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COVID-19 Treatment Development: Updates and Recent FDA Guidance

Posted by Theresa Scocca and Monica Frazier on Wed, May 27, 2020 @ 09:00 AM

The FDA continues to release additional information and update their website as the COVID-19 pandemic continues and both regulatory professionals and drug developers react to the potential for novel and repurposed products to treat COVID-19. This blog post is the latest installment in a series of COVID-19 related blog posts and updates information provided in a recent webinar on Potential COVID-19 Products: Choosing the Right Path with FDA.

Recent changes to the Coronavirus Treatment Acceleration Program (CTAP) webpage have included additional details about how to proceed based on whether the product of interest will be reviewed by CDER or CBER (or if jurisdiction is undetermined). For products under the jurisdiction of CDER, submission of a package through typical channels is expected; sponsors of products under jurisdiction at CBER should contact their Division to confirm next steps. Of note, the Agency clarifies that medical devices are not part of CTAP and that sponsors of these products should contact CDRH directly communication regarding the development of IVDs and non-IVD medical devices.

In addition, two new guidance documents for COVID-19 treatment development have been released in May 2020. The first, COVID-19 Public Health Emergency: General Considerations for Pre-IND (Investigational New Drug application) Meeting Requests for COVID-19 Related Drugs and Biological Products, includes information on best practices for obtaining feedback from the Agency for streamlining the time to initiation of clinical trials for COVID-related drugs and biologics. The guidance specifically states that sponsors should initiate discussions regarding the development of COVID-19 treatments via the pre-IND pathway rather than through a pre-emergency use authorization (EUA) request as products are likely not ready to proceed directly to a successful EUA request. In addition, this guidance clarifies that despite the public health crisis due to the COVID-19 pandemic, a draft/brief study synopsis without a full meeting package to support a pre-IND meeting will likely be considered inadequate for review, and may result in a sponsor’s request not receiving prioritization with the Agency.

Details in the guidance include information on the type of data and information that sponsors should provide across functional areas (clinical, nonclinical, and quality) to support these meeting requests. Important to considerations for submitting a meeting request are that all relevant materials for FDA’s evaluation should be included with the request, including the meeting package, questions, and proposed clinical protocol. A summary of the data and literature supporting the proposed use of the drug for treatment or prevention of COVID-19 is expected. A detailed list of content that should be included in the package is provided.

Per the guidance, the sponsor should submit with the pre-IND meeting request a draft protocol that includes phase of development, mechanism of action, overall design, subject population with inclusion and exclusion criteria, endpoint(s), safety assessments, and brief statistical considerations. It should also include a detailed safety monitoring plan and detailed time and event table with end of trial and follow-up plans. A detailed list of all content that should be included in the package is provided.

The second new guidance, COVID-19: Developing Drugs and Biological Products for Treatment or Prevention, includes focused information on the design of studies in support of the development of drugs and biologics with direct antiviral activity or immunomodulatory activity. Considerations are provided related to study population, trial design, efficacy endpoints, safety considerations, and statistical considerations. In addition, an Appendix with examples of baseline severity categorization is provided to assist Sponsors in protocol development. This guidance will be essential to review in advance of and in parallel with clinical protocol development for COVID-19 products.

Rho supports Sponsors at all stages of product development, including but not limited to assistance navigating the ongoing development of regulatory guidance for COVID-19 products; development of protocols, meeting requests (including question formulation by functional experts), briefing packages, and meeting moderation and attendance; program management; submission support for all stages from pre-IND through marketing application; and full-service clinical study execution at all study phases, from project management, site management, and clinical monitoring, through data management and statistical analysis, to preparation of submission-ready reports to support marketing applications.

Theresa4-1Theresa Zucchero Scocca, PhD, RAC, Research Scientist, manages and contributes to multiple integrated product development programs at Rho and has over 18 years of experience in research, scientific and regulatory writing, and project management. In addition to leading programs ranging from the preclinical through the marketing application stages, her experience includes authorship of multiple regulatory and clinical documents, including draft product labels, briefing packages, protocols, clinical study reports, and marketing application modules such as the Clinical Overview and integrated summaries of safety and efficacy. She has also participated in multiple FDA meetings at various stages of development. Her management and regulatory authorship experience spans drug, biologic, medical device, and combination products and a broad range of therapeutic areas, including CNS, infectious disease, gastrointestinal diseases, osteoarthritis, analgesia, asthma, dental products, ADHD, inner ear disorders, and ophthalmology.

