Rho site logo

Rho Knows Clinical Research Services

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.

Key Questions for the Effective Implementation of eCOAs in your Clinical Trial

Posted by Lisa Payne on Thu, May 21, 2020 @ 09:45 AM

With the industry-wide push towards patient-centricity, electronic clinical outcome assessments (eCOAs) have become a more widely used strategy to streamline patient data collection, provide real-time access to data for review and monitoring, enhance patient engagement, and improve the integrity and accuracy of clinical studies. While many companies have chosen to partner with eCOA vendors to provide electronic devices for use in a clinical study, other sponsors are exploring “bring your own device (BYOD)” strategies to save costs and start-up time. Rho answers some commonly asked questions about eCOAs.

Q: What is an eCOA?
A: Using technology such as smartphones, tablets, or computers to allow patients, health care professionals, or caregivers to directly report outcomes from clinical trials.

Business woman working on empty tablet with pencil

Q: What are some examples of eCOA assessments and devices?
A: There are a variety of electronically captured assessments, including patient reported outcomes (PROs), clinician-reported and health-care professional assessments (ClinROs), observer reported outcomes (ObsROs), and patient performance outcomes administered by health-care professionals (PerfOs). The main methods for collection of eCOA data include computers, smartphones, and tablets, as well as telephone systems.

Q: What is the difference between those eCOA assessments?
A:  The differences in the eCOA assessments mentioned above are:

  • Patient Reported Outcomes (PRO) – A report on the status of a patient’s health condition that comes directly from the patient. For example, asking a patient, on scale of 1-10, what is your level of pain today.
  • Clinical Reported Outcomes (ClinRO) – When a health-care professional observes the patient and records the clinical data. In this scenario, the health-care professional often provides his/her interpretation of a patient’s observable behavior of physical signs. For example, a Parkinson’s disease patient may be unable to report through ePRO. Instead, the clinician would report that patient’s clinical outcomes.
  • Observer Reported Outcomes – When clinical data is reported by an observer that is not a health-care professional, such as a parent or caretaker. This data does not include a medical judgement or interpretation. In this case, the patient typically cannot respond themselves. This is often the case when studying infants or patients that are mentally impaired.
  • Performance Outcomes (PerfO) - Data that is generated when a patient performs a tasks according to instructions provided by a health-care professional. For example, performing memory recall or other cognitive testing.

Q: What are some considerations when deciding if an eCOA is right for your clinical trial or program?
A: There are 2 critical factors to consider before embarking on this path:

     1. Need - Is there a need to collect clinical outcome data from a person and is there a benefit to collect this data electronically? For a given clinical outcome or assessment tool is there a benefit to the study collecting the data directly from the patient? For certain endpoints eCOA data is more appropriate than for others. If the study objective is to understand the subjective impact of a product on the patient or health-care community, a well-designed eCOA can be a valuable tool to capture this information. These data can tell you specific information about your product and help inform the labeling language that will be included in the package insert of your marketed product. The eCOA device can be configured to require daily or weekly data entry and real-time review by site personnel prior to the next scheduled clinic visit. Additionally, the eCOA system can send out alerts and reminders to patients (to ensure data is entered in a timely manner) and to health-care personnel (to ensure timely review and verification of data and subsequent follow-up with patients as needed).

     2. Cost/ benefit of eCOA vs paper - Many studies still use paper methods to collect clinical outcome data, and there are cases when it may make more sense to achieve your study objectives through paper rather than electronic methods (e.g., Phase 1 studies with limited subjects). However, several types of clinical outcome data can be collected more efficiently, at lower cost, and at higher quality with electronic approaches (e.g., diary data or daily pain scores). From an efficiency standpoint, data can be entered directly into a device and integrated.

Q: What are some considerations during the planning phase?
A: Studies that include eCOA for data collection require additional time and planning to ensure successful implementation. eCOA instruments often require additional validation (such as equivalence testing), licensing, translation, vendor management, user acceptance testing, and training for both patients and site personnel.

