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Considerations for Implementing Decentralized Clinical Trials

Posted by Marina Acosta Enslen on Wed, Jul 01, 2020 @ 10:22 AM
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The COVID-19 pandemic has accelerated the implementation of decentralized (also referred to as virtual, remote, or hybrid) solutions for clinical trials. In addition to keeping your clinical trials on-track during the pandemic, decentralized solutions can often provide the following added benefits:

1) An improved patient experience (i.e. reduced burden and increased engagement)
2) Lower barriers to patient recruitment
3) Increased patient retention and lower drop-out rates
4) Higher data quality

Our teams have helped many sponsors navigate and implement decentralized solutions for their clinical trials and programs. This includes providing recommendations for the level of decentralization required (e.g. a fully virtual trial or a hybrid approach), as well as the development of strategic plans for remote and central monitoring, technology integration, IP management, and site and patient engagement.

Based on our experience, we believe that the best decentralized solutions are patient-centric, customized, and rooted in a robust Risk-Based Quality Management (RBQM) framework, as specified by the E6R2 guidance.

Below we will discuss some considerations for successfully implementing decentralized solutions:

Risk Analysis - A formal risk analysis is the foundation for implementing a decentralized solution. A data-driven RBQM process that allows you to identify and evaluate risks early, monitor those risks and provide insights to make adjustments throughout your trial is essential. A robust RBQM process led by an experienced CRO will help determine the type of decentralized solution needed for your clinical trial (e.g. fully virtual or hybrid). It will also help you make decisions around the most appropriate use of monitoring strategies, including risk-based monitoring, central monitoring, off-site monitoring and targeted source data verification (TSDV), as well as provide insight into other critical considerations for subject safety and data integrity.

Patient Centricity and Study Logistics - The patient must be the central focus of any decentralized solution. This includes considerations for safety, engagement, and study logistics. When clinical sites are closed and/or patients aren’t able to travel to sites, it’s important to consider the following:

1. Remote consenting – We have consulted with IRBs to implement remote informed consent processes that meet regulatory requirements. It’s important to have this process in place before starting a decentralized clinical trial. If your trial started prior to the pandemic, you may need to update and re-consent subjects based on necessary changes made to trial design in regard to subjects visits and even potentially for the remote review of subject data.

2. Remote Recruitment and Enrollment Processes – Discussions regarding the digital management of recruitment and enrollment should be held with the clinical sites at the feasibility and qualification stage. Ongoing conversations with clinical sites and any vendors (if used) should continue through the site activation period to ensure sites are prepared to begin recruitment and enrollment activities as soon as they are initiated. If implemented and managed well, these remote processes have the potential to increase patient engagement and overall retention.

3. Telemedicine Visits – Many of our sites have implemented telemedicine visits to evaluate subject safety throughout a decentralized trial. Telehealth is the use of digital information and communication technologies, such as computers and mobile devices, that allow patients to access health care services remotely. In a telemedicine visit, the clinical site staff connect with the patient via phone or web conference to assess new and/or ongoing adverse events and any changes to the patient’s medications.

4. Home Health Care – A common home health care solution we have implemented pairs a trained Home Health Care medical professional with patients for in-person evaluations. The patient chooses a time and location that is convenient, and during the appointment, the Home Health Care professional performs safety procedures, such as blood collection and vital sign review and evaluation. It’s important to note that clinical sites might not immediately embrace home health solutions because of a perceived lack of control of the patient’s care. We have had success by addressing these concerns with the sites and investigators early in the process to ensure buy-in and support.

5. Lab Draws – It’s important not to overlook a local laboratory as an option for certain blood collections. Allowing a patient to have blood draws done at a lab closer to the his or her home, can reduce patient burden. We have also partnered with a vendor that provides the patient the ability to collect blood, urine, saliva and stool samples in their own home and send it directly to the lab for analysis.

6. Direct to patient (DTP) Investigational Product (IP) shipments – We have developed strategies for the dispensation of IP, such as home delivery or use of courier services for shipment of IP directly to patients’ homes. To ensure IP maintains a specific temperature in transit, our shipping partners use a controlled temperature shipper and a temperature tracking device.

7. Off-Site Monitoring – We have implemented many types of off-site monitoring processes to meet the needs of specific decentralized clinical trials. These solutions have included customized approaches to and levels of risk-based monitoring, off-site monitoring and targeted site data verification (TSDV). The right combination of these solutions for your clinical trial will depend on the risks identified in the RBQM process, along with the status of your clinical trial or program (e.g. a new study that has not begun yet versus a study that has been on-going and needs to implement a decentralized solution partway through), and the level of access to your clinical sites.

8. Centralized Monitoring and Data Visualization – Remote evaluation of clinical data (e.g. centralized monitoring) is a critical component of any decentralized solution, and it becomes more important as direct access to clinical sites and patients is reduced. Centralized monitoring is used to identify trends in the clinical data, including information pertinent to site management activities and data related to safety events. Our teams have the centralized monitoring tools to identify key quality and risk indicators early and monitor them throughout the study to provide actionable and timely insights that will help manage your decentralized clinical trial.

