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16 min read
Mwango Kashoki, MD, MPH
Timing and data are critical to winning Breakthrough Therapy designation for rare disease drugs
8 min read
Steve Winitsky, MD
Five regulatory myths about CGT orphan drug development
Multiple Contributors
Regulatory strategies for EU orphan drug development: Roundtable
3:45 video
Effective regulatory strategies for rare disease
Rare disease drugs utilize multiple regulatory programs, often simultaneously, to expedite clinical development and regulatory review. In this section, Parexel experts and former regulators share insights on winning FDA Breakthrough Therapy designation, common misconceptions about developing orphan cell and gene therapies, and how to conduct an efficient and successful development program for an orphan-designated drug in the EU.
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How to Maximize the Chance of Regulatory Success for Rare Disease Drugs
Mwango Kashoki, MD, MPH Senior Vice President, Regulatory Strategy Consulting, Parexel International
Mwango has 16 years of drug review, development, and regulatory experience at the FDA. Before joining Parexel, she was the Associate Director for Safety in the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER) and was responsible for ensuring OND’s implementation of the policies and processes related to CDER safety programs, including the Safety First and Sentinel Initiatives. She has particular expertise in the development of analgesic and addiction (alcohol and opioid) therapies and post-approval activities such as pharmacovigilance, risk management, and Phase 4 studies.
Many companies developing rare disease drugs have one urgent regulatory question: “How—and how soon—can we get FDA Breakthrough Therapy designation (BTD)?"
SOURCE: Parexel analysis based on primary FDA data obtained from Drugs@FDA, annual reports, biological approvals by year, press releases, and databases. We analyzed all new drug applications (NDAs) and biologics license applications (BLAs) approved by the FDA’s Center for Drug Evaluation and Research (CDER) and Center forBiologics Evaluation and Research (CBER) from January 1, 2017, to December 31, 2022. Totals reflect approvals for new molecular entities (NMEs) (novel drugs and original BLAs) and exclude supplemental NDAs/BLAs (new indications), abbreviated NDAs/BLAs (generics), and Type 3 and 5 NDAs (new dosages, new formulations). A total of149 orphan-designated products approved by CDER and a total of 15 orphan-designated products approved by CBER are included in this dataset (CBER approvals exclude assays, fractionated plasma products, patch tests, reagents, vaccines, and tissue transplant products). Breakthrough Therapy (BT) approvals were counted just once, evenif the product was approved in multiple indications simultaneously (the FDA counts each indication as a distinct BT approval). Our analysis includes two 2021 approvals (Tepmetko and Welireg) as BT approvals even though the FDA does not list themas such in its annual report. Agency briefing documents reveal they had BT designation.
80 of 86 orphan BT drugs got Priority Review
86 of 119 Breakthrough Therapy (BT) drugs were orphan
164 of 307 approvals were orphan drugs
FDA novel drug and biological approvals, 2017-2022
Numbers
Percentages
53% of all approvals were orphan drugs
53%
72% of all Breakthrough Therapy (BT) drugs were orphan
72%
93% of all orphan BT drugs got Priority Review
93%
164/ 307
86/ 119
80/ 86
Because BTD targets drugs intended for serious conditions with unmet medical needs, it is frequently central to rare disease drug development. However, obtaining BTD can be challenging; success depends on timing and the data supporting the application. Companies know BTD confers valuable benefits, including increased FDA interactions and intensive guidance that could expedite drug development. They also know it often provides external validation to a company’s investors that an investigational product has—based on preliminary clinical data—shown significant potential to the FDA and for patients. BTD has become a core component of the regulatory strategy for rare disease drugs. A Parexel analysis of FDA novel drug approvals from 2017-2022 found that orphan drugs comprised 53 percent (164/307) of all approvals and 72 percent (86/119) of BTD approvals. Additionally, 93 percent of BTD orphan products received an expedited review under Priority Review.
