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21st Century Cures Act and Patient Centered Drug Development
| 작성자 | 임이슬 | 카테고리 | 전문가 인사이트 |
|---|---|---|---|
| 작성일 | 2017-11-15 | 조회수 | 4,210 |
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| 출처 | |||
21st Century Cures Act and Patient Centered Drug Development
- 글 은주 퍼시피시
(Eunjoo Pacifici) - 국제규제과학센터
(International Centerfor
Regulatory Science)
University of
SouthernCalifornia
학력사항
- 1992 University of Southern California 독성학, 박사
- 1988 University of Southern California 약학(Pharm D.)
- 1984 Univerisyt of California Los Angeles 생화학, 학사
경력사항
- 2012-현재 International Center for Regulatory Science, Assistant Professor of Clinical Pharmacy,Associate Director
- 2015-현재 SC-CTSI Regulatory Knowledge and Support, Director
- 2012-2013 SC CTSI Preclinical Translation & Regulatory Support, Member
- 2003-2012 University of Southern California, Adjunct Professor
- 1992-2000 Amgen Inc., Associate Director, International Product Development, Asia Pacific - Latin America
- 1990-1991 Hospital of Good Samaritan, Clinical Pharmacist
- 1988-1992 University of Southern California, Research Assistant
세부 전문분야 및 컨설팅 내용
- 임상실험, 임상개발 치료, 제품개발(특히 아시아 태평양 및 남미 지역), 규제과학
1. Introduction
The 21st Century Cures Act (Cures Act) was enacted into law in the United States on December 13, 2016 as one of the last bills signed by president Obama before leaving office at the end of his second term (Figure 1). It was the result of discussions held over the last few years among bipartisan members of the United States Congress and other key stakeholders to find ways to streamline and accelerate biomedical innovation; which culminated in a discussion document in 2015 and legislation in 2016. The Cures Act contains provisions that impact the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), which are both under the Department of Health and Human Services (HHS). The law provides funding for specific areas of biomedical research like the Precision Medicine Initiative (PMI) and the Cancer Moonshot Initiative. In addition, the law calls for Food and Drug Administration (FDA) to create or modify pathways for the approval of regulated medical products and take a more patient-focused approach to new drug development and review. This latter concept, one that has been evolving over the last few decades, will be the focus of a closer examination here.
2. Five titles under 21st Century Cures Act
The five titles under the Cures Act are: (1) Innovation projects and state responses to opioid abuse; (2) Discovery; (3) Development; (4) Delivery; and (5) Savings (Figure 2).
Title I provides funding for NIH to support innovative biomedical research, including the Precision Medicine Initiative (PMI), the Brain Research through Advancing Innovative Neurotechnologies Initiative (BRAIN), the Cancer Moonshot Initiative, and Regenerative Medicine using adult stem cells. Title I also has provisions for HHS to support state responses to the opioid crisis through grant activities. For the FDA, Title I provides funding under “innovation projects” that include patient-focused drug development, advancing new drug therapies, and medical device innovations.
Title II includes support for young investigators, pediatric research, collaborative research, and precision medicine efforts.
Title III focuses on modifying the drug and device approval pathways at the FDA to support innovation. This title specifically calls for patient-focused drug development in addition to advancing new drug therapies, modernizing clinical trial design, and improving access to therapies and information. This Title also includes provisions that will impact medical device approval pathways and vaccine development.
Title IV focuses on improving health care delivery by promoting the adoption and use of electronic health record (EHR) technology, expanding telehealth services, and promoting price transparency.
Title V provides Medicare and Medicaid savings by increasing oversight of payments for specific services like infusion drugs and false claims. For the purpose of this article, we will focus on Title III – Development.