Q: Where does the FDA stand on the use of eCOAs?
A: FDA has encouraged the use of PROs to capture certain data endpoints, such as pain intensity, from a patient population who can respond themselves. Recent regulatory agency guidance has encouraged the use of eCOAs to evaluate clinical outcome data. The fifth authorization of the Prescription Drug User Fee Act (PDUFA V), which was enacted in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA), included a commitment by the FDA to more systematically obtain patient input on certain diseases and their treatments. FDA holds COAs to the same regulatory and scientific standards as other measures used in clinical trials. To support these efforts, the FDA has developed an extensive Clinical Outcome Assessment Qualification Program, which is designed to review and assess the design, validity, and reliability of a COA for a particular use in a clinical study.

Q: How is the integrity and accuracy of the data maintained when using an eCOA?
A: For the cases where an instrument was developed for paper-based collection or an instrument is collected using multiple modes, it may be necessary to test for equivalence and additional validation. This regulatory expectation is often required (especially for primary and secondary endpoints) to ensure that the electronic version of the instrument is still valid and data collected with mixed modes are comparable. The qualification of an eCOA often requires input from patients and/or health-care professionals to evaluate the effectiveness of the assessment. This input is necessary for the regulatory agency to determine whether the eCOA can accurately measure what it’s supposed to measure (validity) and to demonstrate that it can measure the outcome dependably (i.e. that the measure is reliable). Make sure the eCOA supports your intended labeling claims because the instrument will be evaluated in relation to the intended use in the targeted patient population..

Q: Is there any research supporting the effectiveness of eCOAs?
A: At this time, there are no reliable metrics on the ROI of eCOA. Some claim that the use of eCOAs can result in higher quality data, less monitoring, and greater patient engagement, including compliance in eCOA trials being 90% compared to 30% for non eCOA trial and a more than 50% savings when data is entered via eCOA instead of on paper. While there is anecdotal evidence to support these numbers, there have been no studies done to officially verify them.

Q: What are some of the caveats of using an eCOA?
A: The data is subject to more bias than other objective measures, so it’s critical to take steps to reduce bias as much as possible. Examples of ways to reduce bias include single- or double-blind clinical trial designs, wherein the patient or assessor is not aware of the assigned treatment, and building in a control arm (e.g., placebo or active comparator) to compare eCOA outcome data across treatment groups. Any downsides to using the electronic data collection methods tend to be associated with the costs and time to implement the system at the beginning of the clinical study.

Q: How do we determine which eCOA is best for data collection in our clinical trial?
A: The most effective choice depends on the protocol design, the length of data collection, what intervals data will be collected at, the type of data, the study phase, the patient population, the instrument being used, and whether the measure is a primary safety or efficacy endpoint. Making your eCOA selection based on those criteria will help ensure that you’re choosing the most appropriate device for your clinical trial.

Q: What value does a CRO bring in working with eCOAs?
A: A CRO well-versed in best practices around eCOAs should be able to advise and support you on the following:

• Determine endpoints where eCOA data is appropriate
• Determine the cost/benefit of electronic versus paper data capture
• Determine the best mode of electronic data capture
• Recommend eCOA vendors when appropriate
• Perform equivalence analysis
• Facilitate discussions with regulatory authorities
• Manage the entire process of eCOA implementation

Rho can partner with sponsors to develop and implement their eCOA strategy and manage the entire process to ensure successful eCOA implementation. 

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.

Considerations When Starting a Vaccine Study

Posted by Gloria David on Tue, Apr 28, 2020 @ 10:00 AM

For over 10 years, Rho has worked in vaccine research and is currently 1 of 5 contract research organizations in the BARDA Medical Countermeasures Clinical Studies Network (MCM-CSN) that designs and conducts clinical studies needed to develop drugs, vaccines, and diagnostic tests that help protect public health. Based on our experience, we understand the risks, challenges, and solutions needed to operationalize a vaccine trial.

One of the biggest considerations for your vaccine program is early planning. The planning conducted during start-up will have the biggest impact on the successful execution of the trial. While this is true for all studies, certain vaccine trials can enroll very quickly, leaving little room for error once enrollment starts; for example, Rho worked on a recent MCM-CSN pandemic influenza vaccine study that enrolled over 360 patients in 3 days at 4 clinical sites. Advanced planning is needed to ensure the sites are trained and ready, because any misunderstanding of the protocol has the potential to affect every subject enrolled. Our teams have mitigated this risk through detailed protocol training and expectation setting during site initiation visits and by having a clinical monitor on-site for the first day of enrollment. The monitor can answer questions and review site documentation to ensure that the study is being conducted and documented, as expected.

