Posted: 14 May 2015 11:17 AM PDT
By James E. Valentine* & Alexander J. Varond –
After giving us a few months to shake our sticks at the nearly 400-page 21st Century Cures Act (the Cures Act) discussion draft, the House Energy and Commerce Committee (the Committee) dropped a 200-page version that was the subject of a Health Subcommittee hearing held on April 30, 2015. Perhaps having found a happy medium, just two weeks later the Committee has issued a 300-page third version. The Health Subcommittee advanced the bill by a vote during a mark-up held on May 14th.
The two most recent versions of the 21st Century Cures Act are organized into three titles – DISCOVERY, DEVELOPMENT, and DELIVERY – reflecting the initiative’s initial goal to accelerate the pace of cures through all points during the innovation cycle. Since the first draft, not only have a number of provisions been removed, but about a quarter of the provisions are new. Many of those retained from the first version are heavily revised. With the next step in the legislative process underway, here is an overview of some of these key changes these bloggers identified when reviewing these revised drafts (additional posts on other provisions may follow).
Discovery
Title I of the bill is almost completely focused on enhancements for the National Institutes of Health (NIH). Of note, the bill includes reauthorization of the NIH (Sec. 1001) and the establishment of an NIH Innovation fund to be made available for precision medicine, young emerging scientists, and at least one other initiative that is to be determined (Sec. 1002). In the April 30th Health Subcommittee hearing, Dr. Kathy Hudson, Deputy Director for Science, Outreach, and Policy at NIH, delivered her thanks to the Subcommittee on Health for this increased funding after a number of years of diminishing funding resulting in the inability to fund good ideas.
Standardization of Eligibility Information in ClinicalTrials.gov: A change to this provision on the standardization in the Clinical Trial Registry Data Bank, or ClinicalTrials.gov, on eligibility for clinical trials (Sec. 1102, the first draft’s Sec. 2081—see post on previous provision here) no longer requires eligibility criteria to be matched to diagnosis or procedure coding systems (e.g., the International Classification of Diseases or the Current Procedural Terminology) and integrated into electronic health records, but would have NIH make use of them to the extent possible.
Data on Natural History of Diseases: This provision, first proposed in the second version and tweaked in the third, would have Health and Human Services (HHS) participate in public-private partnerships and award grants to patient advocacy groups to establish or facilitate the collection, maintenance, analysis, and interpretation of data on the natural history of diseases, with a particular focus on rare diseases (Sec. 1123). The private-public partnerships would sponsor or maintain disease registries and registry platforms, develop or enhance a secure information technology system that builds on and cooperates with other disease registries, and provide advice on the design and conduct of natural history studies. Support for and further development of disease registries and registry platforms would facilitate generations of natural history data valuable for use in drug development. This would help to better understand disease progression and aid in the development of clinical trial protocols as well as the identification and development of outcome measurements (e.g., biomarkers, clinical outcome assessments), as a source of recruiting research subjects, for interpreting results, and as a historical control.
Development
Title II of the bill shifts the focus to medical product development activities regulated by the Food and Drug Administration (FDA or the Agency). A concern voiced during the discussion at the April 30th hearing by FDA’s Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research, and Dr. Jeff Shuren, Director of the Center for Devices and Radiological Health, was that there were a number of new responsibilities for the Agency, yet the draft legislation did not increase funding for the Agency to carry out the additional work. Dr. Woodcock informed the Subcommittee that, to the extent the 21st Century Cures Act created statutory requirements and timelines, FDA would have to prioritize those activities. She warned that there is a tradeoff between implementation and review work, citing Food and Drug Administration Amendment Acts as an example of when unfunded mandates impacted performance. There was an appreciable dip in review time because of the burdens of implementing the law’s provisions without additional resources. Dr. Woodcock urged the Subcommittee to not break what is fixed: the current drug review program. A number of Subcommittee members echoed this concern and their desire to ensure that any new programs are adequately funded. Meanwhile, the third version of the bill has included only a few small authorizations for appropriations.
