinical trials by modernizing eligibility criteria and reducing barriers to trial access, Gottlieb said.

“This transformation isn’t optional,” he said. “The dysfunction of current drug pricing models is driven by an outdated construct for clinical trials, at least in part where failure is typically expensive and routine, and success is the exception. Without significant gains in productivity, the status quo is on the path to financial and scientific and clinical unsustainability. We need to make entire process more efficient without sacrificing one bit the scientific rigor.”

 

Trial eligibility and design

Traditional trial eligibility criteria often exclude patients most likely to receive the studied agent once it enters the market, Gottlieb said. These groups include the elderly, patients with poor performance status, and those with organ dysfunction or other comorbidities.

“The irony is that, even with broad exclusion criteria, oncology trials still have a staggering failure rate,” Gottlieb said.

He cited a study from researchers at MIT that showed the overall success of oncology trials in 2015 was 8.3%.

“High failure rates contribute to the high costs of drug development, putting upward pressure on drug prices,” Gottlieb said. “It also reduces the amount of competition that new drugs face when they enter the market.”

FDA has provided additional guidance to trial sponsors about how to include more underrepresented patients in trials, Gottlieb said. Last week, the agency issued a new guidance document for the inclusion of adolescents with cancer in adult oncology trials.

“Although most cancers in children and adults are distinctly different entities, there are some diseases that occur in both and span the adolescent age groups,” Gottlieb said. “If there’s no evidence that an investigational drug might have exaggerated toxicity in younger patients, then we’re encouraging sponsors to enroll adolescents into disease appropriate trials. [Because] the pharmacological parameters of adults and adolescents for most agents are comparable, early access to innovative drugs is warranted where there’s proof of principle and adequate dosing information to maximize potential for clinical benefit.”

 

Real-time oncology review

Gottlieb also introduced two pilot projects FDA has undertaken that are intended to improve how new applications are evaluated during the clinical portion of the review.

FDA’s Oncology Center for Excellence is piloting real-time oncology review, designed to make sure applications include the most relevant information to inform the agency’s review of a product’s effectiveness and safety, and that these data have been appropriately analyzed.

“Sometimes sponsors take an ‘everything but the kitchen sink’ approach to their applications because they don’t have clear guidance on what’s most pertinent,” Gottlieb said. “Or, the way they analyze data isn’t consistent with how FDA evaluates results. This can extend review timelines and obscure the most relevant facts.”

In the pilot effort, sponsors who decide to file for FDA approval immediately would begin sharing bottom-line data with the agency. Submissions would include key raw data and derived datasets, information about the study protocol and a draft of the package insert.

The agency essentially would “pre-review” the data to ensure completeness and adequacy, Gottlieb said.

“This informed pre-analysis gives reviewers and sponsors an early opportunity to address data quality issues,” he said. “The FDA can provide early feedback to a sponsor on the most effective way to analyze data to properly address key regulatory questions. By the time the sponsor files the application with the FDA, the agency’s review team would already be very familiar with the data and the analysis. Review teams will be in a better position to conduct a more efficient, timelier and thorough review.”

This approach may reduce the reviewer’s time by up to 30%, Gottlieb said.

“As we gain experience with this model, we believe that we can use this approach to create a dynamic data submission system that aligns the process around data quality based on early feedback and engagement with review teams,” he said. “Sponsors and reviewers will share real-time feedback, where issues of data quality and integrity can be addressed early in the process.”

Initially, the pilot will be focused on new efficacy supplements for already-approved cancer therapies. If proven effective, it could be applied to drugs and biologics under consideration for initial approval, Gottlieb said.

 

Assessment aid

FDA also is piloting use of a voluntary submission form an applicant uses to facilitate the agency’s assessment of a drug application.

“Under this templated approach to receiving applications, we’ll be using the sponsor’s structured file, which follows a new template format that we’re piloting, as the basis for our review,” Gottlieb said. “Instead of writing a separate analysis of the file, we’ll use the sponsor’s own submission as the document for layering in our review. Under this approach, we’ll annotate the sponsor’s drug file with our assessment rather than creating a separate document that recapitulates many of the same data tables.”

The template includes two parts — the applicant’s position, and FDA’s assessment of that position.

“This creates a more agile platform for reviewing data after the sponsor’s database is locked,” Gottlieb said. “The assessment aid reduces the administrative burden on FDA reviewers. This permits them to focus on key results and perform critical analyses that may have been omitted by the company. Importantly, the new format leads to a more dynamic review process where key regulatory questions can be answered more thoroughly and effectively.”