Additionally, having data management, data standards, and statistics involved early in the process will support the data cleaning and issue and trend detection that is needed. To ensure the safety of participants in the study, detecting events that meet stopping rules as quickly as they occur is needed. Rho typically sets-up automatic alerts when events that can lead to a stopping rule occur, so the study team is prepared for a rapid response. By working to have datasets programmed prior to first patient in, all safety monitoring tools can be ready once the study starts enrolling and any ad hoc Safety Monitoring Committee (SMC) meetings can be held quickly. On a recent MCM-CSN Anthrax vaccine trial, a stopping rule for SMC review occurred while enrollment was still ongoing and participants still had to receive subsequent vaccinations. With these measures in place prior to enrollment starting, we detected the potential safety concern and held a SMC meeting to review the cases within 3 days of the event occurring. This allowed us to continue with enrollment and subsequent rounds of vaccinations on-schedule after SMC approval to move forward. Having an integrated approach to risk assessment, prevention, and mitigation strategies during protocol development and study start-up made for quick identification, escalation, and mitigation of the issues as they arose.

However, not all vaccine studies enroll quickly. While the same approach to risk-based quality management is needed during protocol development and study start-up, if enrollment will be a challenge, additional considerations about patient education need to be reviewed during this time. Slower enrollment in vaccine trials can occur because of misperceptions about vaccines. Potential participants could be concerned that the vaccine would cause them to get the illness or that the trial will expose them to the disease. Working with the site to provide additional education about the vaccine, the risks, and the benefits of the trial is needed to support recruitment and retention.

Another concern of potential participants is what happens if the vaccine causes them harm. Informed consent documents will detail study specific information, and sites should be prepared and trained to answer the questions participants might have. Certain vaccines will need additional language in the informed consent based on the Public Readiness and Emergency Preparedness Act (PREP Act). In October 2010, the PREP Act went into effect and established the Countermeasures Injury Compensation Program (CICP) that is designed to provide benefits to individuals who sustain some types of serious physical injuries as a direct result of use of certain countermeasures that are detailed on the Health Resources and Services Administration’s website. If the vaccine being studied is covered under the PREP Act, additional language discussing CICP should be added to the informed consent and an additional information sheet about CICP, including how to file a claim, should be provided to each participant.

Early preparation and a robust risk based quality management process is essential for any trial’s success. For vaccine studies, given the high potential for fast enrollment and frequent safety reviews, having the study team work together during protocol development and study start-up to identify risks and provide prevention and mitigation strategies for them is needed for the trial to be conducted successfully. Having a partner who understands the risks and the best strategies to mitigate or prevent them can set you on the right path.

If you need help conducting your vaccine trial, our experts can support your protocol development and study conduct, providing guidance on operational considerations and risk mitigation strategies.

gloria-3Gloria David, PhD, MHSc, Principal Research Scientistholds a PhD in Pharmacology and Molecular Sciences from Johns Hopkins University School of Medicine, a Master of Health Sciences in Clinical Research from Duke University School of Medicine, and a BS in Biochemistry from the Pennsylvania State University. Dr. David serves as Rho PI for the Medical Countermeasures Clinical Studies Network (MCM-CSN) contract funded by the Office of the Assistant Secretary for Preparedness and Response (ASPR), Biomedical and Advanced Research Development Authority (BARDA). Under this contract, Rho provides clinical services to facilitate medical countermeasures product development toward licensure. Trials evaluate chemical, biological, radiological, nuclear, pandemic influenza, and emerging infectious diseases countermeasures. Dr. David has provided scientific and technical leadership for 6 vaccine studies funded by the NIAID. She served as PI on 2 studies in patients with atopic dermatitis examining the safety and immunogenicity of an intradermal influenza vaccine. She also served as co-PI on a study assessing the safety and immunogenicity of the 2009 H1N1 vaccine in adults and children with severe asthma. She has provided leadership for a yellow fever vaccine study and a varicella vaccine study in patients with atopic dermatitis and for a keyhole limpet hemocyanin adjuvant study. Dr. David currently serves as PI for 2 vaccine studies funded by BARDA: a Phase 2 study to investigate the efficacy of H7 influenza vaccine with adjuvants as a safeguard to the public against pandemic influenza and a study to investigate the safety and immunogenicity of anthrax vaccine in individuals over 65.