Technology – Technology is a key component of most decentralized solutions. At Rho, we have implemented eCOA and ePRO solutions, along with devices and wearables that capture data directly from patients. Technology solutions have the potential to significantly reduce patient burden and increase patient engagement if implemented properly. It’s important to map out a strategy early in the process, which includes robust plans for site and patient training. It’s also important to ensure that the CRO you’re working with has developed strong partnerships with any technology vendors they bring to the table.

Continuous Assessment - Any decentralized solutions during this pandemic must be both customized and agile. The conditions at research sites and patient availability has been shifting rapidly and will continue to be uncertain for the foreseeable future. This means that it’s even more important to have a decentralized approach that’s grounded in a robust RBQM framework, which can provide data and triggers to determine when a shift in approach is necessary.

Updating Study Plans/Protocols – To document potential changes to your decentralized strategy, make sure to update study plans and protocols throughout your trial or program. Study plans include the project management plan, clinical monitoring plan, and the statistical analysis and data management plans, among others. Updating plans and protocols, will ensure compliance and result in reliable data that supports endpoints.

In conclusion, we’d like to emphasize that decentralized solutions are not one-size fits all. The right solution for your trial or program needs to be determined and managed using a robust RBQM process, which will identify risks upfront and monitor them throughout and let you know when changes need to be made. And a reliable CRO partner is critical to implementing a decentralized solution that will help you realize all the advantages and benefits of a truly decentralized approach.

MarinaAE-1Marina 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.

COVID-19 Treatment Development: Updates and Recent FDA Guidance

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

Drug Shortages During the COVID-19 Pandemic

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

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

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

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

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

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

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
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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
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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.

sduffy

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.

 

MarinaAE-1

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.

Development of COVID-19 Therapies: FDA Pathways

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

Changes to Study Visits and Assessments During COVID-19:  Subject Safety Considerations

Posted by Monica Frazier, Jamie Chang, and Jack Modell on Thu, Apr 09, 2020 @ 10:00 AM
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The COVID-19 pandemic has understandably generated a surge of concern among clinical researchers about how best to minimize the risk to study subjects of exposure to COVID-19 while also preserving study integrity and a favorable risk-benefit of study participation for subjects. In general, research principles don’t change because the world is going through a public health crisis, and the principles of Good Clinical Practice, risk-benefit, subject safety, and ethics remain as fundamental priorities of clinical research. However, we can shed some light on specific topics that might be considered during this time, which are also approached in the recent April 2020 update to the FDA Guidance on Conduct of Clinical Trials of Medical Products during the Covid-19 Pandemic.

It is critical during the COVID-19 pandemic that sponsors consider each clinical trial circumstance specifically, including potential unique or increased risks associated with continued study conduct, taking into consideration the nature of the investigational product (IP), the appropriateness and feasibility of continued or changed safety monitoring, supply chain limitations, and the nature of the disease under study. Any changes made to the study plans should be communicated to subjects and study institutional review boards (IRBs) as soon as possible and documented appropriately via protocol amendments and the clinical study report.

Some common questions related to study conduct during the crisis include the following:

• Should ongoing study recruitment be halted? Some of the considerations that should be included in this decision include the ability of site and site staff to remain available throughout the intended duration of the trial; the operational status of study-associated vendors, supply providers, and information technology systems; and the ongoing availability of Data Monitoring Committee members, when applicable. Product specific considerations may be necessary as well, depending on the potential mechanism of action of the product in development, and whether it has a possible risk of increasing COVID-19 infection risk or seriousness to subjects.

• What if enrolled subjects cannot travel to the study site for protocol specified visits? Alternative methods for safety assessments, including phone visits, virtual visits, or alternative locations should be considered when necessary and feasible. We encourage study sites to have open discussions about the potential impact of study visit changes with their IRBs and study sponsors before any changes are implemented. When alternative methods to complete study assessments are inadequate to maintain a favorable study risk-benefit and/or study integrity, the study may need to be modified to achieve this or halted if this is not possible.

• In what ways can we reduce risk of subject infection while maintaining access to IP? Sponsors should consider whether home assessments and delivery of IP is feasible for their studies. The latter may require special shipment considerations if warranted by IP storage and handling requirements. It is important to note that any changes in IP distribution should follow existing regulatory requirements for IP accountability and should be fully documented.

While assuring the safety of trial participants is paramount and deviations from a clinical study protocol to achieve this are allowed in acute emergency situations, during this ongoing crisis it remains essential to maintain compliance with good clinical practice (GCP) and ethical standards of research conduct, and to minimize risks to trial integrity. In other words, it is neither necessary nor appropriate to violate research standards or guidelines during this crisis. In order to continue a clinical study – whether in its original or modified form – the study must still have a favorable risk benefit for the subjects, the assessment of which includes three important components:

i) The risks and benefits of the study intervention during a viral pandemic,
ii) the ability to adequately monitor and assure subject safety during the trial, and
iii) the ability to continue to gather meaningful and reasonably complete study data, since without this an essential component of ethical research conduct cannot be met.