3. Patient-focused drug development is a top priority
At the top of title III for development is a provision for patient focused drug Development (Figure 3). There are other provisions targeted to incentivize innovation and expedite development. For example, there is great emphasis on exploring ways to shorten clinical trials and reduce the rising cost of drug development. Subtitle B calls for establishing a process for the “Qualification of Drug Development Tools” that would include biomarkers, clinical outcome assessment, or others, which could be used in drug development and regulatory review. This provision adds a new section 507 under U.S. Federal Food, Drug, and Cosmetic Act (FFDCA) to prioritize review of a qualification submission. If qualified, a biomarker may be used as a surrogate endpoint to enable a new medication to reach the market faster using expedited regulatory mechanisms like the “Accelerated Approval”
But an area that may have the greatest impact on development and review of new drugs may be the concept of patient-focused or patient-centered drug development. This provision follows the current movement to increase patient participation in the drug development process as laid out in the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. This law included fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V) and added a new FFDCA Section 569C “Patient Participation in Medical Product Discussion,” by soliciting the views of patients during the medical product development process and regulatory discussions. Over the past 5 years, FDA has actively engaged patients through various programs and initiative. The agency’s Office of Health and Constituent Affairs (OHCA) coordinates recruitment, training, and retention of patient representative who now number over 200 . These patient representatives participate on FDA Advisory Committees and review division meetings to provide patient perspectives. FDASIA also prompted the creation of the FDA Patient Network to help patients and their families find patient-oriented FDA resources, including webinars, information about public meetings and draft policies. FDA’s Patient-Focused Drug Development Initiative included a commitment by the FDA to hold at least 20 public meetings, each focusing on a specific disease are, to capture the “Voice of the Patient”. The reports from these meetings are publically available . The Cures Act takes the concept of “patient participation” in medical product development and review a step further to “patient-focused” drug development.
4. What is patient focused drug development?
Let’s first examine what is meant by patient focused drug development (Figure 4). The Cures Act describes patient focused drug development as engaging patients and including their experiences in drug development and review. Hence, this law takes the provisions in FDASIA one step further by not only soliciting the perspectives of patients, but mandating the FDA to enable the inclusion of patient experience data in the drug development process and in the agency’s review process. Furthermore, the law requires public disclosure of patient experience data and related information submitted and reviewed as part of a new drug application (NDA) process. FDA is also mandated to provide companies (sponsors) with guidance on how to meet this new expectation by developing and issuing guidance for the collection of patient experience data and their use in drug development. For example, it is not clear what would be considered acceptable as patient experience data or how such information can impact drug development and regulatory review. Therefore, the guidance will provide methods that could be used to collect and submit patient experience data as well as the methodologies, standards, and technologies that could be used to collect and analyze clinical data for regulatory decision-making. FDA must also track the progress of this new mandate and report on how patient experience data are used in drug development and review. We will examine these requirements in more detail below.
4-1. Who can provide patient perspective?
Of course, patients are most ideally suited to provide their perspectives on experiences and treatments related to their condition. But information related to patient perspective can also be provided by family members, caregivers, patient advocacy organizations, and disease research foundations like SMA foundation (for spinal muscular atrophy), Michael J Fox foundation (for Parkinson’s disease, and CHDI foundation (for Huntington’s disease) in addition to researchers and drug manufacturers. According to the new law, “patient experience data” is defined as
“(1) data that are collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and drug manufacturers); and (2) are intended to provide information about patients’ experiences with a disease or condition, including—(A) the impact of such disease or condition, or a related therapy, on patients’ lives; and (B) patient preferences with respect to treatment of such disease or condition.”
Therefore, it seems that anyone can provide information about patient experiences with a disease or condition related to the impact of disease or therapy and patient preference for treatment (Figures 5). It is important to note that the FDA has been actively gathering patient perspectives over the past few years by convening patient groups as part of their “voice of patient” initiative as its requirement under FDASIA (described above). The Cures Act reemphasizes patient engagement and directs the Agency to include the patient’s voice in drug development and review. Furthermore, the law requires FDA to disclose publically how patient experience data was included in the submission and used in the review of a drug or biologic marketing application.
4-2. Providing guidance to industry
To provide biopharmaceutical companies with a clear understanding of what would be acceptable as patient experience data, how such data should be gathered and incorporated into registration packages, and how information would be reviewed by the regulators, the Cures Act requires the FDA to issue guidance in the coming years. The details are included in the FDA work plan along with the associated budget (Figure 6).
We should expect draft and final guidance from the FDA, over the next five years. Through its guidance, the FDA is anticipated to address methods and approaches that can be used by drug sponsors, patient advocacy groups and others to collect information that will measure disease and treatment outcomes that are important to patients. The new guidance should include methods and approaches for capturing and measuring patient experiences and perspectives and provide industry with information needed to integrate patient experience data in its drug development programs. We should expect a series of four guidance documents as described in Figure 7 that would drive the development of fit-for-purpose tools to collect meaningful patient experience data that can be used in regulatory decision making.