If a drug application moves through the process, the completed review — using the assessment aid — will be presented at an FDA Oncologic Drugs Advisory Committee meeting.

So far, the assessment aid will be used only for supplemental applications.

 

Manufacturing efficiency

FDA also has tried to maximize efficiency in manufacturing of approved cell-based oncology therapeutics, including chimeric antigen receptor (CAR) T-cell therapies.

“In contrast to traditional drug review, where 80% of the review is focused on the clinical portion of a file and maybe 20% is focused on the product issues, I’d say that this general principle is almost completely inverted when it comes to cell and gene therapy,” Gottlieb said. “The clinical efficacy is often initially established early, and sometimes in small series of patients. It’s the product questions that are more complex and uncertain.”

Representatives of FDA’s Center for Biologics Evaluation and Research are working with NCI and others to create requirements for good manufacturing processes related to cell-based manufacturing and how to optimize and standardize production processes.

“Creating more standardization across the FDA’s requirements for manufacturing requirements could enable more facilities — like hospitals or research facilities — to scale up cell-based manufacturing, and expand local treatment options for patients,” Gottlieb said. “It could also allow them to distribute production costs over larger patient populations, and avoid product shortages.

“Different treatments could share a common platform for manufacturing and delivering these therapies,” he added. “This could reduce the amount of novelty as institutions take on the task of delivering multiple different cell and gene therapy products. It could also make it cheaper and easier for one platform to be used to manufacture and deliver multiple different treatments.”

 

CAR T database

FDA also will expand its development of a CAR T database, Gottlieb said.

The goal is to aggregate more data about long-term toxicity potentially related to cytokine release syndrome, neurological side effects and off-target effects, as well as long-term patient outcomes.

“Better understanding these toxicities may help us make better recommendations to help prevent them,” Gottlieb said. “Also, many of the potential issues associated with gene therapy are long-term considerations related to off-target effects and the durability of response that these treatments offer.”

More than 1,000 patients should be included in the database by this summer, Gottlieb said.

“We’re planning to use these data to conduct research on how to best manage class-wide effects and identify potential predictive biomarkers for durable remission approaches that can help improve the benefit and risk of these promising new treatments,” Gottlieb said. “Eventually, we may develop ways to allow outside investigators to interrogate some of this information. Our aim is to expand scientific opportunities to evaluate key public health questions, while making sure that we safeguard nonpublic information.”

 

‘A turning point’

Some consider any FDA change in regulatory policy or the policy requirements the agency imposes “as a binary choice between speed and safety,” Gottlieb said.

He characterized that as “a false dichotomy.”

“If we are adopting the right policies, if we’re focused on incorporating the best science and making our own process more efficient, we can achieve greater certainty around the parameters that matter most to patients and providers,” he said. “And yes, we can also make the overall development process itself less costly, less risky and less time consuming. In this way, we can lower the barriers to bringing new science forward with the ultimate goal being to make sure more patients can benefit sooner from new advances.”

Gottlieb said the initiatives he outlined are designed to create new efficiencies and “help unlock the opportunities offered by better science.”

“We’re at a turning point in the history of cancer, and the openings that science offers,” he told ASCO attendees. “We’re challenging ourselves at the FDA to make sure that we have the best approach to evaluating new products. And we’re doing so in ways that are modern and efficient, so that we’re making the best us of our own resources, we’re facilitating innovation and we’re fulfilling the needs of patients. We look forward to working with you on these and many other efforts as we advance our shared goals: To reduce the personal and societal burden of cancer and to bring more patients hope for a cure.” – by Mark Leiser

Reference:

Gottlieb S. FDA commissioner’s remarks. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosure: Gottlieb reports no relevant financial disclosures.

Scott Gottlieb
Scott Gottlieb

CHICAGO — FDA officials are taking several steps designed to make the drug development review process more efficient while reducing costs and creating more opportunities for innovation, according to agency Commissioner Scott Gottlieb, MD.

Those strategies — which Gottlieb outlined during remarks at ASCO Annual Meeting — relate to all aspects of the continuum, including clinical trial recruitment, application submission and evaluation, and postmarket data collection.

