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The Sunsetting of Rare Pediatric Disease Designation

Posted by Joseph Watson on Mon, May 18, 2020 @ 09:30 AM
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As with other incentive programs, FDA created the Rare Pediatric Disease (RPD) designation to encourage drug development in products with questionable financial viability; in this case, the treatment of certain rare pediatric diseases.  One of the main benefits of RPD designation is the potential to receive priority review vouchers, which can be used to obtain priority review on a subsequent human drug or biologic application, should the product with RPD designation be approved.  Priority review vouchers have few restrictions, and can be used by the sponsor or sold/transferred to a separate organization.  In some cases, priority review vouchers have sold for over $100 million.superhero-team

While the potential financial benefits of RPD designation are compelling, the program, as mandated by the 21st Century Cures Act, has limited availability.  As things currently stand, FDA is sunsetting the program, and may not award priority review vouchers for any product unless the product has received RPD designation by September 30, 2020.  Therefore, as of the time of this article, pharmaceutical companies have approximately 5 months to receive the designation from the Office of Orphan Products Development (OOPD) at FDA.  FDA does have a review clock on such an application, but only under specific circumstances.  Section 529(d)(2) provides that a sponsor shall submit a request for RPD designation at the same time that they submit either an orphan drug application or a fast track designation; FDA has interpreted “at the same time” to mean within 2 weeks.  If a timely submission occurs, then section 529(d)(3) directs FDA to make a decision on the request no later than 60 days after the submission.  Note that, if the application is submitted in a timely fashion, information in an orphan drug application can be cross-referenced rather than transferred into the RPD application itself.  If submitted outside of a request for orphan drug or fast track designation, then FDA is under no time frame for review.

How can a sponsor increase the chances of a favorable first round review?  The first step is to ensure that the proposed indication meets the requirements for orphan designation, as the RPD application itself requests very similar information.  Second, we recommend that sponsors include data from the literature to support the early and serious effects of the disease in children.  Seriousness of the disease in childhood is critical to approval, and providing solid evidence from the literature or other data sources to substantiate this claim is the most important element that is needed for the RPD designation request beyond what one would provide for an orphan designation request.  Based on our previous experience, this means showcasing to the OOPD that greater than greater than 50% of the affected population in the US is between birth and 18 years of age.  This can generally be achieved by summarizing prevalence of serious symptoms by age. 

Finally, even if a sponsor’s product receives RPD designation, the guidance notes that, after September 30, 2022, FDA may not award any RPD priority review vouchers.  While this may cause some sponsors to hesitate, especially if their product is early in development, we note that legislative extensions can occur, and therefore seeking RPD designation may still be valuable.  

In any case, Rho can help your company move forward with a timely RPD submission.  Please contact our business development group if you have any questions.

 Joseph1-1Joseph Watson, PhD, RAC, Research Scientist at Rho, has experience in both regulatory submissions and clinical document preparation, with over fifteen years of experience in scientific writing and editing clinical and nonclinical documents, including numerous publications in peer-reviewed journals.  Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates.  His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology.

Drug Shortages During the COVID-19 Pandemic

Posted by Charity Duran on Thu, Apr 23, 2020 @ 10:45 AM
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As the United States struggles to keep pace with the rapidly escalating COVID-19 pandemic, demand for healthcare services and supplies has revealed the precariousness of our healthcare system and supply chains in the face of such extreme challenges. Shortages of ICU beds, ventilators, and proper personal protective equipment for healthcare providers have been a frequent point of discussion. Shortages of these items will have very visible and immediate impacts on public health, but as the number of COVID-19 hospitalizations increases, another growing threat to the US healthcare system’s ability to respond to the pandemic is emerging: shortages of essential drugs diverted from patients with their primary indications to treat patients infected with COVID-19.

On March 31st two anti-malaria drugs, hydroxychloroquine (which is also used to treat lupus and rheumatoid arthritis) and chloroquine, were added to the FDA’s drug shortages webpage due to a “significant surge in demand.” This surge in demand is driven by the fact that these drugs are viewed as potential treatments for COVID-19, a stance that is only based on the results of small clinical studies with conflicting results and anecdotal evidence (double-blind randomized controlled trials have not yet been conducted). Both drug products were recently granted emergency use authorization by the FDA, which allows for the drugs to be “donated to the Strategic National Stockpile to be distributed and prescribed by doctors to hospitalized teen and adult patients with COVID-19, as appropriate, when a clinical trial is not available or feasible.” The US Department of Health and Human Services (HHS) has already accepted 30 million doses of hydroxychloriquine sulfate and one million doses of Resochin (medical grade chloroquine phosphate) for this purpose. Due to this surge in demand, per an FDA New Release, “The agency is working with manufacturers to assess their supplies and is actively evaluating market demand for patients dependent on hydroxychloroquine and chloroquine for treatment of malaria, lupus and rheumatoid arthritis. All manufacturers are ramping up production, and…the FDA is working with manufacturers to ensure this can happen expeditiously and safely.”

While drug shortages of hydroxychloroquine and chloroquine dominate the news, there are shortages of other essential drugs that are equally concerning. As the demand for ventilators has increased, so has the demand for drugs associated with their use. Intubation is incredibly uncomfortable, and requires adequate sedation to ensure proper placement of a breathing tube while avoiding damage to the patient’s vocal cords during placement. Intubated patients are typically given strong sedatives and pain medicine (such as propofol and fentanyl), and also paralytics, to keep them comfortable. Data released from healthcare companies reveal dramatic spikes in demand for sedatives, pain medications, paralytics, and other drugs often required for patients on ventilators. This demand is driven not only by the overwhelming number of COVID-19 patients, but by the prolonged duration of a typical COVID-19 ICU stay - two weeks or more - as opposed to the average stay of one week. Some of these drugs, including midzaolam and fentanyl, are now listed on FDA’s drug shortages webpage.

Ramping up the manufacturing of drugs experiencing shortages will not be easy. Contributing to the shortage is that most of drug manufacturing is on a “just-in-time” schedule; although manufacturers typically have 2-3 months of safety stock on hand, with the increased utilization of these drugs for COVID-19 patients, these stores will be depleted at an expedited rate. As drug manufacturing is highly regulated, ancillary manufacturers cannot readily be converted to drug manufacturers. Increasing domestic manufacturing will be contingent upon currently available manufacturing capacity and the availability of active pharmaceutical ingredient (API).

Rho is actively monitoring drug shortages, as well as additional new information as it is released from the FDA regarding the current COVID-19 pandemic.

Charity DuranCharity Duran, PhD, RAC, Integrated Product Development Associate, works with companies at all stages of development to support their regulatory submissions. She has over a decade of experience in scientific and regulatory writing. Her experience includes the development and production of documents supporting regulatory submissions (modules of NDAs and INDs), the preparation of briefing packages to support regulatory meetings, and the development of clinical study documents, including clinical study protocols and clinical study reports.

Programs to Support Drug Development in Infectious Disease

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Generating Antibiotic Incentives Now (GAIN) and the Qualified Infectious Disease Product (QIDP) Designation, and the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD)

According to the Centers for Disease Control and Prevention (CDC), more than 2.8 million people a year are sickened by antibiotic-resistant infections, and more than 35,000 people die as a result [1]. Antibiotic resistance is on the rise as bacteria continue to grow impervious to currently available antibiotics. Antibiotic-resistant microbes can spread quickly across communities, the food supply, and healthcare facilities and can share their ability to become resistant with other microbes that have not been exposed to antibiotics. When microbes are resistant to antibiotics, not only does this limit the ability to fight routine infections but it also erodes the ability to provide treatments that may immunocompromise patients, such as cancer treatments or organ transplants, and to safely perform more routine procedures that require a certain level of sterility, such as joint replacements.