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The BTD program took effect in 2012 as a new FDA authority under the FDA Safety and Innovation Act (FDASIA), sparked by the efforts of a cancer research group. Investigational products intended to treat a serious or life-threatening disease—and for which preliminary clinical evidence shows substantial improvement over existing therapies on one or more clinically significant endpoints— are eligible to participate. It’s not easy to attain BTD status: From the program’s inception through December 2022, the FDA has granted 40 percent of BTD requests (439/1098), denied 47 percent (512/1098), and companies have withdrawn the remaining 13 percent for various reasons. However, drugs for orphan-designated indications are more likely to attain BTD than drugs for common diseases—perhaps because of their comparative advantage in meeting the unmet need criteria. Parexel’s analysis of FDA data shows that 52 percent (86/164) of novel orphan drugs approved since 2017 qualified for the program. In addition to BTD, other FDA expedited programs are Fast Track (FT) designation, Accelerated Approval (AA), and Priority Review (PR). Parexel’s analysis shows that 60 percent of approved orphan BTD drugs used two or more expedited development programs. These data align with a recent study of “stacked” expedited program utilization in rare disease drug development.
SOURCE: Parexel analysis. See chart above for data sources and methodology.
Companies with drugs that receive Breakthrough Therapy designation earlier in development have more interactions with the FDA over time and more opportunities to align on streamlined programs.
Mwango Kashoki Senior Vice President, Regulatory Strategy Consulting, Parexel International
Choosing the appropriate strategy and timing for a BTD request is a crucial challenge for companies. To maximize the program’s advantages, a company should submit a BTD request as soon as possible, ideally before Phase 3 trials begin. When feasible, although uncommon, companies can seek BTD even based on Phase 1 findings. For example, at Parexel, we’ve helped clients design early-phase clinical trials, such as dose-finding studies that include preliminary efficacy assessments to support BTD. When we assess a drug’s potential to qualify for BTD, we focus on the following:
One recent example of a product that utilized multiple expedited programs in a rare disease setting is Krazati (adagrasib), an irreversible KRASG12C inhibitor for non-small cell lung cancer patients with the KRASG12C mutation. The FDA granted accelerated approval to Krazati on December 12, 2022, about four years after the first patient was dosed in the FIH trial. It won BTD in June of 2021, roughly halfway through development, and also benefitted from FT designation (but did not get PR). Krazati’s overall development time of 4.1 years was six years faster than the recently reported average of 10.1 years for orphan-designated products. In addition to utilizing the AA, BTD, and FT programs, Krazati was reviewed under the FDA’s Real-Time Oncology Review and Assessment Aid programs.
Identifying the scope and nature of clinical evidence required for quantifying the magnitude and clinical meaningfulness of the product’s effects
Analyzing the purported clinical effects of competitor drugs in development for the same target indication
After this comprehensive, multidisciplinary assessment, we help a company decide if the available (or future) clinical data could “move the needle” of clinical benefit far enough to support a BTD request. Regulators focus on how persuasive the data are—and this is both compound- and program-dependent. At Parexel, we encourage companies to float the possibility of BTD with the FDA early if their drug shows potential for eligibility. For example, for some drugs, we recommend including a question about BTD for discussion at the pre-IND meeting. We advise clients to ask FDA if it would be reasonable to request BTD at a future time, based on a particular set of investigations and assuming there are data to support the anticipated advantages of the investigational product. In some instances, where there are no prior therapies or the clinical endpoints proposed to support clinical benefit are novel, the FDA may offer high-level feedback on the kind of information they would consider informative for a BTD request. If it is premature to ask this question, the agency will be frank about it. Recently, one of our clients obtained FDA confirmation at the pre-IND meeting that it would be reasonable to seek BTD for its product, a reformulated version of an approved drug. The reformulation uses a new route of administration and treats a new patient population with a serious disease for which few rapidly acting and effective therapies exist. The developer can consider the FT program if a drug is not yet eligible for BTD (or never will be). The evidentiary threshold for FT is lower than for BTD, and FT also comes with practical advantages such as frequent interactions with the FDA, increased opportunity for guidance, and other features to shorten FDA review of the marketing submission.