Since joining Rho in 2004, Dr. David has served as co-PI of the Statistical and Clinical Coordinating Center (SACCC) for the National Institute of Allergy and Infectious Diseases (NIAID)-funded Inner-City Asthma Consortium (ICAC; 2004-2015) and as PI of the NIAID-funded Atopic Dermatitis Vaccinia Network (ADVN; 2008-2011) and the Atopic Dermatitis Research Network (ADRN; 2010-2015) Coordinating Centers. Dr. David also currently serves as a Lead Scientist for the Asthma and Allergic Diseases Group for the NIAID Division of Allergy, Immunology, and Transplantation: Statistical and Clinical Coordinating Center (2015-2022). She is responsible for the scientific and technical oversight of the performance of the coordinating center’s work, including clinical operations, data management, and statistical, technical, regulatory, and administrative support. She works directly with the NIAID Project Office and clinical investigators to define project needs and is responsible for building cross-functional teams at Rho to meet those needs and for coordinating all activities to ensure the successful completion of all projects. She also provides oversight for subcontractor activities (e.g., drug distribution, safety labs, sample analysis, and repository sample storage).

Drug Shortages During the COVID-19 Pandemic

Posted by Charity Duran on Thu, Apr 23, 2020 @ 10:45 AM

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.

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.

COVID-19 FDA Response:  Site Management and Monitoring

Posted by Sharon Duffy and Marina Acosta-Enslen on Mon, Apr 20, 2020 @ 10:00 AM

This blog post is the next in a series related to maintenance of the reliability and validity of ongoing clinical trial data during the COVID-19 pandemic. Previous topics included changes to study visits and assessments during COVID-19: subject safety considerations and documenting changes made during COVID-19: protocol amendments and the clinical study report. A future post is planned on data integrity: handling COVID-19 related missing data.

In this post, the focus is on site management and monitoring changes during COVID-19.

In 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 and April 2nd (with questions and answers), FDA addresses questions related to delays in on-site monitoring during the COVID-19 pandemic and recognizes access to trial sites may be limited or not available. With a focus on participant safety and trial data quality and integrity, the FDA expectation is that sponsors will identify alternative approaches to on-site monitoring and document these in updates to the Clinical Monitoring Plan. Some alternative approaches include enhanced centralized monitoring and off-site (remote) monitoring: review of subject status, data entry and query resolution, training, regulatory document review and collection, investigational product (IP) compliance, and safety reviews. More frequent off-site (remote) monitoring may need to be considered.

FDA has indicated that delays in monitoring should be carefully documented. Additionally, documentation should track protocol deviations and other GCP non-compliance issues that are a result of delayed monitoring visits due to COVID-19.

Side view of three artists working on computer at the office-1Study teams will be expected to conduct targeted risk assessments specifically focused on risks related to COVID-19 impacts on study conduct: new safety risks to trial participants; ability/willingness of trial participants to travel or travel restrictions that limit travel; continued availability of investigators, site staff and facilities; availability of trials supplies, vendors, and IP; gaps resulting from shifts in monitoring strategy due to restricted on-site monitoring. The outcome of this risk assessment should drive the mitigation response, which may include, but is not limited to: protocol amendments, holds on screening and enrollment, and updates to monitoring strategy and Clinical Monitoring Plan.

Study teams will need to determine which altered monitoring strategy best fits the current status of their studies. The study team should collect information on restrictions and the duration of those restrictions both for study participants and for on-site monitoring and confirm whether or not the site allows remote review of their electronic medical records (if applicable) or has some other secure way of reviewing site data remotely.

Study teams should ensure succession planning for themselves in the event of team member absences, limitations, or sickness related to COVID-19.

Vendor limitations or changes in service and reporting should be tracked and communicated to sites if impact is expected.


Sharon Duffy, Associate Director, Clinical Monitoring at Rho, has over 25 years of clinical research experience at both large and small CROs and sponsor companies. Starting as a CRA, she later moved into monitor training, process and compliance support. She received her B.A. in Biology from the University of Virginia.