It is critical for drugmakers to develop treatments for antibiotic-resistant infections. However, it is difficult to identify patients with highly resistant bacterial infections and to enroll them in sufficient numbers for traditional, large-scale clinical trials [2]. Historically, there was also little incentive to develop new antibiotics because these drugs tend to generate smaller revenue compared with “blockbuster” drugs such as those for high blood pressure treatment, which are taken by many more people daily [3].Antibiotics. Medical Report with Composition of Medicaments - LIght Green Pills, Injections and Syringe. Blurred Background with Selective Focus.

Generating Antibiotic Incentives Now (GAIN) and the Qualified Infectious Disease Product (QIDP) designation and the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD), described below, were designed by the FDA to streamline development and encourage investment into targeting infections that lack effective therapies [4].

GAIN and the QIDP Designation
In 2012, GAIN was signed into law as part of the Food and Drug Administration Safety and Innovation Act [3]. GAIN established the QIDP designation, which extends the exclusivity period during which certain antibiotics—those that treat serious or life-threatening infections—can be sold without generic competition by 5 years. This 5-year market protection is in addition to any existing exclusivity (e.g., 5 or 3 years under Hatch-Waxman, 7 years under orphan drug designation, and 6 months for pediatric exclusivity). Important highlights of the FDA Draft Guidance on QIDP designation [5] include:

• A sponsor may request a QIDP designation any time prior to submission of a marketing application.
• FDA will consider a drug to be “intended to treat a serious or life-threatening infection” if it is intended to diagnose, prevent, or treat such an infection.
• Biologic products and devices are not eligible for QIDP designation. However, the regenerative medicine advanced therapy (RMAT) designation is intended to incentivize the development of biologic products for the treatment of serious conditions [6].
• Drugs that are intended to treat a serious or life-threatening bacterial or fungal infection caused by a pathogen that is not included on the list of qualifying pathogens may be eligible for designation as a QIDP.

Between 2012 and 2017, FDA designated 147 QIDPs; the number of QIDP designation requests has grown steadily each year [7]. The 5 most common indications that have received QIDP designation include acute bacterial skin and skin structure infection, complicated urinary tract infection, community-acquired bacterial pneumonia, hospital and/or ventilator-associated bacterial pneumonia, and complicated intra-abdominal infections. Between 2012 and 2017, 12 drugs with QIDP designation were approved by the FDA, including Solosec (secnidazole) granules for treatment of bacterial vaginosis in adult women and Vabomere (meropenem and vaborbactam) injection for treatment of complicated urinary tract infections.

The FDA grants fast track and priority review status to drugs that fall under GAIN, which undergo an expedited regulatory approval process. As part of GAIN, FDA was required to issue a new guidance on the development of pathogen-focused antibiotics and to compile a list of “qualifying pathogens” that have the potential to pose a serious threat to public health, which is updated every 5 years [8].

LPAD
Although GAIN and QIDP provided a financial incentive and more clarity to spur antibiotic drug development, there was still a need to further incentivize antibiotic drug development for serious conditions in which only a small number of patients—a limited population—are likely to be diagnosed [2].

In 2016, the FDA responded to this need by adding the LPAD program to the Federal Food, Drug, and Cosmetic (FD&C) Act through section 3042 of the 21st Century Cures Act [9]. The goal of this program was to aid approval of antibacterial and antifungal drugs to treat serious and life-threatening infections in a limited population of patients with unmet needs by streamlining approaches to clinical development, which could involve smaller, shorter, or fewer clinical trials. Given that clinical programs might have fewer subjects, trials, or shorter study duration as compared with other indications, drugs approved under the LPAD program are required to have prominent labeling stating “Limited Population” on all labeling and advertising so that healthcare providers can identify the patients for whom the FDA determined the benefits of the drug outweigh the risks. The FDA has the authority to pre-review all promotional materials for these products to ensure that messaging is clear that the drug’s approval was based on a benefit-risk assessment on a limited population. This is because the benefit-risk calculation for the sickest patients who lack other treatment options and who might otherwise die from infection is different from the risk of broader populations with more easily treatable infections [2].

Important highlights of the FDA Draft Guidance on the LPAD program [10] include:

• The LPAD program requires FDA to take into account in its determination of safety and effectiveness the severity, rarity, or prevalence of the infection a drug is intended to treat and the lack of alternative treatment in the limited population a drug is intended for.
• FDA anticipates that early and frequent communications between the Agency and sponsors interested in pursuing approval under the LPAD program for their products can help reduce overall product development timelines. Sponsors interested in the LPAD program should clearly state their intentions during discussions with FDA.
• FDA will make the determination of whether a drug meets the criteria for the LPAD program at the time of the drug’s approval.

In the past 4 years since the LPAD was added to the FD&C, two drugs have been approved under the program [9]:

• Arikayce (amikacin liposome inhalation suspension), was approved for the treatment of lung disease caused by Mycobacterium avium complex, in patients with the disease who do not respond to conventional treatment (refractory disease) based on a single randomized controlled trial of 89 subjects using sputum cultures as a surrogate endpoint.
• Pretomanid Tablets in combination with bedaquiline and linezolid was approved for the treatment of a specific type of highly treatment-resistant tuberculosis of the lungs based on a study of 107 subjects versus a historical control.

Rho has provided regulatory strategy and submission support for products that have utilized these programs and other programs meant to spur development in infectious disease such as the tropical disease priority review voucher program [11]. Our regulatory experts can help guide sponsors through GAIN and the QIDP, LPAD, and other regulatory programs so more drugs that treat life-threatening infections can be developed and save lives.

References:
1. CDC. Antibiotic Resistance Threats in the United States, 2019: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
2. Pew. LPAD: A Regulatory Pathway to Develop Antibiotics and Fight Drug-Resistant Infections, 2015: https://www.pewtrusts.org/en/research-and-analysis/articles/2015/06/lpad-a-regulatory-pathway-to-develop-antibiotics-and-fight-drug-resistant-infections
3. Pew. GAIN: How a New Law is Stimulating the Development of Antibiotics, 2013: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics
4. FDA News Release. FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation, 2018: https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-serious-lung-disease-using-novel-pathway-spur-innovation
5. FDA. Qualified Infectious Disease Product Designation Questions and Answers Guidance for Industry, 2018: https://www.fda.gov/media/111091/download
6. FDA. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance for Industry, 2019: https://www.fda.gov/media/120267/download
7. Department of Health and Human Services (2018) Report to Congress on Generating Antibiotic Incentives Now (GAIN): https://www.fda.gov/media/110982/download
8. FDA. Establishing a list of qualifying pathogens under the Food and Drug Administration Safety and Innovation Act. Final rule. Federal Register, 2014: https://www.govinfo.gov/content/pkg/FR-2014-06-05/pdf/2014-13023.pdf
9. FDA. Limited Population Pathway for Antibacterial and Antifungal Drugs – the LPAD Pathway, 2019: https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway
10. FDA. Limited Population Pathway for Antibacterial and Antifungal Drugs Guidance for Industry, 2018: https://www.fda.gov/media/113729/download
11. FDA. Tropical Disease Priority Review Voucher Program, 2018: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program

Yael SYael Symes, PhD, Integrated Product Development Associate, has over 10 years of experience in writing and editing scientific documents, including 9 publications in peer-reviewed journals. She has participated in the authoring and preparation of clinical protocols, modules of NDAs and INDs, clinical study reports, and other regulatory documents in a variety of therapeutic areas. Her therapeutic area experience includes oncology, infectious diseases, respiratory diseases, ophthalmology, and pain. Dr. Symes received a fellowship for her graduate training in cancer prevention and control from the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center and received her PhD in Health Behavior at the University of North Carolina at Chapel Hill Gillings School of Global Public Health. Her PhD was focused on examining psychosocial predictors of smoking cessation (e.g., health-related quality of life) and e-cigarette use in cancer survivors. Dr. Symes is a current member of the Regulatory Affairs Professionals Society (RAPS) and the North Carolina Regulatory Affairs Forum (NCRAF).