Companies with drugs that receive BTD earlier in development have more interactions with the FDA over time and more opportunities to align on streamlined programs. As a result, they may shorten the development timeline. However, BTD is not a guarantee of development speed or success. For example, companies developing precision medicines for rare diseases may need to conduct natural history studies or gather external control data. They may need to identify and validate genomic biomarkers, which requires developing assays and identifying laboratories competent to run testing. And they must recruit patients who may be scattered geographically. BTD will not reduce this essential workload. More commonly, because of the nature of the clinical evidence needed to fulfill BTD criteria, BTD can only be obtained after Phase 2 of development. Getting BTD later in development is still valuable because it guarantees agency interactions and receipt of agency advice on improving the efficiency of drug development.
Understanding the available therapies for the target indication and how the investigational product is differentiated
Estimating the expected therapeutic effects of the investigational product and their clinical significance
Understanding
Estimating
Identifying
Analyzing
New regulatory strategies for rare disease
Orphan drugs frequently benefit from BTD
Attaining BTD requires optimal evidence and timing
Getting BTD early is best, but it’s valuable at any time
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FDA-approved novel orphan BTD drugs and biologicals, 2017-2022 (n=86)
Use of FDA expedited development programs
40%
30%
22%
7%
BTD alone
BTD + Accelerated Approval (AA)
BTD + Fast Track (FT)
BTD + AA + FT
34
26
20
6
No. of FDA Expedited Mechanism(s) Used
60% percent of approved orphan BTD drugs used a “stacked” expedited program utilization
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Breakthrough therapy designation
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Steve Winitsky, MD Vice President, Technical, Parexel International
Steve spent more than 11 years at the FDA as a former Medical Officer, Team Leader, and Acting Branch Chief in the Center for Biologics Evaluation and Research’s (CBER’s) Office of Tissues and Advanced Therapies, which has recently been renamed the Office of Therapeutic Products (OTP). He has extensive experience with the review and supervision of cell and gene therapy (CGT) applications, including sponsor requests for Breakthrough Therapy and Regenerative Medicine Advanced Therapy designation. He also supervised numerous Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) and pre-IND meetings for CGTs.
In my earlier work at the FDA, and now with Parexel clients, I have encountered several persistent misconceptions about how the agency’s Center for Biologics Evaluation and Research (CBER) and Office of Tissues and Advanced Therapies (recently renamed the Office of Therapeutic Products) view orphan drug-designated cell and gene therapies (CGTs). Here are five of them:
Myth 1
Myth 2
Myth 3
Myth 4
Myth 5
Expedited programs lower the evidence bar and accelerate development
Many companies are thrilled to win a valuable FDA designation, such as Breakthrough Therapy (BTD) or Regenerative Medicine Advanced Therapy (RMAT). They often hope the designation will allow them to progress with a smaller and less persuasive volume of efficacy data, especially for an orphan CGT product. When I worked at the FDA, CGT companies would approach us regularly, asking for a reduction in the number of trials or the quality of evidence because they had an RMAT designation. We would explain that expedited program designations do not reduce the evidentiary requirements for licensure. The FDA often approves a novel drug or biologic in an orphan drug-designated indication on smaller, single-arm pivotal trials. But additional studies may be required if the product is not associated with a large, transformative clinical benefit. A well-designed natural history study—or other rigorous external control data—may also be required. These requirements may slow development down, not speed it up.