Monica1Monica Frazier, PhD, RAC, Research Scientist, leads and contributes to multiple integrated product development programs at Rho, where she has experience in management of regulatory submissions at multiple stages of product development (INDs, NDAs, etc.) as well as in development of clinical documents to support clinical studies and regulatory submissions. She has over fourteen years of research; scientific and regulatory writing; and project management experience. Her experience includes leading and managing scientific authoring and editing teams, as well as preparing modules of regulatory submissions; briefing packages to support regulatory meetings; clinical study protocols; and clinical study reports.

The Sunsetting of Rare Pediatric Disease Designation

Posted by Joseph Watson on Mon, May 18, 2020 @ 09:30 AM

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.

Maintaining Trial Integrity During COVID-19: Some Statistical Rules of Thumb

Posted by Rob Woolson and Ben Vaughn on Tue, Apr 21, 2020 @ 09:30 AM

The COVID-19 pandemic is having a substantial impact on many ongoing clinical studies in all phases of product development. Numerous difficult decisions are being made and steps are actively being taken to ensure the safe execution, or future resumption, of ongoing studies. While patient safety is paramount and should drive all study conduct related decisions, many of these decisions can impact the interpretability of estimates of efficacy at study conclusion. Changes that may seem innocuous on the surface can have a substantial impact on trial integrity, including the validity and reliability of results. Careful consideration, in consultation with a statistician, should be given to the impact that protocol changes, visit schedule amendments, collection methods, and incomplete or missing information will have on the final analysis and interpretation of results.

The FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic makes several thoughtful recommendations regarding methods to maintain the integrity of ongoing clinical studies through the COVID-19 pandemic. While the considerations raised are important to ongoing studies in all phases of clinical research, many of the issues raised take on added importance in the randomized phase 3 confirmatory trial setting. Changes to study design, assessment methods, and visit schedules, in addition to the possibility of higher rates of missing or incomplete information, may make it difficult to obtain an unbiased estimate of differences between treatment and comparator groups in these pivotal efficacy studies.

It is heartening to recognize that some of the study conduct and data-related issues we are presently confronting, including a few of the concepts discussed in the Guidance document, are not new to clinical research and are issues that investigators, protocol sponsors, and statisticians confront frequently, albeit under less difficult circumstances.

While a statistician should be consulted, we are providing some statistical rules of thumb (some are covered directly in the Guidance document) surrounding considerations related to data collection and missing/incomplete information in ongoing studies during the COVID-19 pandemic.

1. Keeping in mind that patient safety is paramount, efforts should be made to collect as much efficacy data as possible within the parameters of the current protocol. Though there will be exceptions, collecting data outside of a visit window or after treatment discontinuation is preferable to collecting no efficacy information whatsoever.

2. Changes to the protocol design may be needed to limit the amount of missing or incomplete efficacy information. However, some changes in study conduct may warrant changes to the planned primary analysis or additional sensitivity analyses.

3. It is important that the reasons for missing data, incomplete data, and patient discontinuations are captured directly, and in an easily identifiable manner, in the case report form. More specifically, this information should be collected in a manner that is readily accessible for analysis and at an appropriate resolution for the degree of missingness (e.g., instrument, visit, patient).

4. Previously unplanned analysis to assess the power of the study before continuing with enrollment may be appropriate. Mature studies which are close to planned enrollment may be sufficiently well-powered to stop early.

5. In many cases, it is likely that incomplete or missing information as a result of COVID-19 conveniently fall into the category of ignorable missing data. The plan for handling missing data due to COVID-19 should be described in the SAP. Sensitivity analyses that explore the missing data space should be planned and documented in the SAP prior to database lock.

6. Documentation in the protocol and SAP are of critical importance. For blinded studies, all decisions and changes to planned data collection, assessment, and analysis should be finalized in advance of database unblinding.