Kathleen Candando.3-1

Kathleen Candando, PhD, Research Scientist, authors regulatory submission documents and contributes to regulatory strategy and product development services. Dr. Candando has more than 10 years of experience in writing, reviewing, and editing scientific documents and frequently leads authorship of regulatory submissions including US IND and NDA modules, clinical study reports, clinical study protocols, and orphan drug designation applications. Dr. Candando’s therapeutic experience is broad and includes multiple areas of allergy and immunology, infectious diseases, oncology, and neurology.

Meagan HeadshotMeagan Spychala, DrPH, Assistant Vice President of Patient Engagement and Program Strategy, has over 15 years of clinical development experience, providing scientific and technical oversight on trials of varying phase, sizes, therapeutic areas/indications, and complexities. Meagan holds a DrPH and MS in biostatistics from the University of North Carolina at Chapel Hill and a BS in mathematics from Washington and Lee University. She has extensive knowledge of all facets of clinical development inclusive of study design, protocol writing, risk management, trial implementation, and regulatory submissions to support marketing applications. Dr. Spychala is able to provide a big-picture view of the clinical development landscape having provided oversight to individual trials and multi-trial programs. She recognizes the uniqueness of each clinical trial, and understands the importance of each patient in the development program. Dr. Spychala engages with sponsors as well as the patient advocacy community to develop the relationships needed to support patient and family-centric clinical research. 

Joseph1-1Joseph Watson, PhD, RAC, Research Scientist, has experience in both regulatory submissions and clinical document preparation, with over 15 years of experience in scientific writing and editing clinical and nonclinical documents, including numerous publications in peer-reviewed journals. Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates. His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology.

Kevin BarberKevin Barber, PhD, RAC, PMP, Vice President of Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has led the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products in therapeutic areas including dermatology, nephrology, urology, women’s health, CNS/neurology, cardiovascular diseases, virology, oncology, immunology, infectious diseases, blood products, and gene therapy. Dr. Barber has significant experience preparing and filing regulatory submissions, including more than 45 US INDs and more than 40 marketing applications in the US, Canada, Europe, Latin America, Australia, and New Zealand. He also has experience with medical device and in vitro diagnostic development programs and regulatory submissions including pre-IDE meetings, IDEs, 510(k)s, and PMAs.

505(b)(2) vs ANDA:  How Complex Drugs Fit In

Posted by Karley St. Pierre on Wed, Feb 05, 2020 @ 04:24 PM
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Choosing the Appropriate New Drug Application and Corresponding Abbreviated Development Pathway

SamanthaHoopes1Samantha Hoopes, PhD, RAC is a Research Scientist at Rho where she is involved in management of clinical studies and regulatory submission programs.  She has over 13 years of clinical research experience across a variety of biological, clinical, and regulatory fields and has served as lead author on clinical and regulatory documents for product development programs for a variety of therapeutic areas.  She works with companies at all stages of development to support their product development plans, clinical study design and execution, and regulatory submission management and authoring activities.

regulatory pathways--ANDA and 505(b)(2)

Over the past few years, we have seen some changes in the regulatory environment with a new Drug Competition Action Plan and FDA guidances focused on introducing more competition into the drug market with the goal of increasing access to drugs that consumers need.  These guidance documents are meant to provide information on abbreviated approval pathways and provide clarity on the regulatory pathway for complex generic drugs in order to speed approval allowing for more competition in the market place, which may impact pricing. 

While it is important to understand how to navigate the complex generic drug approval pathway, it is first necessary to determine whether your drug product should be submitted as an abbreviated new drug application (ANDA) for approval as a generic or if it requires submission of a 505(b)(2) new drug application.  This particular issue is addressed in a guidance, finalized May 2019, “Determining Whether to Submit an ANDA or a 505(b)(2) Application.”  The guidance defines an ANDA as an application for a duplicate of a previously approved drug product that is the same with respect to the active ingredient[s], conditions of use, route of administration, dosage form, , strength, conditions of use, and labeling [with certain permissible differences]) of a previously approved drug product that relies on FDA’s findings that the previously approved drug product, the reference listed drug, is safe and effective.  Some examples of permissible labeling differences may include changes to certain inactive ingredients, exclusion of certain conditions of use, and changes due to the generic drug product and reference listed drug being produced or distributed by different manufacturers.  An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product.  A 505(b)(2) application contains or references full reports of safety and effectiveness and one or more of the investigations relied upon by the applicant for approval were not conducted by the applicant and for which the applicant has not obtained a right of reference or use from the company by or for whom the investigations were originally conducted [Guidance for Industry:  Applications Covered by Section 505(b)(2)].

The guidance outlines regulatory considerations for ANDA and 505(b)(2) applications as described below.  FDA will generally refuse to file a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval via an ANDA.  An applicant may submit a suitability petition (21 CFR 314.93) to the FDA requesting permission to submit an ANDA, known as a petitioned ANDA, for a generic drug product that differs from the RLD in its dosage form, route of administration, strength or active ingredient (in a product with more than one active ingredient).  The FDA will not approve a suitability petition if determined that safety and effectiveness of the proposed changes from the reference listed drug cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA or the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA.  The FDA will not accept an ANDA for filing for a product that differs from the reference listed drug until the suitability petition has been approved.

In some circumstances, an applicant may seek approval for multiple drug products containing the same active ingredient(s), known as bundling, when some of the products would qualify for approval under the 505(b)(2) pathway and some of the products would qualify for approval under the ANDA pathway.  The FDA allows the applicant to submit one 505(b)(2) application for all such multiple drug products that are permitted to be bundled.  An example referenced in the draft guidance where bundling into one 505(b)(2) submission would be allowed includes an applicant seeking approval of multiple strengths of a product where only some of which are listed in the Orange Book, as reference listed drugs. 

There is potential market exclusivity with an ANDA or 505(b)(2); however, the length of exclusivity depends on the specific scenario and the type of application.  An approved ANDA may result in 180 days of market exclusivity or none; only the first submitted and approved ANDA for a generic of a reference listed drug is eligible for 180 days market exclusivity.  A 505(b)(2) may be granted 3 years market exclusivity if one or more of the clinical investigations, other than bioavailability/bioequivalence studies, was essential to approval of the application.  A 505(b)(2) application may be granted 5 years market exclusivity if it is for a new clinical entity or 7 years market exclusivity if it is for an orphan drug product [Guidance for Industry:  Applications Covered by Section 505(b)(2)

CollaborateOver the past few years, FDA has released guidance documents and manuals of policies and procedures (MAPPs) and held workshops focused on their initiatives to increase scientific and regulatory clarity with respect to complex generic drug products.  A draft guidance titled “Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA” was issued in October 2017 to provide ANDA applicants information on preparing and submitting meeting requests and meeting materials for complex generic drug products.  Complex products are defined as 1)  complex active ingredients (peptides, polymeric compounds, mixtures of active pharmaceutical ingredients, naturally sourced ingredients,) complex formulations (liposomes, colloids), complex routes of delivery (locally acting drugs such as dermatological products and complex ophthalmological products and otic dose forms that are formulated as suspensions, emulsions, or gels), complex dosage forms (transdermals, metered dose inhalers, extended-release injectables), 2)  complex drug-device combination products (auto-injectors, metered dose inhalers), or 3) other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.  The guidance describes 3 types of meetings for complex products that may be submitted as an ANDA:  product development meetings, pre-submission meetings, and mid-review-cycle meetings. The draft guidance includes details for how it is determined if meetings are granted and the review timeframe goals for FY2018 through FY2022. In addition, FDA released the MAPP:  Evaluating Request for and Conducting Product Development and Pre-Submission Pre-ANDA Meetings in September 2019.  In April 2019, FDA also launched a website dedicated to providing information on upcoming product-specific guidances for complex generic drug product development.  A list of past workshops, guidances, and MAPPs focused on complex generic drug products can be found at the FDA website featuring news and information about the Drug Competition Action Plan.