An orphan CGT will automatically get special attention from the FDA
In the current environment of constrained FDA resources, development programs for CGTs may languish due to a lack of intensive interaction with regulators, even if they are first-in-class and address a rare and serious unmet medical need. In September 2022, the FDA announced that it “elevated” OTAT to a “Super Office” within CBER—and renamed it the Office of Therapeutic Products (OTP), citing the current and anticipated increase in workload. As a former regulator, this suggests to me that the agency lacks the resources to handle the influx of sub-specialized CGT applications. BT or RMAT designation is now a prerequisite for prioritized meetings with OTP, as Director Wilson Bryan recently observed. Without BT or RMAT status—or exceptional preliminary clinical data— orphan designation on its own will not necessarily attract regulatory attention for a CGT. A benefit of RMAT designation is the RMAT Initial Comprehensive Meeting, a multidisciplinary discussion of the sponsor’s clinical trial and manufacturing development strategy. We’ve received feedback from several clients that the initial meeting is a boon, and every meeting for an RMAT-designated program will be scheduled at a Type B priority. We’ve helped clients prepare for these interactions to maximize the opportunity.
An orphan CGT can get Accelerated Approval on a clinically meaningful endpoint
In the European Union, the European Medicines Agency (EMA) has a licensure option known as conditional marketing authorisation (CMA), under which products that address unmet needs are approved on “less comprehensive data than normally required.” The CMA mechanism allows patients access to drugs despite incomplete benefit-risk data. The closest comparable pathway to CMA in the United States is the FDA’s Accelerated Approval (AA) pathway. But there is a critical difference between the two. CMA relates to the amount of evidence available for a drug, while the FDA interprets AA to relate to efficacy data collected for a specific type of endpoint. Thus AA for CGTs requires the use of a surrogate efficacy endpoint that is “reasonably likely” to correlate with clinically meaningful outcomes. Companies often confuse the CMA and AA pathways. I have seen them ask for AA based on a clinically meaningful primary efficacy endpoint and fail because it’s not a surrogate. Regardless of precedent, making assumptions about an expedited regulatory pathway is risky. Sponsors should discuss and agree on endpoints and other aspects of the AA pathway with OTP before they finalize their development plans.
Long-term follow-up CGT studies don’t yield much value for the sponsor
Some sponsors view long-term follow-up (LTFU) trials of approved orphan drugs as a line item on a long checklist of post-approval requirements. They must do the trials because regulators mandate them: for example, the FDA requires 15 years of safety follow-up for lentiviral-based gene therapies. And scientific advances, such as the emergence of gene editing platform technologies, will make longitudinal follow-up data for genomically-targeted treatments even more critical. But well-designed LTFU trials can add value for the sponsor. LTFU trials can cost almost as much as the pivotal trial—as much as $30 million—because any type of healthcare follow-up is costly. However, sponsors can design and execute LTFU studies to collect data that promote patient safety, support a product’s value proposition, and optimize product lifecycle management. At Parexel, when we design LTFU studies for a client, we always ask whether they want to meet the bare minimum FDA requirement for safety monitoring or whether they also want to generate data that could differentiate their product.
Regulators will make critical development decisions for you
Early meetings with the FDA offer sponsors a chance to de-risk their development strategy and optimize trial designs, endpoints, and the evidence generation plan before submitting an investigational new drug (IND) application. Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT) and pre-IND meetings are two such meetings. (The FDA’s Prescription Drug User Fee Act VII, signed into law on September 30, 2022, expanded the use of INTERACT to CDER products). These are valuable opportunities if sponsors prepare for them. Many developers hope to receive definitive answers to complex development questions during these exchanges. But regulators have neither the expertise nor the remit to make pivotal development decisions for companies. When I worked at the FDA, companies sometimes asked us to weigh in on two different products—or two routes of administration—and signal which would be more acceptable. We offered a stock reply that products with the most favorable benefit-risk profile should advance. In the end, developers have to make the critical decisions. The best way for them to arrive at good ones is to listen carefully to regulators and then, with all the data at their disposal, use their best judgment to make thoughtful tradeoffs and take defensible calculated risks.
Steve Winitsky Vice President Technical, Parexel International
At Parexel, when we design long-term follow-up studies for a client, we always ask whether they want to meet the bare minimum FDA requirement for safety monitoring or whether they also want to generate data that could differentiate their product.