Qualification of Drug Development Tools: The new version of the legislation provided a revised section (Sec. 2021) that replaces Sections 1021-1024 of the first discussion document. The revised section is broader, as it now addresses biomarkers, surrogate endpoints, and other drug development tools; the first discussion draft focused primarily on surrogate endpoints. On the other hand, it is narrower because it does not affect devices. The section also removes many of the formal procedures and timelines from the first discussion draft and provides FDA with more discretion in the development of the program.
The revised section would add Section 507 to the Federal Food, Drug, and Cosmetic Act (FD&C Act), which would call upon FDA to facilitate the availability of qualified biomarkers, including surrogate endpoints, and other drug development tools (e.g., clinical outcome assessments, patient reported outcomes). FDA would be required to develop guidance with respect to standards for qualification and establish a process for qualifying biomarkers and other drug development tools. Such a drug development tool would be qualified only for “its proposed context of use,” which would be specified by the requestor.
Accelerated Approval Development Plans: One provision, first proposed in the second version of the bill (Sec. 2022) and modified in the third version, would establish a process for a sponsor of a drug eligible for accelerated approval to voluntarily submit, and for FDA to agree to, an “accelerated approval development plan” for purposes of facilitating early interactions and agreement between sponsors and FDA on designing studies to generate evidence for purposes of accelerated approval. An accelerated approval development plan would need to include (1) a surrogate endpoint to be assessed under the plan, (2) the design of the study that will utilize the surrogate endpoint, and (3) the magnitude of the effect of the drug on the surrogate endpoint that would be sufficient to form the primary basis of a claim that the drug is effective.
These plans would create an opportunity earlier in development for sponsors and FDA to consider the appropriateness of accelerated approval for each new therapy, as well as for sponsors to receive advice on how an accelerated approval could be achieved. If an accelerated approval development plan is pursued, like a Special Protocol Assessment, it would provide a means for sponsors and FDA to come to an agreement, thereby reducing regulatory uncertainty.
Precision Medicine: Congress finally provided some detail about precision medicine in the second version of the 21st Century Cures Act (Sec. 2041). While the second version of the bill provided a definition of precision medicine, the latest version would have FDA define the term. The revised provision would require FDA to issue a guidance document to assist sponsors in the development of such drugs.
This provision also allows for applications of a precision medicine that has been designated “for a rare disease for a serious condition” to rely upon data or information previously developed by the sponsor for a prior approved drug or indication in order to expedite clinical development of a precision medicine or indication that is using the same or similar approach as that of the prior approved drug. In addition, the provision specifies that applications for precision medicines should be considered as to whether they are eligible for accelerated approval.
Broader Application of Bayesian Statistics and Adaptive Trial Designs: A provision retained from the first version (Sec. 2061, the first draft’s Sec. 3021), no longer requires the establishment and implementation of a framework through which sponsors could submit to FDA a proposal for the incorporation of adaptive trial designs, Bayesian methods, or alternative statistical methods into proposed clinical protocols and marketing applications. The requirements for FDA to issue guidance and host a public meeting, however, were retained.
Utilizing Evidence from Clinical Experience: Yet another provision added in the second draft (Sec. 2062) would require FDA to establish a program to evaluate the potential use of evidence from clinical experience (i.e., data derived from sources other than randomized controlled trials, including observational trials, registries, and therapeutic use) to help support the approval of a new indication for a drug and to help support or satisfy post-approval study requirements. While it is unclear what the standards for such evidence will be, this provision would result in an expansion of the types of safety and effectiveness data that can support an approval, creating new opportunities for the development of new drugs. The section would also expand the type of safety and effectiveness data that could be used to satisfy post-approval study requirements.