In many cases, perhaps a majority, we believe that these components can be met and the clinical research can be safely and ethically continued. Sponsors and investigators must, however, recognize that in cases where necessary study modifications are impractical or inadequate to achieve these required components, the study may need to halted or delayed until such time that external conditions sufficiently improve to allow the study to safely and ethically resume.

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.

Jamie2

Dr. Jamison Chang, Medical Officer, is a board-certified internist with over 15 years of clinical experience with a broad range of disease entities in both the ambulatory and hospital settings. After completing his residency and chief residency at UNC Chapel Hill, he obtained additional training in nephrology as well as a master’s degree in clinical research (MS-CR). These experiences allow Dr. Chang to meld clinical pragmatism with scientific rigor to help plan and conduct high quality clinical trials. As a medical officer at Rho, Dr. Chang’s responsibilities include pharmacovigilance and advising project teams on the clinical and scientific issues to ensure safe and well-executed clinical trials.

jackJack Modell, Vice President and Senior Medical Officer, is a board-certified psychiatrist with over 35 years of experience in clinical research, including 20 years conducting trials, teaching, and providing patient care in academic medicine, and 15 additional years of experience in clinical drug development (proof of concept through market support), medical affairs, successful NDA filings, medical governance, drug safety, compliance, and management within the pharmaceutical and CRO industries. Jack has authored over 50 peer-reviewed publications across numerous medical specialties and has lead several successful development programs in the neurosciences. Jack is a key opinion leader in the neurosciences and is nationally known for leading the first successful development of preventative pharmacotherapy for the depressive episodes of seasonal affective disorder.

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

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

Working with BARDA: Funding collaborations for your emerging infectious disease program

Posted by Meagan Spychala & Arlo Grady on Wed, Apr 01, 2020 @ 10:00 AM
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As part of BARDA’s Medical Countermeasures Clinical Studies Network (MCM-CSN), we have had sponsors ask us about funding collaborations for their infectious disease programs, including COVID-19. We understand that it can be confusing to navigate this process, and we are happy to provide some guidance based on our experience working within the BARDA network.

While it depends on your program, typically we recommend looking into the BARDA’s Broad Agency Announcement, or BAA, and taking advantage of the TechWatch meetings that are offered. Under the BAA, BARDA is soliciting proposals for the research and development of MCMs, such as vaccines, therapeutics, diagnostics and devices to address several threats, including pandemic influenza and emerging infectious diseases.

The BAA submission requires a Quad Chart and White Paper, which provide BARDA with a brief overview of your project, including a technical discussion of your objective, approach, level of effort, and nature and extent of the anticipated results. Prior to your submission, BARDA also offers the opportunity to participate in a TechWatch meeting , which we highly recommend taking advantage of. While not a prerequisite for the BAA, it is an invaluable experience, which allows sponsors to hear expert advice from a panel of scientific, technical, and contracting professionals from BARDA, and potentially other agencies (e.g. National Institute of Health, Center for Disease Control, Department of Defense, and Food and Drug Administration). Getting this feedback and incorporating it into the White Paper/Quad Chart submission may increase your chances of moving forward in the acquisition process detailed in the graphic below.BARDA blogpost pictureDue to the 2019 Novel Coronavirus, BARDA is currently focusing on COVID-19 responses only; however, the process is the same, and you can request a CoronaWatch meeting in place of the TechWatch meeting. Additionally, with the CARES Act recently being passed, BARDA’s Other Transactions Authority Agreements (OTAs) program might also be a good avenue for funding, as there is no longer a cap on the funding proposed for each project. OTAs also tend to offer more flexibility than other federal contracting mechanisms. These agreements are not subject to typical federal laws and regulations and give the contractor and BARDA the most contracting flexibility to advance research and development.

If you need help preparing for your TechWatch/CoronaWatch meeting, White Paper, or OTA, Rho experts can provide guidance on operational considerations and risk mitigation strategies that will better support your program.

Meagan HeadshotMeagan Spychala, DrPH, Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s advisor on patient-focused clinical research activities and works to incorporate the patient and caregiver voice and experience into the clinical development program. She serves as the co-PI for the Medical Countermeasures Clinical Studies Network (MCM-CSN), a federal contract that provides support for clinical studies relevant to the Biomedical Advanced Research and Development Authority’s (BARDA) vision to create a nation with the capability to respond quickly and effectively to deliberate, natural, and emerging threats by providing a range of clinical study services.

ArloGArlo Grady, MBA, Assistant Director of Business Development at Rho, is a former Army combat medic, with over 15 years of experience selling to both federal and commercial clients. In his CRO experience, he has regularly participated in communications with Biomedical Advanced Research and Development Authority (BARDA) Contracting Officers (COs) regarding contract competitive range negotiations, modifications, extensions, and authorizations (COAs).  Mr. Grady also works with commercial sponsors seeking federal funding for early Phase 1 and Phase 2 clinical trials and has supported their efforts in securing BARDA, DoD, and DARPA funding.