Additionally, a draft guidance released on 03 January 2018 “Good ANDA Submission Practices,” addresses common, recurring deficiencies seen in ANDAs that may lead to delay in approval.  Common deficiencies include not correctly addressing patent and exclusivity information for the RLD, not providing adequate and properly prepared clinical summary data tables for bioequivalence studies, and not submitting draft container and carton labels with an accurate representation of the formatting that will be used for the final printed labels.  In a statement from Dr. Gottlieb, FDA commissioner at the time, “it currently takes on average about 4 cycles for an ANDA to reach approval – not necessarily because the product will not meet our standards, but sometimes because the application is missing the information necessary to demonstrate that it does” (Press Release 03 January 2018).  This guidance as well as a manual of policies and procedures (MAPP:  Good Abbreviated New Drug Application Assessment Procedures) aim to help reduce the number of review cycles ANDAs undergo prior to approval.  In June 2019, FDA finalized a guidance, ANDA Submissions – Content and Format, meant to assist applicants in preparing a complete; high-quality ANDA for submission.  This guidance describes information that should be included in an ANDA and identifies additional guidance documents that would help applicants during preparation of their submission.  

These guidance documents provide clarity on abbreviated approval pathways and highlight priorities of the FDA to increase competition in the marketplace with a focus on speeding generic approvals, including complex generic drug products. 

 

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Four Considerations for Every Rare Disease Development Program: Summary of CBI’s Rare Disease Clinical Development and Access Summit

Posted by Meagan Spychala & Karl Whitney on Thu, Jan 23, 2020 @ 09:17 AM
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Rho representatives joined regulators, industry scientists, and numerous patient-advocacy groups at CBI’s Rare Disease Clinical Development and Access Summit in Washington this past December. Attendees were able to share best practices in product development for rare disease programs in formal presentations and through informal networking. The following are 4 considerations for your development program that were highlighted during the conference.

1)  Seek early engagement for patient and caregiver perspectives and with key  payers.
Sponsors need patient and caregiver perspectives in order to ensure clinical studies are properly designed to provide evidence speaking to issues that truly matter to patients and their caregivers. These interactions should start as early on in the process as possible, even as early as initial animal proof-of-concept stage. Patient advocates advised companies to be open, transparent, and humble in approaching their communities for these insights; patients and caregivers want their perspectives heard and know that increasingly they have great influence in shaping product development for their conditions. Because of this increasing influence, some patient groups are not waiting for outreach from product developers, and have conducted or are planning formal Patient-Focused Drug Development or FDA listening sessions so that the community can proactively shape FDA’s understanding of key concerns Young pretty girl giving the sick woman glass of waterand priorities for product development.

It's also important to engage with key payers such as Centers for Medicare and Medicaid Services (CMS) no later than End of Phase 2 so that the pivotal studies can provide data that will support reimbursement. Often this means exploring persistence of effect in a longer study than might be minimally required by FDA. And, on that note, don't forget the perspectives of payers outside the US, including via the Health Technology Assessment processes in EU member states.

2)  Regulatory authority investment in rare disease development programs means more opportunities for dialog between regulators and sponsors: prepare for and embrace the increased access.
It is useful to note that in all these discussions about the development program, sponsors should make the most of milestone meetings and other opportunities to gain consensus with FDA on your plans. In 2018, 58% of the approvals were for rare disease indications and FDA speakers shared freely about how important and exciting this time is for them, patients, and industry. Precisely because FDA and similar stakeholders are so invested in these programs, and because these programs often include novel or challenging development issues, an iterative process in arriving at agreements should be expected. This will particularly be the case for topics lacking clear precedent owing to the rare nature of the disease in question. Therefore, it is imperative to identify key development questions and discuss them transparently with FDA and in hopes of settling key program questions by End of Phase 2.

3)  Plan early for Chemistry Manufacturing Controls (CMC).
Once your lead is selected, it's critical to provide sufficient resources and advanced planning to the CMC development program. All too often, especially for a program benefiting from enhanced support and guidance from FDA via Breakthrough Therapy or Regenerative medical pills industry  factory and production indoorMedicine Advanced Therapy designations, sponsors find themselves with near-complete clinical programs backed by incomplete CMC packages. Proper planning and support is the only way to ensure nimble scale-up as development proceeds and as the team begins to prepare for marketing. In that light, as much as possible, avoid tweaks to the investigational product to avoid having an even higher hill to climb for the CMC program. By the same token, if the product needs a specialized delivery device, work to settle the design and performance features of this as early as possible to allow the team to focus on other things like running efficient trials. Finally, the same plan-ahead advice likely applies to the nonclinical program. Interested in knowing more about how to plan for your CMC development program? In the near future, another blog post will address this topic, so be on the look-out.                                                                    

4)  Strategize for how to streamline your clinical trials while still supporting your claims.
In rare disease, recruitment and retention for clinical trials can be increasingly difficult due to the small population size. Creating a streamlined program strategy that will support your potential label will assist in a more efficient product development program. If the disease course, genotype, and phenotype are poorly understood, a natural history study is an absolute must to gain valuable information about the disease and potential endpoints that would be of value to your proposed claims. Remember that the first-in-human study may end up being the pivotal study, so it has to be well designed and as flawlessly executed as possible to deliver the best possible data. Perhaps this is easier said than done, but it's a fundamental pillar of successful product development, particularly for rare diseases. Even if your first-in-human study does not become your pivotal, you should look into alternative study designs that can reduce your sample size and discuss with the agency the composition of the program to understand the expectations for that indication and claim.

Topical, targeted industry meetings like this are excellent opportunities to share ideas and best practices in a small setting with a wide range of highly experienced people, which is why Rho staff regularly attend and contribute to such meetings. No meeting can offer a comprehensive view of everything that can come up in your development program or risks and opportunities to consider, which is why having an expert partner can be invaluable to your program. Contact us at any point in your development program for a free expert consultation; you'll be pleased with our team's thoughtful and creative review.

Meagan3-1

Meagan Spychala, PhD, Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s expert on patient-focused clinical research activities and incorporates the patient and caregiver voice and experience into the clinical development program.  She recognizes the uniqueness of each clinical trial, which is especially true within rare disease clinical research, and understands the importance of each patient in the development program.

karlKarl Whitney, PhD., Assistant Vice President of Product Development, leads multiple integrated drug development programs spanning the development spectrum by planning, managing, and overseeing concurrent manufacturing, nonclinical, clinical, and regulatory activities. Dr. Whitney has also contributed to preparation of many regulatory submissions,  clinical protocols and amendments, and numerous other documents. 