Five myths about orphan CGTs
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Rachel Smith Executive Director, Rare Disease Center of Excellence, Parexel International
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Sinan Sarac, MD, PhD, MSc Vice President, Regulatory, Parexel International
Simona Stankeviciute, MD, MSc Principal Consultant, Parexel International
Jorge Camarero, PhD, MSc Vice President, Regulatory, Parexel International
Jorge has more than 17 years of experience in the European Union’s regulatory system, primarily in oncology and rare diseases and in evaluating advanced therapies, small molecules, monoclonal antibodies, biosimilars, and other protein products. He served at the European Medicines Agency (EMA) in the Netherlands as a member of the Oncology Working Party and an alternate member of the Committee for Medicinal Products for Human Use. Before his tenure at the EMA, he was head of the oncology area for the Spanish Agency of Medicines and Medical Devices (AEMPS), a pharmaceutical inspector for the Spanish Government’s health department; and a regulatory clinical assessor in Oncology for the AEMPS. He provides strategic, regulatory, and technical advice to Parexel clients on clinical-development strategy, applications for scientific advice and accelerated pathways, and marketing authorization submissions.
Sinan has worked with the EU regulatory system for more than a decade. At the EMA, he has served as a member of the Committee for Medicinal Products for Human Use, the Committee for Advanced Therapies, and the Scientific Advice Working Party, and as a member and chair of CHMP’s Oncology Working Party. He also served as chief medical officer at the Danish Medicines Agency. He was responsible for the scientific evaluation of new cancer products, the extension of indications, and national scientific advice. His experience covers oncology, hematology, rare diseases, advanced therapies, small molecules, monoclonal antibodies, and other protein-based products.
Rachel brings more than a decade of experience in every development phase of rare disease and cell and gene therapy (CGT) clinical trials to her work with Parexel’s rare disease clients. Previously, she served as Vice President of Clinical Operations, Portfolio Director of Rare Disease, and Global Head of the Cell & Gene Center of Excellence at Veristat LLC. She led programs in ADA-SCID, Canavan disease, congenital adrenal hyperplasia, Fabry disease, Gaucher disease, metachromatic leukodystrophy, and Wiskott-Aldrich Syndrome. Rachel has expertise in clinical development strategy, novel and adaptive trial design, decentralized trials, and other creative solutions for rare disease products with a non-classical route to market.
Prior to joining Parexel, Simona served as a clinical and clinical pharmacology assessor for centralized procedures at the Lithuanian State Medicines Control Agency, and she served as an alternate member of EMA’s Committee for Medicinal Products for Human Use. She was also trained in health-technology assessment for medicines and has served as a head of HTA unit. She has regulatory and clinical expertise in multiple therapeutic areas—including dermatology, neurology, and infectious disease—and modalities, including advanced therapy medicinal products, biologics, and small molecules. She helps Parexel clients prepare for scientific advice meetings with the EMA; submit marketing-authorization applications, line extensions, and Type II variations; and perform advanced pharmacokinetics, pharmacodynamics, and basic modeling and simulations.
Moderator
Participants
Parexel experts and former senior EU regulators share the regulatory challenges sponsors must understand to navigate the EU’s orphan drug designation process and gain authorization.
Peter Kiely, MD, MSc Vice President, Regulatory, Parexel International
Peter joined Parexel from the Irish Health Products Regulatory Agency (HPRA), where he worked as a clinical assessment manager. In addition to his more than 17 years of experience in regulatory assessment, including parallel assessment with the FDA, Peter was also an alternate member of the EMA’s Committee for Medicinal Products for Human Use, an alternate member of the Scientific Advice Working Party, an observer to the Rheumatology and Immunology Working Party, and a member of the Summary of Product Characteristics advisory group. He has extensive expertise in the assessment of marketing authorization applications, indication extensions, clinical trials, and combination products and is experienced in seeking and maximizing scientific advice, both nationally and at the EU level.
Clinical Development
EU orphan drug development