Marina Acosta-Enslen, Associate Director, Clinical Management is a diversely skilled clinical research professional with 20 years of experience across Phase 1 through 4 studies. Prior to joining Rho, Ms. Acosta-Enslen has held positions in the areas of clinical monitoring, site level study coordination, site start-up, and clinical study management. Ms. Acosta-Enslen has extensive experience working on regional and global HIV, Oncology, Acute Pain and Vaccine clinical trials. Nearly half of her career has been focused in HIV/AIDS research working on NIH and industry funded clinical trials.

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.

Development of COVID-19 Therapies: FDA Pathways

Posted by Kevin Barber and Theresa Scocca on Wed, Apr 15, 2020 @ 10:30 AM

FDA is currently using 3 programs to expedite development of COVID-19-related therapies, with the goal of making new treatments available to patients in the US as quickly as possible. Note that the need and ability to utilize these programs will be dependent upon the status of the COVID-19 pandemic at the time your drug product is available and whether you are in a position to potentially engage with FDA in these programs.

At a high level, there are basically 3 (inter-related) programs that FDA has in place to make drug product available for COVID-19 patients in an expedited manner or under an “emergency” use status for products that are ready to initiate clinical studies, are already undergoing clinical development prior to approval of a new drug application, or are already approved in other indications:

Coronavirus Treatment Acceleration Program (CTAP)
Emergency Use Authorization (EUA)
Expanded Access

The CTAP program is a special emergency program created by FDA, announced on 31 March 2020, to expedite their review of clinical study protocols and development programs for possible therapies to treat COVID 19. The overarching goal is to move new treatments to patients as quickly as possible, while at the same time finding out whether they are helpful or harmful. This program may be worth considering for your product if it has strong scientific merits as a COVID-19 therapy, is at an appropriate stage of development for clinical studies, and can be identified as a possible priority product in US Government documents. The CTAP Program has been rapidly triaging requests from product developers with potential COVID-19 therapies and providing interactive input on development plans. Many protocols are being provided review within 24 hours of submission. FDA is also working to expedite quality assessments on these products and mitigations for potential supply disruptions. It should be noted that, for products still in very early development, FDA is continuing to recommend submission of a Pre-IND request to the appropriate Division at FDA. The Division of Antivirals has provided some guidance for this process (https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/covid-19-therapeutics-general-information-interested-stakeholders). FDA’s press release FDA Combating COVID-19 with Therapeutics contains many helpful links for interested product developers.

Emergency Use Authorization (EUA) gives FDA the authority to allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by chemical, biological, radiological, and nuclear (CBRN) agents when there are no adequate, approved, and available alternatives. For COVID-19, FDA has already granted EUAs for a range of medical devices (diagnostics, personal protective equipment, ventilators) and chloroquine phosphate and hydroxychloroquine sulfate. To qualify for an EUA, a product generally needs to be in an advanced phase of development or already approved and on the market, with submission of a request for an EUA and full supporting data for the proposed use. FDA’s Guidance for Industry and Other Stakeholders: Emergency Use Authorization of Medical Products and Related Authorities provides more information about EUAs and the process for making a request. This guidance recommends that any sponsor considering an EUA request be in contact with the appropriate FDA Center prior to submitting any formal request. FDA expects product development to continue in parallel with an EUA.

Expanded Access provides a potential pathway for a patient with an immediately life threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. Expanded Access includes expanded access for individual patients including for emergency use, expanded access for intermediate-size patient populations under a treatment protocol submitted to an existing IND, and expanded access for widespread treatment use through a treatment IND or treatment protocol designed for use in larger patient populations. For COVID-19, under the CTAP program, FDA has prioritized the review of single patient expanded access requests to occur around-the-clock, generally within 3 hours of request.

Thus far, these programs are focused on quickly delivering potentially effective COVID-19 therapies to patients as quickly as possible or expediting the review of development programs and protocols to test potentially effective COVID-19 therapies. The CTAP program or other FDA communications have yet to address whether there will be additional expedited processes available for review and approval of marketing applications, beyond potential priority review, for therapies that demonstrate effectiveness for the treatment of COVID-19 in clinical trials.

Rho is continually evaluating new information released from FDA regarding the Agency’s response to the COVID-19 pandemic, and our regulatory experts are available to consult with anyone attempting to determine if any of these pathways might be applicable to their product development program.

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.

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.

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).