Facilitating Responsible Communication of Scientific and Medical Developments: Completely new in the latest version of the 21st Century Cures Act is a provision (Sec. 2102) that would have FDA issue draft guidance within 18 months of enactment on “facilitating the dissemination of responsible, truthful, and non-misleading scientific and medical information not included on the label of drugs.” This provision is consistent with continued pressure on FDA, especially in light of the Caronia decision (see previous coverage here) and the recent Amarin suit, to update its interpretation of the drug promotion regulations to permit drug manufacturers to share truthful and non-misleading information with healthcare professionals that would be considered off-label.
The Orphan Product Extensions Now (OPEN) Act: The text of the OPEN Act, which was removed in the second draft of the bill, was reinserted in the latest draft (Sec. 2151, the first draft’s Sec. 1261). This provision would provide an extension of exclusivity periods for a drug approved for a new indication for a rare disease or condition (see our previous post on the OPEN Act here). This provision is intended to increase the number of rare disease therapies and address many off-label reimbursement problems faced by rare disease patients.
Reauthorizing the Rare Pediatric Disease Priority Review Voucher Program: Completely new in the latest version of the 21st Century Cures Act is a provision to reauthorize the Rare Pediatric Disease Priority Review Voucher incentive program (Sec. 2152). With the 1-year sunset clause for this program was triggered with the issuance of the third rare pediatric disease priority review voucher on March 17th (see our previous post here), it is not surprising that Congress would take the opportunity to extend this program. The reauthorized program would extend through June 30, 2022. We view this proposal to be better than Representative Butterfield’s “Advancing Hope Act of 2015” since it does not make a potentially counterproductive change to the Tropic Disease Priority Review Voucher program (see our previous post here).
Keeping 21st Century Cures Alive
While NIH, FDA, CMS, and others will have quite of few new programs and functions to implement (if even a fraction of the 70+ current provisions make it through mark-up and into an actual bill), the Energy & Commerce Committee added another provision to the 21st Century Cures Act (Sec. 1141) that would keep this multi-stakeholder, cross-discovery-development-
After the bill makes it through mark up by the Health Subcommittee, it would likely move up to the full committee by next week for a vote. The bill will also be referred to multiple House Committees for review for 30 days, as per the standard procedure. The final bill should come up for a vote on the floor of the full House of Representatives sometime in June.
* Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.
After giving us a few months to shake our sticks at the nearly 400-page 21st Century Cures Act (the Cures Act) discussion draft, the House Energy and Commerce Committee (the Committee) dropped a 200-page version that was the subject of a Health Subcommittee hearing held on April 30, 2015. Perhaps having found a happy medium, just two weeks later the Committee has issued a 300-page third version. The Health Subcommittee advanced the bill by a vote during a mark-up held on May 14th.
The two most recent versions of the 21st Century Cures Act are organized into three titles – DISCOVERY, DEVELOPMENT, and DELIVERY – reflecting the initiative’s initial goal to accelerate the pace of cures through all points during the innovation cycle. Since the first draft, not only have a number of provisions been removed, but about a quarter of the provisions are new. Many of those retained from the first version are heavily revised. With the next step in the legislative process underway, here is an overview of some of these key changes these bloggers identified when reviewing these revised drafts (additional posts on other provisions may follow).
Discovery
Title I of the bill is almost completely focused on enhancements for the National Institutes of Health (NIH). Of note, the bill includes reauthorization of the NIH (Sec. 1001) and the establishment of an NIH Innovation fund to be made available for precision medicine, young emerging scientists, and at least one other initiative that is to be determined (Sec. 1002). In the April 30th Health Subcommittee hearing, Dr. Kathy Hudson, Deputy Director for Science, Outreach, and Policy at NIH, delivered her thanks to the Subcommittee on Health for this increased funding after a number of years of diminishing funding resulting in the inability to fund good ideas.
Standardization of Eligibility Information in ClinicalTrials.gov: A change to this provision on the standardization in the Clinical Trial Registry Data Bank, or ClinicalTrials.gov, on eligibility for clinical trials (Sec. 1102, the first draft’s Sec. 2081—see post on previous provision here) no longer requires eligibility criteria to be matched to diagnosis or procedure coding systems (e.g., the International Classification of Diseases or the Current Procedural Terminology) and integrated into electronic health records, but would have NIH make use of them to the extent possible.