“There are more reasons than ever for [patients with cancer] to expect to live longer lives, and to have a greater shot at long-term remission or even a cure,” Gottlieb told ASCO attendees. “To harness these opportunities, we need to make sure our regulatory processes are as sophisticated as the drugs we’re being asked to evaluate. ... That means building a dynamic regulatory environment across the entire lifecycle of product development.”

The success of this effort will hinge on establishment of a framework that breaks down artificial silos between clinical research and clinical practice, harnesses real-world data at the point of care, and enabling greater access to experimental therapies under evaluation in clinical trials by modernizing eligibility criteria and reducing barriers to trial access, Gottlieb said.

“This transformation isn’t optional,” he said. “The dysfunction of current drug pricing models is driven by an outdated construct for clinical trials, at least in part where failure is typically expensive and routine, and success is the exception. Without significant gains in productivity, the status quo is on the path to financial and scientific and clinical unsustainability. We need to make entire process more efficient without sacrificing one bit the scientific rigor.”

 

Trial eligibility and design

Traditional trial eligibility criteria often exclude patients most likely to receive the studied agent once it enters the market, Gottlieb said. These groups include the elderly, patients with poor performance status, and those with organ dysfunction or other comorbidities.

“The irony is that, even with broad exclusion criteria, oncology trials still have a staggering failure rate,” Gottlieb said.

He cited a study from researchers at MIT that showed the overall success of oncology trials in 2015 was 8.3%.

“High failure rates contribute to the high costs of drug development, putting upward pressure on drug prices,” Gottlieb said. “It also reduces the amount of competition that new drugs face when they enter the market.”

FDA has provided additional guidance to trial sponsors about how to include more underrepresented patients in trials, Gottlieb said. Last week, the agency issued a new guidance document for the inclusion of adolescents with cancer in adult oncology trials.

PAGE BREAK

“Although most cancers in children and adults are distinctly different entities, there are some diseases that occur in both and span the adolescent age groups,” Gottlieb said. “If there’s no evidence that an investigational drug might have exaggerated toxicity in younger patients, then we’re encouraging sponsors to enroll adolescents into disease appropriate trials. [Because] the pharmacological parameters of adults and adolescents for most agents are comparable, early access to innovative drugs is warranted where there’s proof of principle and adequate dosing information to maximize potential for clinical benefit.”

 

Real-time oncology review

Gottlieb also introduced two pilot projects FDA has undertaken that are intended to improve how new applications are evaluated during the clinical portion of the review.

FDA’s Oncology Center for Excellence is piloting real-time oncology review, designed to make sure applications include the most relevant information to inform the agency’s review of a product’s effectiveness and safety, and that these data have been appropriately analyzed.

“Sometimes sponsors take an ‘everything but the kitchen sink’ approach to their applications because they don’t have clear guidance on what’s most pertinent,” Gottlieb said. “Or, the way they analyze data isn’t consistent with how FDA evaluates results. This can extend review timelines and obscure the most relevant facts.”

In the pilot effort, sponsors who decide to file for FDA approval immediately would begin sharing bottom-line data with the agency. Submissions would include key raw data and derived datasets, information about the study protocol and a draft of the package insert.

The agency essentially would “pre-review” the data to ensure completeness and adequacy, Gottlieb said.

“This informed pre-analysis gives reviewers and sponsors an early opportunity to address data quality issues,” he said. “The FDA can provide early feedback to a sponsor on the most effective way to analyze data to properly address key regulatory questions. By the time the sponsor files the application with the FDA, the agency’s review team would already be very familiar with the data and the analysis. Review teams will be in a better position to conduct a more efficient, timelier and thorough review.”

This approach may reduce the reviewer’s time by up to 30%, Gottlieb said.

“As we gain experience with this model, we believe that we can use this approach to create a dynamic data submission system that aligns the process around data quality based on early feedback and engagement with review teams,” he said. “Sponsors and reviewers will share real-time feedback, where issues of data quality and integrity can be addressed early in the process.”

PAGE BREAK

Initially, the pilot will be focused on new efficacy supplements for already-approved cancer therapies. If proven effective, it could be applied to drugs and biologics under consideration for initial approval, Gottlieb said.

 

Assessment aid

FDA also is piloting use of a voluntary submission form an applicant uses to facilitate the agency’s assessment of a drug application.