 

Current Gene Therapy Landscape:  Overview, Challenges, and Benefits

Posted by Kristin Gabor on Wed, Jan 15, 2020 @ 11:22 AM
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In 2017, the US Food and Drug Administration (FDA) approved its first gene therapy, a chimeric antigen receptor T-cell (CAR-T) product to fight acute lymphoblastic leukemia (Kymriah). That same year, another CAR-T therapy was approved to fight certain types of B-cell lymphoma (Yescarta). Since then, 4 additional products have been approved to treat serious diseases such as B-thalassemia, spinal muscular atrophy, a rare form of vision loss and a rare form of primary immunodeficiency. There are currently over 450 gene therapy and gene-based medicine companies worldwide and around 800 gene therapy and gene-modified cell therapy clinical trials being conducted (ARM Q3 update).

Significant progress has been made in developing safe gene therapy products in recent years. Just over 20 years ago, the tragic case of 19-year old Jesse Gelsinger who died during a gene therapy trial led to a temporary collapse in the gene therapy field. Since then, the gene therapy industry has come a long way. In a joint statement made in January 2019, FDA Commissioner Scott Gottlieb and CBER Director Peter Marks noted that based on an assessment of the current pipeline and clinical success rates of gene therapy products, the FDA anticipates that by 2020 they will be receiving more than 200 INDs per year for cell-based or directly administered gene therapies and by 2025 the FDA will be approving 10 to 20 cell and gene therapy products a year.

The basics – what is gene therapy?kristin1

Gene mutations can be inherited or occur as cells age or become exposed to certain chemicals. Small changes to our genetic material can have large impacts on cellular function.

Gene therapy products mediate their effect by transfer of genes or alteration of human genetic sequences. It can be thought of as the introduction, removal, or change of genetic material within patient cells – for instance, repairing a faulty gene in order to produce new or modified proteins, increase proteins that will fight disease, or reduce proteins that cause disease. This can be achieved by gene replacement, gene silencing, gene addition, or gene editing.

The genetic material is typically transferred into patient cells using a specific type of delivery mechanism (described below). Once inside the cell, the gene will make functional protein or target the disease-causing gene.

Gene Delivery Mechanisms

Gene therapy administration can occur via ex vivo or in vivo mechanisms. With ex vivo gene therapy, targeted cells (eg, chimeric antigen receptors (CAR) T cell therapies, T cell receptor (TCR) therapies) are extracted from the patient and the cells are genetically modified in vitro before they are transferred back into the patient. In vivo administration occurs via direct delivery to the patient using a viral or non-viral vector and the target cells remain in the body of the patient.kristin2

Vectors (carriers of the gene), can come in the form of viral vectors, which are genetically engineered viruses that replace the virus genome with the therapeutic gene. Examples of viral vectors are retroviruses, lentiviruses, and adeno-associated virus (AAV; of note, the AAV method is believed by many to be the future of gene therapy). Plasmids (small DNA circles or “naked” DNA), engineered bacteria, and liposomes are other vectors of gene therapy administration to either carry and deliver a replacement gene or to help or silence an existing gene.

Another type of gene therapy product is genome edited cells, which can be generated using zinc finger nucleases (ZFNs); transcription activator-like effector-based nucleases (TALEN), or nucleases such as Cas9 and Cas12a that derive from the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas). For instance, one company is using a genome editing platform called ARCUS derived from a natural genome editing enzyme called a homing endonuclease in their CAR-T development programs.

Challenges and Benefits in Developing Gene Therapies

The unique benefits of gene therapy are that it targets the cause of the disease and has the ability to treat or maybe even cure rare, debilitating diseases that have few to no treatment options, often with a single administration. Over time, the high price tag of gene therapy could reduce or eliminate the need for a lifetime of expensive and/or painful ongoing treatments that many in this patient population would require.

Although gene therapy offers a number of unique benefits, a number of challenges exist that make the development of gene therapies difficult as well as expensive. Those include:

• Length of clinical trial process – long term safety follow up due to uncertainty surrounding the potential durability of effect and long-term safety effects or complications;
• Manufacturing is complex and time intensive, and many sponsors have faced capacity constraints due to the difficulty in mass production (of viral particles, for instance);
• Individual response variability;
• Some conditions have many mutations leading to a given disease and one gene therapy approach may only work for a subset of affected individuals;
• May stabilize disease pathology but not actually reverse existing damage;
• The efficiency of gene transfer with vectors and the limited control over where integrating viral vectors will integrate;
• Dose of vectors may be high and large doses may be needed to reach target tissues; vectors could be filtered out in the liver or cleared by an immune response;
• Unlike other therapeutics, once administered there is no dose titration and no ability to control expression levels; gene therapy cannot be turned on or off. It is also very likely that there is no ability to do repeat dosing due to immunity developed during initial treatment.

An Advancing Field

Gene therapy offers the potential for significant breakthroughs and a lot of exciting progress hBlue DNA helix background-1as been made with scientific advances in gene therapy and the recent FDA approvals. Their complexity to develop should not be underestimated, as evidenced by the FDA’s release of 6 additional guidances in 2018 intended to help product developers. The gene therapy industry is poised for the future, but due to its complexity the development process needs to be thoughtfully planned and managed. Critical to the success of the field will be the capacity to scale up for AAV manufacturing or other gene therapy manufacturing factories and a streamlined regulatory landscape.

Rho Can Help

There are several unique aspects of gene therapy clinical trials. Rho is currently leading several gene therapy studies and has conducted over 20 gene/cellular therapy trials in over 1000 patients.  One of our sponsors commented, “Our collaborative relationship with Rho has been instrumental in the implementation of a complex and rigorous first in human genetic medicine study, including strategic solutions for unique challenges faced in rare disease gene therapy trials.  Rho has leveraged existing relationships with patient advocacy organizations and worked closely with a centralized biosafety review partner early in study startup to help identify and mitigate potential challenges. “   

From both a clinical and regulatory standpoint, our experts can offer advice on your gene therapy trial from the preclinical phase through post-submission. For additional gene therapy considerations from our experts, please view our webinar, "Development Advice for Gene Therapy Products"  and for regulatory considerations,  David Shoemaker's article, "The Gene Therapy Product Development Process."

Need support designing and executing your next gene therapy trial? Ask our experts for help.

Kristin Gabor smallKristin Gabor, PhD, RAC, Research Scientist, has experience in both regulatory submissions and clinical operations management, with over 10 years of experience in scientific writing and editing clinical and nonclinical documents, which includes numerous publications in peer-reviewed scientific journals.  Dr. Gabor has led and participated in the authoring, review, and preparation of several regulatory and clinical documents, including protocols, clinical study reports, annual safety reports, modules of regulatory submissions (NDA, IND, etc.), and other regulatory documents in a variety of therapeutic areas at various stages of integrated product development programs. Her experience spans a spectrum of therapeutic areas, including cystic fibrosis, sickle cell disease, inflammation and immunology, infectious diseases, atopic dermatitis, multiple sclerosis, and rare diseases. Dr. Gabor earned an interdisciplinary PhD in Functional Genomics from the University of Maine and subsequently received an Intramural Research Training award from the NIH/NIEHS for her postdoctoral studies investigating the role of cholesterol metabolism and cell membrane perturbations in regulating the innate immune response in a rare genetic disease.  Dr. Gabor received her Regulatory Affairs Certification from the Regulatory Affairs Professionals Society (RAPS) in 2018 and is a current member of RAPS and the North Carolina Regulatory Affairs Forum (NCRAF).