Data on Natural History of Diseases: This provision, first proposed in the second version and tweaked in the third, would have Health and Human Services (HHS) participate in public-private partnerships and award grants to patient advocacy groups to establish or facilitate the collection, maintenance, analysis, and interpretation of data on the natural history of diseases, with a particular focus on rare diseases (Sec. 1123). The private-public partnerships would sponsor or maintain disease registries and registry platforms, develop or enhance a secure information technology system that builds on and cooperates with other disease registries, and provide advice on the design and conduct of natural history studies. Support for and further development of disease registries and registry platforms would facilitate generations of natural history data valuable for use in drug development. This would help to better understand disease progression and aid in the development of clinical trial protocols as well as the identification and development of outcome measurements (e.g., biomarkers, clinical outcome assessments), as a source of recruiting research subjects, for interpreting results, and as a historical control.
Development
Title II of the bill shifts the focus to medical product development activities regulated by the Food and Drug Administration (FDA or the Agency). A concern voiced during the discussion at the April 30th hearing by FDA’s Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research, and Dr. Jeff Shuren, Director of the Center for Devices and Radiological Health, was that there were a number of new responsibilities for the Agency, yet the draft legislation did not increase funding for the Agency to carry out the additional work. Dr. Woodcock informed the Subcommittee that, to the extent the 21st Century Cures Act created statutory requirements and timelines, FDA would have to prioritize those activities. She warned that there is a tradeoff between implementation and review work, citing Food and Drug Administration Amendment Acts as an example of when unfunded mandates impacted performance. There was an appreciable dip in review time because of the burdens of implementing the law’s provisions without additional resources. Dr. Woodcock urged the Subcommittee to not break what is fixed: the current drug review program. A number of Subcommittee members echoed this concern and their desire to ensure that any new programs are adequately funded. Meanwhile, the third version of the bill has included only a few small authorizations for appropriations.
Qualification of Drug Development Tools: The new version of the legislation provided a revised section (Sec. 2021) that replaces Sections 1021-1024 of the first discussion document. The revised section is broader, as it now addresses biomarkers, surrogate endpoints, and other drug development tools; the first discussion draft focused primarily on surrogate endpoints. On the other hand, it is narrower because it does not affect devices. The section also removes many of the formal procedures and timelines from the first discussion draft and provides FDA with more discretion in the development of the program.
The revised section would add Section 507 to the Federal Food, Drug, and Cosmetic Act (FD&C Act), which would call upon FDA to facilitate the availability of qualified biomarkers, including surrogate endpoints, and other drug development tools (e.g., clinical outcome assessments, patient reported outcomes). FDA would be required to develop guidance with respect to standards for qualification and establish a process for qualifying biomarkers and other drug development tools. Such a drug development tool would be qualified only for “its proposed context of use,” which would be specified by the requestor.
Accelerated Approval Development Plans: One provision, first proposed in the second version of the bill (Sec. 2022) and modified in the third version, would establish a process for a sponsor of a drug eligible for accelerated approval to voluntarily submit, and for FDA to agree to, an “accelerated approval development plan” for purposes of facilitating early interactions and agreement between sponsors and FDA on designing studies to generate evidence for purposes of accelerated approval. An accelerated approval development plan would need to include (1) a surrogate endpoint to be assessed under the plan, (2) the design of the study that will utilize the surrogate endpoint, and (3) the magnitude of the effect of the drug on the surrogate endpoint that would be sufficient to form the primary basis of a claim that the drug is effective.
These plans would create an opportunity earlier in development for sponsors and FDA to consider the appropriateness of accelerated approval for each new therapy, as well as for sponsors to receive advice on how an accelerated approval could be achieved. If an accelerated approval development plan is pursued, like a Special Protocol Assessment, it would provide a means for sponsors and FDA to come to an agreement, thereby reducing regulatory uncertainty.