But prior to the issuance of each of the draft guidance, FDA is expected to conduct a public workshop to gather input from patients, family, caregivers, patient advocacy organizations, academic and medical researchers, industry, and other stakeholders. This process should inform the FDA as it develops the draft guidance documents. For those interested, the public workshops are often streamed via webcast allowing the proceedings to be more widely available. In addition, the briefing documents and presentation materials as well as reports should be available on FDA’s website. Companies interested in following this initiative should attend the workshop in person or via webcast examine the workshop materials. For example, the first public workshop has already been announced to take place on Monday, December 18, 2017 and will be live streamed . In addition, the Cures Act specifies that the FDA must publish final guidance 18 months after the close of the public comment period. This ensures that a guidance does not remain in an ambiguous state as “draft”. A finalized guidance provides industry with regulatory clarity and thereby would promote the incorporation of patient experience data as part of its drug development strategies.
To track the implementation of this new initiative, FDA is required to report on the use of patient experience in drug development and regulatory review on its website. The Cures Act directs FDA to issue reports at 5-yr intervals on the use of patient experience data in regulatory decision making. Those interested should expect to see the FDA issue its first report in 2021 and subsequent ones in 2026 and 2031. These reports should provide insights into how the patient experience data are incorporated into new drug development strategies and considered in clinical trial design, study endpoints, and benefit-risk framework.
5. History of patient participation in drug development and review
Why is there this great emphasis on patient participation at the moment? To understand this development, it would be helpful to examine the history of patient involvement in the drug development process. Following the thalidomide tragedy in the 1950s when more than 10,000 babies were born with a severe birth defect due to the drug’s fetal toxic effects, U.S. enacted the Kefauver-Harris Amendments strengthening the nation’s regulatory framework for new drugs. This law included, among others, a requirement for adequate and well-controlled clinical trials to demonstrate substantial and scientific evidence of efficacy. It is the origin of the controlled regulatory process for new drug development and approval that exists today. The concept of "adequate" or "well-controlled" has come to include the use of control groups, randomization in the allocation of patients to control and treated groups, and blinding to prevent bias. The process has traditionally included three key stakeholders: sponsor, investigator, and regulatory authority. Patients had very little input into how a drug is developed or reviewed. Meanwhile, the process of drug development has become increasingly lengthy, difficult, expensive, and unpredictable. Most recent figures estimate that it takes about 14 years and 2.6 billion US dollars for a product to reach the market. That is, if it makes to the market at all. A molecule has only 1 in 10,000 chance of making it from discovery to regulatory approval. At the same time, the patients were left out of the process. Because drug development was considered a scientific and regulatory matter, the process and the associated decisions were left to the scientists and the regulators. Several developments occurred starting in the 1980s (Figure 8).
It was the campaign by patient groups that led to the passage of the Orphan Drug Act in 1983. It was the activism by patients with AIDS that officially expanded the access of investigational drugs to patients through “treatment IND” (1987) and “parallel track” (1992) mechanisms. Since then, there has been continued pressure to expedite drug development, provide expanded access to investigational products, and incorporate the patient perspectives in the process. Moreover, with the reauthorization of the Prescription Drug User Fee Act (PDUFA) that need to occur every five years, the congress has the opportunity to direct the FDA to address specific issues that are germane to the times. Hence, it is not surprising that the 2012 Food and Drug Administration Safety and Innovation Act, which is the fifth reauthorization of PDUFA, directs the FDA to include patient participation in medical product discussions and hold patient voice forums. Both the Cures Act and the FDA Reauthorization Act of 2017 (FDARA, also known as PDUFA VI) emphasize patient engagement and involvement. In fact, FDA has established the Patient Engagement Advisory Committee (PEAC) and held its inaugural meeting in October 2017. It is clear now that the patient groups are not only at the table as a key stakeholder but may be at the center, driving the drug development and review process (Figure 9).
6. A new paradigm for drug development and approval?
There is a sense that the traditional approach to drug development may be shifting. In the near future, we will see increasing involvement of patient groups at the table when new products are discussed, incorporation of patient experience data in new drug applications, and consideration of patient perspectives in the benefit-risk framework that guides FDA review process. But, in fact, we may not need to look to the future. A recent example makes it clear that the voices of patient groups are already impacting the drug development and review process.
Figure 10 reflects all the new drugs approved by the U.S. FDA in 2016. The numbers represent the number of clinical trial subjects included in the product review. As expected orphan drugs required far fewer patients than non-orphan drugs. But one orphan drug in particular stood out from the rest. Eteplirsen was approved on September 19, 2016 amidst severe controversy. As the first drug for Duchenne muscular dystrophy (DMD), a deadly disease that affect male children, the patient advocacy was instrumental in the approval process. Although both FDA’s own review team and its external advisory committee recommended to reject the new drug application, there was a strong pressure from parents of children with DMD and advocacy groups to approve the drug (Figure 11).