As described in the Guidance, amendments to key elements of efficacy data collection, assessment, and/or analysis should be discussed with the appropriate reviewing division. In consultation with a statistician, study sponsors should prepare now for regulatory interactions to discuss and gain agreement on any proposed changes.

robwoolsonRob Woolson, MS, JD, Chief Strategist, Biostatistics & Standards for Regulatory Submissions, has 18 years of experience as an applied statistician. Mr. Woolson brings an extensive background of statistical and project leadership experience on US and ex-US regulatory submissions, having led the biostatistical and technical aspects of 12 CDISC-compliant marketing applications, having guided the creation of ISS/ISE statistical analysis plans; integrated analysis dataset design and production; integrated display design and production; and submission-related documentation development. He has conducted statistical analyses in all phases of drug development (Phase I through IV, NDAs, and BLAs) and has led SDTM/ADaM dataset conversion projects in multiple therapeutic areas. Rob works extensively as a consultant advising sponsors on integrated statistical analysis planning, integrated database design, regulatory data submission requirements, and CDISC standards application and implementation. He has authored responses to numerous FDA queries and has represented sponsors at numerous FDA face-to-face meetings, including Advisory Committee meetings. Mr. Woolson’s educational background includes a Bachelor’s degree in mathematics from Northwestern University, a Juris Doctor degree from DePaul University, and a Master’s degree in applied statistics from DePaul University.

ben-vaughn-1Ben Vaughn, MS, RAC, Chief Strategist, Biostatistics & Protocol Design, has over twelve years of experience in clinical research. He has participated in over 25 regulatory submissions and is an expert on CDISC standards. His work has included serving as lead statistician to complete displays and datasets for ISS/ISEs and co-producing the ISS/ISE for multiple products, including six NDAs reviewed by DAAAP. Ben also co-produced the ISE for two opioid products; and provided statistical consultation, display generation and submission work for four separate products for OA knee pain. He has authored responses to FDA queries regarding NDAs, PMAs, IDEs, and SPAs and has represented sponsors in FDA meetings. In the past three years, he has supported five sponsors at DAAAP FDA advisory committee meetings. Additionally, he has represented sponsors in FDA teleconferences and face-to-face meetings for both OA knee pain products and opioid products. His analytic experience includes cross-over studies, survival analysis, non-parametrics, and extensive work with linear and non-linear repeated measure models.

Programs to Support Drug Development in Infectious Disease


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].

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.

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.

COVID-19 FDA Response:  Guidance on Protocol Amendments and Clinical Study Reports in Affected Ongoing Trials

Posted by Patricia Edkins on Mon, Apr 13, 2020 @ 09:30 AM

Patricia Edkins, MD, Research Scientist at Rho, has 19 years of experience writing and editing clinical documents for the pharmaceutical industry, including documents supporting submissions, individual clinical studies, and product launches. In addition to her writing background, Dr. Edkins has 17 years of clinical practice experience at an academic medical center and NCI-Designated Comprehensive Cancer Center.

iStock-Coronavirus_blueandgreenOne of the impacts of the COVID-19 pandemic on the conduct of ongoing and planned clinical trials will be the need for protocol modifications to adjust for COVID-19 control measures and COVID-19 illness. The recent FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic offers advice on managing protocol amendments and deviations and documenting changes to the trial.

The FDA recommends that sponsors document all changes to the protocol and the reasons for such changes, in particular, the extent of the changes (duration, subjects affected) and how the changes were related to COVID-19. Subject and staff screening for COVID-19 as required by the local health care authorities does not require a protocol amendment, except when these assessments will be a new part of the research. While institutional review board approval is generally required for protocol amendments, changes to immediately eliminate or reduce subject risk associated with COVID-19 can be made prior to IRB approval, but should be followed as soon as possible by filing of an amendment. The rationale for any changes to the protocol should be documented in all amendments. If an amendment to a study intended to provide efficacy data to support registration requires amending the data management and/or statistical analysis plans, FDA recommends consulting the appropriate review division.