Precision Medicine: Congress finally provided some detail about precision medicine in the second version of the 21st Century Cures Act (Sec. 2041). While the second version of the bill provided a definition of precision medicine, the latest version would have FDA define the term. The revised provision would require FDA to issue a guidance document to assist sponsors in the development of such drugs.
This provision also allows for applications of a precision medicine that has been designated “for a rare disease for a serious condition” to rely upon data or information previously developed by the sponsor for a prior approved drug or indication in order to expedite clinical development of a precision medicine or indication that is using the same or similar approach as that of the prior approved drug. In addition, the provision specifies that applications for precision medicines should be considered as to whether they are eligible for accelerated approval.
Broader Application of Bayesian Statistics and Adaptive Trial Designs: A provision retained from the first version (Sec. 2061, the first draft’s Sec. 3021), no longer requires the establishment and implementation of a framework through which sponsors could submit to FDA a proposal for the incorporation of adaptive trial designs, Bayesian methods, or alternative statistical methods into proposed clinical protocols and marketing applications. The requirements for FDA to issue guidance and host a public meeting, however, were retained.
Utilizing Evidence from Clinical Experience: Yet another provision added in the second draft (Sec. 2062) would require FDA to establish a program to evaluate the potential use of evidence from clinical experience (i.e., data derived from sources other than randomized controlled trials, including observational trials, registries, and therapeutic use) to help support the approval of a new indication for a drug and to help support or satisfy post-approval study requirements. While it is unclear what the standards for such evidence will be, this provision would result in an expansion of the types of safety and effectiveness data that can support an approval, creating new opportunities for the development of new drugs. The section would also expand the type of safety and effectiveness data that could be used to satisfy post-approval study requirements.
Facilitating Responsible Communication of Scientific and Medical Developments: Completely new in the latest version of the 21st Century Cures Act is a provision (Sec. 2102) that would have FDA issue draft guidance within 18 months of enactment on “facilitating the dissemination of responsible, truthful, and non-misleading scientific and medical information not included on the label of drugs.” This provision is consistent with continued pressure on FDA, especially in light of the Caronia decision (see previous coverage here) and the recent Amarin suit, to update its interpretation of the drug promotion regulations to permit drug manufacturers to share truthful and non-misleading information with healthcare professionals that would be considered off-label.
The Orphan Product Extensions Now (OPEN) Act: The text of the OPEN Act, which was removed in the second draft of the bill, was reinserted in the latest draft (Sec. 2151, the first draft’s Sec. 1261). This provision would provide an extension of exclusivity periods for a drug approved for a new indication for a rare disease or condition (see our previous post on the OPEN Act here). This provision is intended to increase the number of rare disease therapies and address many off-label reimbursement problems faced by rare disease patients.
Reauthorizing the Rare Pediatric Disease Priority Review Voucher Program: Completely new in the latest version of the 21st Century Cures Act is a provision to reauthorize the Rare Pediatric Disease Priority Review Voucher incentive program (Sec. 2152). With the 1-year sunset clause for this program was triggered with the issuance of the third rare pediatric disease priority review voucher on March 17th (see our previous post here), it is not surprising that Congress would take the opportunity to extend this program. The reauthorized program would extend through June 30, 2022. We view this proposal to be better than Representative Butterfield’s “Advancing Hope Act of 2015” since it does not make a potentially counterproductive change to the Tropic Disease Priority Review Voucher program (see our previous post here).
Keeping 21st Century Cures Alive
While NIH, FDA, CMS, and others will have quite of few new programs and functions to implement (if even a fraction of the 70+ current provisions make it through mark-up and into an actual bill), the Energy & Commerce Committee added another provision to the 21st Century Cures Act (Sec. 1141) that would keep this multi-stakeholder, cross-discovery-development-
After the bill makes it through mark up by the Health Subcommittee, it would likely move up to the full committee by next week for a vote. The bill will also be referred to multiple House Committees for review for 30 days, as per the standard procedure. The final bill should come up for a vote on the floor of the full House of Representatives sometime in June.
* Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.
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