 

Is a Target Product Profile Worth the Effort?

Posted by David Shoemaker on Wed, Dec 18, 2019 @ 09:32 AM
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David2

David Shoemaker, PhD, SVP R&D, has over 25 years of experience in pharmaceutical product development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with ensuring products meet regulatory standards at all stages of the development process.

A recent study by the MIT Sloan School of Management determined only 14 percent of clinical studies succeed, indicating there is room for vast improvement in the pharmaceutical industry’s ability to develop needed therapeutics more efficiently1. Inasmuch as the clinical develop program for a product comprises several to dozens of clinical studies to achieve marketing approval, chances are that one or more studies will fail during development. Coincidentally, this success rate of 14 percent approximates the age-old estimate that 10 to 20 percent of products that enter human studies make it to the market2,3. However, an eventual failure rate of 80 to 90 percent for products entering Phase 1 speaks to more than simply clinical study failure rate. The failure rate indicates an overall development process shortcoming that begins during the preclinical stage and destines product development programs for failure. This is due in part to the fact that companies are in many cases not doing the correct clinical study on an efficient path to marketing a needed therapeutic product. They do not possess a road map for success.

As a contract research organization who works extensively with late stage development companies collaborating on the preparation of their marketing applications, Rho continually observes product sponsors who fail during late stage development due to preventable missteps with their product development program. We are always buoyed by starting a new relationship with a company who has taken the time to prepare a Target Product Profile (TPP) because we know we have a client who understands the importance that prescribing information and market position play in the ultimate approval of a product by the regulatory authorities and the commensurate successful market capture. Simply achieving marketing approval is not the goal. The goal is to provide a useful therapy that will meet the needs of patients, physicians, and payers and hopefully advance current therapeutic options. The TPP provides a road map for development of a product, laying out all the key development performance criteria that the investigational product must meet in order to ultimately become the useful therapy the sponsor wants it to be; failure to meet any of these key criteria means the investigational product will not succeed as a useful marketed product and development should be abandoned or somehow re-engineered.

The crafting of a TPP is enabled by a detailed understanding of not only the disease and its associated market, but also unmet patient, physician and payer needs. The goal posts for each of the stakeholders need to be determined by identifying the minimal and the optimal characteristics for a variety of TPP elements. The major criteria to meet patients’ needs reside primarily in efficacy and safety elements, but satisfying dosage, route of administration, and specific patient reported outcomes also must be considered. Obviously physicians’ primary needs will be met if the patients are satisfied but there may be additional considerations regarding route of administration as well as ease and efficiency of therapy. Payer value is derived from beneficial differentiation of efficacy and safety but there may also be differential market forces to consider based on geographical regions (e.g., free market, US; clinical effectiveness, France and Germany; cost effectiveness, UK and Canada). If it becomes clear at any point in development that you will fail to meet the minimal criteria for your product to satisfy any one of these stakeholders’ regulatory or commercial requirements, a company is well advised to abandon development. Also, it is simply common sense for companies to Data analysis chart and graphs-2identify their principal competitive product on the market as well as potential competitive products in development prior beginning their development program in earnest. A comprehensive TPP should contain all of these elements.

The organization of the TPP is understandably varied across the industry with some people using the US Prescribing Information as a template and others adopting the European Summary of Product Characteristics. The FDA even issued guidance back in 2007 advocating the use of the US Prescribing Information organization (https://www.fda.gov/media/72566/download). The advantages of these strategies include the fact that you are effectively preparing your US annotated package insert during your development plan. These documents help both with minimizing and focusing development activities and organizing your marketing application, and they are in a format optimal for discussions with regulators. However, a complete TPP should still include an independent payer assessment that is of no interest to regulators. Other companies prefer more general categories than are found in product labeling such as efficacy, safety, payer value, dosage, indication, population and juxtapose these elements with the attributes of their target competitive product for a more commercially oriented TPP. This allows one to easily see when your product comes up short against a competitor thereby rendering a course correction or a No Go decision.

By focusing both the developmental and marketing goals in the TPP at the preclinical stage a company is able to build a commercial differentiation strategy into their early development plan. Preclinical studies are a lot less expensive to conduct than clinical studies and hypotheses can be tested versus competitive products efficiently. These preclinical experiments may or may not lead to earlier examination of active comparator studies in the clinic. However, it will most certainly enforce the understanding that validating a novel mechanism of action is less important than clinical differentiation from a competitive product. These experiments may allow a company to distinguish between competitors and identify the key competitive product to compete against. Demonstrating proof of concept in no way guarantees profit on return, so it is imperative that companies explore pharmacodynamic activity versus competitive products in their preclinical development programs.

A common reason small or inexperienced companies do not prepare a TPP is the proposed cost and amount of time that must be devoted to its preparation. Companies with an exit strategy at proof of concept or prior to phase 3 often claim the cost is not justifiable. However, the value created by a well-run development program that checks all the boxes for an intelligent investor is worth much more than the cost invested in the preparation of the TPP. Investment firms and big pharma are primarily looking for investments where the risks have been minimized and a program that has been conducted efficiently focusing on the ultimate appropriate indication and patient population while examining carefully the commercial landscape holds enormous value.

Perhaps the greatest value of the TPP is as a communication tool. The ultimate goal of the communications-networkdevelopment program is shared clearly and continually with all the company disciplines, e.g., clinical, preclinical, chemistry manufacturing and controls, regulatory, and marketing. The TPP is also able to be used as an external communication tool that facilitates interactions with regulatory authorities, investors, and the media. The document can be used to help structure regulatory and investor briefing documents as well as press releases. The TPP’s additional use as a communication tool is as an educational document for new team members whether they are within the company or at regulatory authorities.

The bottom line is, you must prepare a TPP early and revise it continually during development if you wish to bring a successful therapeutic to market to advance patient treatment or you are left relying on nothing more than good fortune.

1 Wong, C.H, Siah, K.W., and Lo, A.W. Biostatistics. 2019; 20(2): 273 – 286.
2 https://www.reuters.com/article/us-pharmaceuticals-success/success-rates-for-experimental-drugs-falls-study-idUSTRE71D2U920110214
3 https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html

 

Orphan Drugs and Single Trials

Posted by Joseph Watson on Thu, Dec 12, 2019 @ 09:00 AM
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Joseph Watson, PhD, RAC, Research Scientist at Rho, has experience in both regulatory submissions and clinical document preparation, with over fifteen years of experience in scientific writing and editing jwatsonclinical and nonclinical documents, including numerous publications in peer-reviewed journals.  Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates.  His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology. 

Since the enactment of the Orphan Drug Act in 1983, the number of orphan drug approvals has risen steadily. In 2018 alone, 34 out of 59 approved novel medications were for orphan diseases. Consistent with the increase in orphan applications reviewed by the Agency, Rho has received an increasing number of sponsor requests for support of programs working towards an orphan drug approval. Our sponsors often think that their product can be approved with support from a single trial, but how realistic is this stance? To better understand when a single trial approval is possible, we look to FDA guidances.Conceptual image with ladder reaching increasing graph-1

In the 1998 Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, FDA spells out the potential circumstances in which a single clinical trial for a novel therapeutic could be sufficient to support an efficacy claim. The guidance states “reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.”

The key points outlined in the guidance are:

1.   The condition must be serious. If the FDA doesn’t believe the condition is serious, they will not consider a single adequate and well controlled trial for a novel therapy.
2.   A second adequate and well-controlled trial is practically or ethically impossible to conduct. This situation could apply for an orphan indication given limited patient populations (and likely assuming point 1 above).