Changes to the trial resulting from the COVID-19 pandemic and the impact on study results should be clearly documented in an ongoing manner and summarized in the clinical study report. Examples of such impacts include subject discontinuations, missing data due to missed visits, changes to the study schedule, and modification of the assessment methods (eg, replacing face-to-face encounters with virtual interactions). Many of these impacts, such as missed visits, may be captured as protocol deviations, whereas others may be documented as changes to the monitoring plan, findings in site visit monitoring reports, or data within the electronic data capture system. If the collection of efficacy assessments for a study intended to provide efficacy support for registration is modified, the FDA recommends consulting the appropriate review division. The clinical study report author should be involved early during the study, eg, writing, or reviewing the protocol and protocol amendments, so that he/she is familiar with the course of events. Following ICH E3 format for clinical study reports, most of the changes incurred by COVID-19 modifications would typically be reported in Section 9.8 (Changes in the Conduct of the Study or Planned Analyses) of the report. For clarity, however, an overview of such changes may be appropriate as a dedicated subsection of Section 9.1 (Overall Study Design and Plan – Description), with more focused comments about changes in specific methodology in the applicable section(s). The impact of changes on reported study results should also be addressed in Sections 10 (Study Patients), 11 (Efficacy Evaluation), and 12 (Safety Evaluation).

COVID-19 FDA Response:  Guidance Released for Conduct of Ongoing Trials

Posted by Monica Frazier on Mon, Apr 06, 2020 @ 09:15 AM

This blog post serves as an introduction to a series of posts related to maintenance of the reliability and validity of ongoing clinical trial data during the COVID-19 pandemic. Upcoming topics include the following:

  • Changes to study visits and assessments during COVID-19: subject safety considerations
  • Documenting changes made during COVID-19: protocol amendments and the clinical study report
  • Data integrity: handling COVID-19 related missing data
  • Site management and monitoring changes during COVID-19

Since the emergence of Coronavirus Disease 2019 (COVID-19) in the US, the FDA has released new guidance and information rapidly and continuously in a comprehensive response to the current pandemic. The Agency is tasked with managing a complex situation, including processing a flood of new requests related to potential products for the treatment of COVID-19, monitoring for drug shortages and manufacturing needs associated with products approved for other indications that have been noted to have potential to treat COVID-19, as well as investigating COVID-19 treatment claims. Importantly, the FDA is also focused on the multitude of clinical trials for other indications ongoing prior to and throughout the pandemic. These clinical trials include products that may result in life saving therapies across a spectrum of indications, and must be carried on in a way that will retain the trial data integrity without adversely impacting subject safety. This is an expectation at any time, but FDA recognizes that the current situation presents some new and unexpected challenges.

The FDA Guidance on conduct of clinical trials of medical products during the COVID-19 pandemic, released initially on March 18th and updated on March 27th (with questions and answers), provides support for industry, investigators, and Institutional Review Boards (IRBs) managing these new challenges. These include, but are not limited to, clinical trial site closures, subject and staff infection with COVID-19 impacts on subject participation, and supply chain issues, among others. The guidance covers topics including factors to consider when deciding whether to suspend or continue an ongoing study, how to manage protocol deviations and amendments, and acceptable changes to the informed consent process that may be required due to COVID-19 subject isolation.

In addition to guidance on how to actively respond to COVID-19 related challenges, the guidance also specifies that sponsors, investigators, and IRBs should clearly document changes to study conduct in response to COVID-19 and these changes are expected to be summarized in the clinical study report (or another separate study-specific document). This includes summarizing any changes to the study plan, procedures, or analyses that were made related to COVID-19, including contingency measures taken, a listing of subjects that had COVID-19 related study disruption, and analyses that address the impact of any implemented contingency measures. Information that can be documented within the subject case report forms can be collected in real-time. However, FDA notes that if COVID-19 related issues require a change to study plans, including the statistical analysis plan, sponsors will need to ensure that revisions are submitted to FDA prior to database lock.

Typically, FDA guidance is released in draft form with a period of public comment prior to finalization, but given the current situation, this guidance was released with immediate implementation.

Rho is actively working with sponsors to address many of the challenges noted above. Our core focus, as we work through these challenges, is and always will be subject safety. Rho will continue to update sponsors, study sites, and subjects as more information becomes available.