The controversy stems from the fact that the review had to be based on a clinical trial of just 12 boys suffering from the condition. Moreover, the study was not properly controlled, lacking a placebo arm, and demonstrated very little evidence that the drug is effective in increasing the dystrophin production. The FDA reviewers and the advisory committee felt that the study was severely flawed and that the scientific evidence was lacking. On April 26, 2017, the advisory committee voted 7-6 against approving the drug. However, following a tremendous show of force (around 1,000 people were present to advocate for the patients) and passionate testimonies by the patients, their parents, and advocates at the advisory committee meeting, the drug was approved through the accelerated approval pathway. Although patients and families were happy to see the fruits of their efforts, the decision received criticism that FDA acted against its scientific judgement. The question that remains is whether this trend will continue. Are we seeing a move against the requirement for substantial evidence of effectiveness (Figure 12)? Should we not withhold a hopeful drug from even one patient that may benefit? There are many scientific, ethical, and even financial factors that need to be considered when asking these questions.
6-1. Establishing substantial evidence of effectiveness
Eteplirsen was approved under “accelerated approval”. As such, the sponsor is required under federal regulation, 21CFR314.510, to conduct further adequate and well-controlled confirmatory clinical trials to verify clinical benefit. The initial approval was based on an increase in dystrophin in skeletal muscle observed in some patients where the clinical benefit has not been established. This approval is conditional in that if the postmarketing trials do not demonstrate clinical benefit, the approval will be withdrawn, which could lead to a product withdrawal, if this is the only indication for the drug. The conditional approval could also be withdrawn if the company fails to conduct the postmarketing trials with due diligence. So if a company fails to conduct the trials in a timely manner, the approval can be withdrawn. For further clarification, FDA has provided clear deadlines that must be met by the sponsor, within the approval letter. For example, the sponsor must submit the draft protocol by October 2016 and final protocol by April 2017. The trial must be completed by November 2020 and the final report submitted by May 2021. According to the FDA approval letter, the confirmatory trial should be designed to…
verify the clinical benefit of eteplirsen, conduct a 2-year randomized, double-blind, controlled trial of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Patients should be randomized to the approved dosage of eteplirsen (30 mg/kg weekly) or to a dosage that provides significantly higher exposure, e.g., 30 mg/kg daily. The primary endpoint will be the North Star Ambulatory Assessment.
As can be seen, the FDA is very prescriptive as to what is needed for the conditional approval to be converted to a full approval. If we look on the ‘clinicaltrials.gov’ website, we can find the details of the double-blind, placebo-controlled, multi-center clinical trial that is currently enrolling.
Therefore, the FDA is not abandoning the requirement for sponsors to demonstrate substantial evidence of effectiveness but rather pushing out this requirement to the postmarketing space. This trend may be worth tracking. Over the past decade, we have seen greater emphasis on examining a product’s safety profile after it has been introduced onto the market with more structured approaches to pharmacovigilance. Instead of just receiving safety reports, sponsors must identify and mitigate drug-related adverse effects with the understanding that the safety profile of a drug continues to evolve long after a product has been on the market. The idea is that a more accurate and complete safety profile of a drug will help to create a better benefit-risk profile to inform regulatory and healthcare decisions. But now this concept is evolving to include the other factor in the equation of “safe” and “effective”. By shifting some of the burden of proof for effectiveness to be demonstrated after a drug is on the market, patients can have expedited access to therapeutics. As depicted in Figure 13, the regulatory balance has been shifting to the direction of listening to the voices of patients, employing regulatory flexibility, allowing surrogate endpoints when appropriate, and putting greater emphasis on the postmarketing surveillance of safety and effectiveness. This development is also consistent with the emphasis on using more real world data for regulatory decision-making.
6-2. Use of real-world data
The Cures Act and FDARA both requires the FDA to explore the use of real-world data with a deadline to issue draft guidance documents by the end of 2021(Figure 14). As can be seen, the FDA is required to hold a public workshop by the end of 2018. Hence, those interested can follow the discussions and gain insights into the key issues that concern the various stakeholders.
7. Conclusions
The shift in regulatory framework that are in play currently may change the way drugs are developed and reviewed. It would be important for those interested in developing new drugs to closely follow the evolving regulatory landscape and formulate regulatory strategies that would strengthen their programs.
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