Both points could apply to an orphan indication; an orphan indication has, by definition, a limited patient population, and many orphan indications are serious. A serious orphan indication falls into the “sweet spot” in which FDA may be willing to show flexibility and accept a single adequate and well-controlled trial.

After considering points 1 and 2 below, FDA must review the single adequate and well controlled trial to determine if it is sufficiently robust and compelling; i.e., does it feature any of 5 characteristics that could make it adequate to support an effectiveness claim (in other words, sufficiently robust & persuasive; FDA’s typical prior to reviewing the data is that the determination will be a review issue):

1.   A large multicenter study
2.   Consistency across study subsets (large trial)
3.   Multiple studies in a single study (e.g., properly designed factorial studies)
4.   Multiple endpoints involving different events (i.e., prospectively identified primary and  secondary endpoints representing different beneficial effects)
5.   Statistically very persuasive findings

For orphan indications, characteristics 1 and 2 are difficult to achieve due to the need for large trials. Characteristic 3 is situational; the example provided by FDA highlights a combination therapy tested as both the combination and as individual parts. Characteristic 4 is typically incorporated into the study designs Rho reviews. Often, this item can be interpreted by sponsors as the “everything but the kitchen sink” approach. In our experience, multiple well thought out, differentiated endpoints can help FDA assess approvability; however, FDA will stress that these endpoints should be independent of each other.

Additionally, FDA will often request that the endpoints be hierarchically ranked; this preserves the overall alpha for the study by preventing companies from fishing for an acceptable endpoint should the primary fail. If the program hits on multiple, well-thought out, agreed upon endpoints, improves significantly on current therapies, and the disease is serious, FDA may consider a single trial appropriate.

Clinical Trial written in search barCharacteristic 5 is likely the most realistic situation orphan drug sponsors can achieve, in spite of the small sample sizes typically observed in orphan trials. Assuming the orphan indication is for a serious indication (as defined above), FDA will at times negotiate with a sponsor those outcomes considered sufficient to support approval with a single clinical trial. Such a strategy should be discussed prospectively with FDA prior to initiating the pivotal trial; assuming FDA agrees with the design, FDA may be willing to consider allowing the filing to proceed if either 1) a highly statistically persuasive and clinically meaningful outcome is achieved or 2) at FDA’s discretion, dependent on FDA’s review of the efficacy data, the severity of the disease, and medical need. In practice, this approach has a high chance of failure, as most companies who work on orphan products move into their pivotal study with either 1) very small proof of concept Phase 1/2 trials that hint at efficacy but are not robust or 2) uncontrolled Phase 2 studies that show efficacy versus natural history data but fail to achieve statistically significant results when conducted as randomized, double-blind studies.

That aside, recently, FDA has taken an active approach for approving products based on a single trial with certain therapeutic paths, particularly anti-infectives. The Limited Population Antibacterial Drug (LPAD) pathway allows antibiotics to be approved and labeled for small populations with unmet needs. As of October 2019, two products have been approved using this pathway with single clinical studies:

•   Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex, in a limited population of patients with the disease who do not respond to conventional treatment, approved with a single trial on a surrogate endpoint (sputum conversion); and
•   Pretomanid Tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis of the lungs, which was approved with a single trial that showed significant benefit relative to historical controls.

The success of these programs demonstrates FDA’s willingness to be flexible when the benefit can be properly assessed and truly outweighs the risk in a specific patient population. However, companies should be cautious when developing an orphan product. Prospectively planning to properly assess efficacy outcomes in reasonably sized, randomized, double-blind Phase 2 trials will help companies make appropriate go/no go decisions earlier in a product’s life cycle, ultimately helping companies spend less time and money on unapprovable products.

North American Cystic Fibrosis Conference: Key Takeaways

Posted by Lisa Payne on Thu, Dec 05, 2019 @ 09:00 AM
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The 33rd Annual NACF conference continues to be an action packed 3 days bringing together scientists, clinicians, health care providers, and caregivers to discuss the latest advances in CF research, care, and drug development.  These are our top 3 takeaways from the meeting and how they will impact clinical research moving forward.

We’ve come a long way, baby.

In the plenary talk on the first day, Marie Egan, M.D., provided an important overview of how far CF research has come over the past 30 years in her talk, “Emerging Technologies for CFTR Restoration in All People with CF”. This talk highlighted innovative technologies, including RNA therapies, gene therapies, and gene editing technology that hold potential to finding a cure. Dr. Egan also discussed the challenges and opportunities presented by these novel therapies as they advance toward the clinical study phases of development. Some of these challenges are very similar to what other rare disease communities are facing as the research of gene therapies increases. For clinical research, recruitment and retention in these trials (that can have a follow-up time of at least 5 years) need to be broached carefully, so participants understand the potential benefits and risks that await.

Excitement around Trikafta approval.

A week and a half before the conference, FDA’s approval of Vertex’s Trikafta was announced. With this approval, 90% of the CF community have a treatment option, which is an outstanding achievement. There was excitement around the approval and what this means to those with CF. What we are hearing from sites is that this also means ongoing clinical research studies are likely to have some delayed enrollment as patients start taking Trikafta. The delay will typically be the result of getting on to a stable dose to meet inclusion criteria, in addition to reduced resources at the site, as more patients are requesting appointments to switch onto Trikafta.

Medical News on Multicolor Puzzle on White Background.In the second plenary, Jane Davies, MD, MBChB, MRCP outlined the progress and promise of highly effective CFTR modulator therapies and the potential impact that Trikafta could have on this population. Whilst celebrating the success of effective modulator therapy, Dr. Davies also discussed challenges that remain, including treatments for people with rare mutations, caring for a patient population that has grown and aged, and providing access to CFTR modulators in more regions of the world.

CFTR modulators are not expected to eliminate the need for additional chronic therapies and drugs. While there is potential that CFTR modulators offer an opportunity to restore function earlier in life and alleviate a lifetime of lung damage that patients fight into adulthood, patients and families have expressed that reducing the treatment burden is a high priority and even patients on effective modulator therapies are not commonly reducing their other treatments. So while daily care has become increasingly effective, it remains complex and burdensome. This highlights the need for additional treatments and a cure for those with CF.

We will not stop until CF stands for Cure Found.

Current NIH director Francis Collins and his team helped discover the cystic fibrosis gene and he emphasized that the recent approval of Trikafta means that 90% of the community have the potential to receive a remarkable treatment; however, there are still patients with CF who might not benefit from this new therapy (including individuals with rare and nonsense mutations) and we must not abandon the 10% of people for whom these drugs will not provide benefit. Work towards finding a cure for all is just getting started.

A new era in CF research is beginning. The CF Foundation recently unveiled the “Path to a Cure” initiative, which will focus on finding treatments for the underlying cause of CF and a cure for every person with CF. The CFF is challenging academia and industry to accelerate progress in CF drug discovery and development. To help this ambitious initiative, the foundation intends to allocate $500 million to the effort through 2025.

This new era means that other recruitment strategies and study designs should be considered to enroll and execute a successful trial. Understanding the new patient population will be critical, and will require being cognizant that the baseline disease severity will vary across the population. New clinical trials in the era of modulator therapy may also require new endpoints,Medicine doctor hand working with modern computer interface as medical concept-1 as incidence or severity of common endpoints such as pulmonary exacerbations may change. Innovative study designs should be considered, but will require an increased amount of regulatory interaction.