Monica1Monica Frazier, PhD, RAC, Research Scientist, leads and contributes to multiple integrated product development programs at Rho, where she has experience in management of regulatory submissions at multiple stages of product development (INDs, NDAs, etc.) as well as in development of clinical documents to support clinical studies and regulatory submissions. She has over fourteen years of research; scientific and regulatory writing; and project management experience. Her experience includes leading and managing scientific authoring and editing teams, as well as preparing modules of regulatory submissions; briefing packages to support regulatory meetings; clinical study protocols; and clinical study reports.

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

Posted by Karley St. Pierre on Wed, Feb 05, 2020 @ 04:24 PM

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

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.


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. 


Update from the top: FDA’s Office of New Drugs ongoing reorganization process

Posted by Karl Whitney on Thu, Jan 02, 2020 @ 11:00 AM

karlKarl Whitney, PhD, RAC, 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.

Rho representatives joined regulators, industry scientists, and numerous patient-advocacy groups at CBI's Rare Disease Clinical Development & Access conference in Washington 03-04DEC 2019. During an opening plenary session, FDA's Office of New Drugs (OND) director Dr. Peter Stein shared comments and took questions from the audience. Participants asked a number of questions that indicate a high degree of interest in (and, perhaps, some anxiety about) OND's ongoing reorganization in general and as it might affect specific current projects at the IND or NDA review stage. This reorganization was announced earlier in 2019 and will, among other things, increase the number of offices overseeing review divisions from 6 to 8, and split and/or redesign review divisions to increase the number of divisions from 19 to 27. The reorganization is being implemented in four phases, with the last set to complete by February 2020. Dr. Stein certainly attempted to address some of the audience's concerns. His key message: the ongoing reorganization is intended to improve review processes while ensuring continuity for individual projects. In short, FDA doesn't want to fix what ain't broke.

Instead, the overall goals are to establish more therapeutically aligned, integrated review teams that take an interdisciplinary and 'problem-focused' approach to reviews; and to modernize and standardize review processes across divisions. In the process, he and hOptimization - Business Concept. Golden Compass Needle on a Black Field Pointing to the Word Optimization. 3D Render.is team are taking great care to ensure OND operates smoothly, and that review teams have a re-energized scientific focus for their work.

On the former, he hopes the reorganization will make for more sensible Division groupings. Some large divisions such as Neurology or GI/inborn errors are being split up so that Division Leadership can spend more time on the science and be more externally facing  (eg, at conferences). Individual review teams are being kept together as much as possible when these new divisional groupings are being designed. Further, he has instructed Division heads overall to avoid revisiting prior agreements made between the sponsor and the review team if the team has moved divisions. He believes strongly that it's in nobody's interest to upend established agreements, though he reminded the audience that of course, FDA reserves the right to update its positions as new data accrue. So, sponsor caveat emptor.

On the latter, OND is trying to enhance reviewer consistency and throughput by using a new review template and improved processes that support efficient, integrated reviews of submissions from IND through to approval/post-approval. In addition, a new non-review office called Office of New Drug Policy has been established to support review teams when novel Orange Business Processes Button on Computer Keyboard. Internet Concept.issues come up that lack clear guiding precedent, so that review teams across the OND approach novel issues with greater consistency. Another new cross-cutting office of interest to conference attendees is the planned Division of Rare Disease and Medical Genetics within the new Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine. This group will not have direct review responsibilities but rather will offer 'consultative support' to help review teams properly exercise 'flexibility' in product development programs for example in terms of expected safety database size, a topic that commonly arises, naturally, with rare disease development programs. These rare-disease sponsor projects will still be overseen by the Division that makes the most sense from a therapeutic area - for example, Division of Anti-infectives. The new Division of Rare Disease and Medical Genetics group will also have a mandate to engage outside FDA with patient groups, other regulatory bodies, academia, and even Advisory Committees to ensure they understand realities for rare disease product development. One can only speculate as to why these new responsibilities were not assigned to the longstanding Office of Orphan Product Development.

Overall, the audience took a wait-and-see approach insofar as the reorganization is ongoing and the chips haven't fallen yet. Time will tell if the major goals of the reorganization are achieved by this structure, but Dr. Stein certainly made his best case for the various rationales for the temporary upheaval. Maybe spring cleaning came a bit early to the OND this year....


Is a Target Product Profile Worth the Effort?

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


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