“Under this templated approach to receiving applications, we’ll be using the sponsor’s structured file, which follows a new template format that we’re piloting, as the basis for our review,” Gottlieb said. “Instead of writing a separate analysis of the file, we’ll use the sponsor’s own submission as the document for layering in our review. Under this approach, we’ll annotate the sponsor’s drug file with our assessment rather than creating a separate document that recapitulates many of the same data tables.”

The template includes two parts — the applicant’s position, and FDA’s assessment of that position.

“This creates a more agile platform for reviewing data after the sponsor’s database is locked,” Gottlieb said. “The assessment aid reduces the administrative burden on FDA reviewers. This permits them to focus on key results and perform critical analyses that may have been omitted by the company. Importantly, the new format leads to a more dynamic review process where key regulatory questions can be answered more thoroughly and effectively.”

If a drug application moves through the process, the completed review — using the assessment aid — will be presented at an FDA Oncologic Drugs Advisory Committee meeting.

So far, the assessment aid will be used only for supplemental applications.

 

Manufacturing efficiency

FDA also has tried to maximize efficiency in manufacturing of approved cell-based oncology therapeutics, including chimeric antigen receptor (CAR) T-cell therapies.

“In contrast to traditional drug review, where 80% of the review is focused on the clinical portion of a file and maybe 20% is focused on the product issues, I’d say that this general principle is almost completely inverted when it comes to cell and gene therapy,” Gottlieb said. “The clinical efficacy is often initially established early, and sometimes in small series of patients. It’s the product questions that are more complex and uncertain.”

Representatives of FDA’s Center for Biologics Evaluation and Research are working with NCI and others to create requirements for good manufacturing processes related to cell-based manufacturing and how to optimize and standardize production processes.

“Creating more standardization across the FDA’s requirements for manufacturing requirements could enable more facilities — like hospitals or research facilities — to scale up cell-based manufacturing, and expand local treatment options for patients,” Gottlieb said. “It could also allow them to distribute production costs over larger patient populations, and avoid product shortages.

PAGE BREAK

“Different treatments could share a common platform for manufacturing and delivering these therapies,” he added. “This could reduce the amount of novelty as institutions take on the task of delivering multiple different cell and gene therapy products. It could also make it cheaper and easier for one platform to be used to manufacture and deliver multiple different treatments.”

 

CAR T database

FDA also will expand its development of a CAR T database, Gottlieb said.

The goal is to aggregate more data about long-term toxicity potentially related to cytokine release syndrome, neurological side effects and off-target effects, as well as long-term patient outcomes.

“Better understanding these toxicities may help us make better recommendations to help prevent them,” Gottlieb said. “Also, many of the potential issues associated with gene therapy are long-term considerations related to off-target effects and the durability of response that these treatments offer.”

More than 1,000 patients should be included in the database by this summer, Gottlieb said.

“We’re planning to use these data to conduct research on how to best manage class-wide effects and identify potential predictive biomarkers for durable remission approaches that can help improve the benefit and risk of these promising new treatments,” Gottlieb said. “Eventually, we may develop ways to allow outside investigators to interrogate some of this information. Our aim is to expand scientific opportunities to evaluate key public health questions, while making sure that we safeguard nonpublic information.”

 

‘A turning point’

Some consider any FDA change in regulatory policy or the policy requirements the agency imposes “as a binary choice between speed and safety,” Gottlieb said.

He characterized that as “a false dichotomy.”

“If we are adopting the right policies, if we’re focused on incorporating the best science and making our own process more efficient, we can achieve greater certainty around the parameters that matter most to patients and providers,” he said. “And yes, we can also make the overall development process itself less costly, less risky and less time consuming. In this way, we can lower the barriers to bringing new science forward with the ultimate goal being to make sure more patients can benefit sooner from new advances.”

Gottlieb said the initiatives he outlined are designed to create new efficiencies and “help unlock the opportunities offered by better science.”

“We’re at a turning point in the history of cancer, and the openings that science offers,” he told ASCO attendees. “We’re challenging ourselves at the FDA to make sure that we have the best approach to evaluating new products. And we’re doing so in ways that are modern and efficient, so that we’re making the best us of our own resources, we’re facilitating innovation and we’re fulfilling the needs of patients. We look forward to working with you on these and many other efforts as we advance our shared goals: To reduce the personal and societal burden of cancer and to bring more patients hope for a cure.” – by Mark Leiser

Reference:

Gottlieb S. FDA commissioner’s remarks. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosure: Gottlieb reports no relevant financial disclosures.

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