Despite this remarkable progress there are significant needs that remain. As the CFF president and CEO, Preston W. Campbell, III, M.D, stated “Don’t stop dreaming of a day when all people with CF can say, ‘I used to have CF’.” Prioritizing innovative approaches to find a cure is at the forefront of the CFF’s mind and a recurring theme at the conference was the sentiment that the most important and challenging work lies ahead – until CF stands for Cure Found.

Need support designing and executing your next CF trial? Ask our experts for help.

JamieA3Jamie Arnott, RN, BSN, OCN®, Rho Project Director, received her undergraduate degree in Nursing from the University of North Carolina at Chapel Hill.  She has extensive experience from both the CRO and sponsor perspectives in the oversight and management of clinical trial operations and outsourcing with more than 12 years’ experience in project management and over 20 years’ experience in healthcare as a practitioner and manager.  Prior to her tenure at Rho, Ms. Arnott was the Director of Clinical Trial Operations for a biotechnology company where she provided oversight and management for all clinical activity for up to four concurrent INDs.  Ms. Arnott has broad therapeutic experience with ENT indications, cystic fibrosis, and multiple oncology indications, including ovarian cancer, hematological malignancies, and advanced solid tumors; she has pediatric experience both within the oncology field as well as orphan diseases. 

Kristin Gabor-2-1Kristin Gabor, PhD, RAC, Research Scientist, has over a decade of experience in writing and editing scientific documents and publications across a variety of biological, clinical, and regulatory fields, which includes several publications in peer-reviewed scientific journals.  Dr. Gabor has led and participated in the authoring and preparation of clinical study reports, clinical protocols, annual safety reports, modules of regulatory submissions (NDA, IND, etc.), and other regulatory documents in a variety of therapeutic areas.  She has also coordinated document review for regulatory submissions and led the management of safety review committees for clinical studies.  She has experience in a broad range of therapeutic areas, including sickle cell disease, allergy, inflammation, and immunology, infectious diseases, rare diseases, atopic dermatitis, multiple sclerosis, and cystic fibrosis.  Dr. Gabor earned an interdisciplinary PhD in Functional Genomics from the University of Maine and subsequently received an Intramural Research Training award from the NIH/NIEHS for her postdoctoral studies investigating the role of cholesterol metabolism and cell membrane perturbations in regulating the innate immune response in a rare genetic disease.  Dr. Gabor received her Regulatory Affairs Certification from the Regulatory Affairs Professionals Society (RAPS) in 2018 and is a current member of RAPS and the North Carolina Regulatory Affairs Forum (NCRAF).

NancyWsmallNancy Woody, MA, PMP, Senior Project Manager, has over eight years of project management experience in a clinical research organization (CRO) supporting and leading Phase 1 through 4 global and regional trials. Prior to working at Rho, Ms. Woody worked primarily on late phase and real-world evidence research studies and the collection of patient outcomes in standard of care settings and existing data sources. She has provided leadership to cross-functional clinical research projects and teams, virtually and co-located, in a wide variety of indications including Rare Disease (cystic fibrosis), CNS (Alzheimer’s, Multiple Sclerosis, spine pain, women’s pain, etc.), endocrinology (Diabetes) and oncology (Multiple Myeloma). As the project manager, Ms. Woody’s responsibilities include the creation and maintenance of project management plans, advising on operational strategies and mitigation plans, close collaboration with sponsor contact, and management of vendors, study team resources, timelines and budgets. She has a background in intercultural training and conflict resolution, which has helped to inform her work in risk management and mitigation on complex trials and within diverse teams. Ms. Woody is a certified Project Management Professional and received her Master’s degree in Intercultural Relations from Lesley University and a B.A. in Communication Studies from the University of North Carolina at Chapel Hill.

Patient-Focused Drug Development: Incorporating the Patient’s and Caregivers’ Perspectives into Product Development

Posted by Lisa Payne on Mon, Nov 18, 2019 @ 10:30 AM
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Meagan3-1 Meagan Spychala, Ph.D., Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s expert on patient-focused clinical research activities and incorporates the patient and caregiver voice and experience into the clinical development program.

 

karl

Karl Whitney, Ph.D., Assistant Vice President of Product Development, leads multiple integrated drug development programs spanning the development spectrum by planning, managing, and overseeing concurrent manufacturing, nonclinical, clinical, and regulatory activities.

Patient-centricity and family-centricity has been a hot topic for the past few years in clinical research, as more groups in pharmaceutical companies and CROs are working on patient engagement and patient-centric approaches to clinical research programs. Recruitment and retention are one part of patient-centricity, but the more important up-front and overarching aspect of patient-centric research comes from Patient-Focused Drug Development (PFDD). PFDD is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into the development and evaluation of medical products throughout the product life-cycle. Patients and caregivers know the disease and understand what would have the biggest impact to their lives; this wisdom can and should significantly inform the clinical research being conducted. If done correctly, the research will collect data on outcomes that matter most to the patient community. Using a PFDD approach to engage patients and caregivers throughout the product development process can lead to better study designs, more relevant data, better trial enrollment, and ultimately better products.

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Since 2012, several key pieces of legislation have been signed into law to support performing more patient-focused research. The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, the 21st Century Cures Act of 2016, and the FDA Reauthorization Act of 2017 collectively position FDA to learn about, promote, and encourage the integration of patient perspectives into the development of drugs, biologics, and devices. FDA has been pursuing a number of initiatives under the auspices of this legislation (see links and references below); one being conducting PFDD meetings, of which there have now been 24. In a parallel development, in 2018 the FDA entered into an understanding (MOU) with the National Organization for Rare Disorders (NORD) to conduct pilot listening sessions to enhance the incorporation of the patient experience into regulatory discussions. Twelve listening sessions have been conducted under the MOU since October 2018 and more are currently being scheduled for 2020.

The FDA is working to collate the principles and insights gleaned across these PFDD meetings into 4 formal guidance documents. Collectively, these guidances will describe the steps, processes, and considerations to bear in mind when collecting information from patients and caregivers. This includes discerning what is most salient, important, and impactful to them; using this information to create or use COA or PRO tools; and potentially validating new tools to be used as endpoints for clinical research. The first draft guidance was issued mid-2018 and focused on who to get input from and how to collect the information needed. This is intentionally an initial overview; therefore, it is a high-level view of key philosophies about patient involvement via providing patient experience data to guide a product development program into using the most sensitive and clinically meaningful endpoints. The second draft guidance, issued October 2019, provided methods for eliciting information from the patient population. Three main methods of research for obtaining information to understand what matters most to patients living with a disease and their caregivers were detailed: qualitative Research - Wordcloud Concept. The Word in Red Color, Surrounded by a Cloud of Blue Words.research, quantitative research and mixed-methods research. Each type has strengths and limitations, so deciding on which method to use to support a research program depends on the patient population and research objectives. No matter what type of research method used, a research protocol, interview or survey guide, training materials, glossary, data management plan, and data analysis plan are needed before proceeding with collecting information and the protocol should be reviewed in a meeting with the FDA.

While it will likely take some time until all four guidance documents are complete, we eagerly await the third and fourth draft guidances, as patient advocacy groups and product development organizations are already moving forward with PFDD and need additional FDA guidance and advice on how to incorporate the patient perspective into clinical research. Even though these documents are not completed, ongoing development programs should still strive to be patient-focused. We have seen from having conducted natural history studies and other patient-centric work how important it can be to have a clear understanding of the disease and patients’ (and caregivers’) perspectives; absent such understanding, it is hard to plan and execute sound development programs that result in products the patients need and benefit from.

Want advice on how to proceed with a PFDD approach? Rho has the scientific, operational, and regulatory strategy experience needed to support your PFDD program.

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