Arvind Chavali

As of the beginning of the month, in many parts of the world, the number of COVID-19 cases continued to rise rapidly as countries enacted strict lockdown and social-distancing countermeasures. Like many sectors of the world economy, the biopharmaceutical industry has been impacted with significant disruptions to clinical development, many of which have been well-documented in recent weeks.

 Patients are less able to travel to sites and comply with studies. Enrollments are drying up. Many resources, supplies, and personnel aren’t available. Studies are missing critical data points and are delayed. Ultimately, important treatments are delayed.

	To combat these disruptions, FDA recently released guidance on the conduct of clinical trials during the COVID-19 pandemic.

 In particular, the agency repeatedly emphasized prioritizing safety for all participants. For example, due to global travel restrictions, the agency recommended that sponsors look for substitute methods to conduct patient safety assessments, and use remote technology where possible. FDA also recommended that sponsors explore alternative delivery methods for investigational products where feasible, such as patients self-administering drugs or visiting other sites, and pursue site monitoring remotely. For patients unable to access trial sites or necessary medications, the agency advised sponsors to put additional safety monitoring programs in place.

	In accordance with FDA’s recommendations, there are four key actions that biopharmaceutical sponsors can take immediately to offset disruptions.

 A survey of U.S. and EU sites have reported that many of their patients are less willing to participate in the clinical trials that they’re already enrolled in. This patient sentiment is only worsening as the crisis continues.

 For clinical studies currently in flight, sponsors need to virtualize their trial operations to avoid jeopardizing the safety of patients as well as site staff.

 In a purely virtual setting, patients are in contact with study teams and trial physicians through smartphone technologies

, and investigational products are shipped directly to patients’ homes. Patients can self-administer therapies, if feasible. For more complex procedures and interventions, sponsors can collaborate with third-party home-trial vendors

 or incorporate at-home nurse visits. Obviously, the feasibility and logistics of this approach need to be analyzed thoroughly. For example, does a protocol involve procedures that cannot be conducted outside of a hospital setting?

If clinical research associates (CRAs) are unable to access sites because of global travel restrictions or local quarantines, sponsors should enable remote monitoring and oversight as the FDA recommends. If not already in place, sponsors may need to enable virtual workspaces for sites to upload the necessary documents for centralized monitoring. The Association of Clinical Research Organizations (ACRO) recently laid out emergency guidelines for sponsors, contract research organizations (CROs), and sites on conducting trial oversight during the pandemic.

		Continuing periodic communication with sites over telephone.

		Using key risk indicators (KRIs) and key performance indicators (KPIs) to identify trends that may require short-term interventions. Indicators could include protocol deviations, missed visits, adverse event reporting cadence, etc.

		Using an electronic data capture (EDC) system to enable remote reviews of patient visits, with particular emphasis on patient safety data and data quality issues. ACRO notes that it does not recommend accessing patient electronic health records remotely unless protocols and procedures for maintaining patient privacy are already in place. Additionally, it does not recommend using fax machines for critical source documents.

3. Engage patients and investigators through proactive communication.

 Developing a communication and remote engagement strategy with patients and investigators that can be sustained throughout the pandemic is vital to ensure motivation and reduce burden. Virtualizing trials or monitoring sites will only be successful if

 sponsors frequently engage and empathize with patients and sites in order to assuage concerns caused by COVID-19.

4. Assess the overall clinical portfolio and evaluate study design, feasibility, and operations as the pandemic evolves.

 For each clinical trial in the portfolio, sponsors need to conduct a thorough assessment exercise aimed at answering key questions related to design, feasibility, and operations in the immediate term, short term, and long term. For example, in the immediate term, sponsors should determine which of their in-flight trials need to pause enrollment and which of their new planned trials need delayed starts. In the short and long term, sponsors should think through:

		Protocol modifications to incorporate remote patient and site assessments or other virtual elements.

		Patient visit requirements and anticipated data collection challenges.

		Effective resumption of activities when the pandemic situation improves.

		Improvements to risk management planning.

		Overall impact on clinical trial and clinical program timelines (including time to approval).

	These are just a few questions among many that need to be sorted out. Moreover, each passing day brings new information about the spread of COVID-19 globally. China and South Korea seemed to have gotten a grip on the spread of the virus (as of early April), while the U.S. and countries in Western Europe continued to struggle as cases rose exponentially. Therefore, to plan for the short and long term, sponsors should go back to the drawing board and reevaluate overall clinical study design, including patient eligibility, feasibility, enrollment, timelines, and budgets against the evolving global landscape.

	Sponsors should note that these strategies may require amendments to study protocols, and FDA guidelines urge sponsors to engage with institutional review boards (IRBs) as soon as possible. However, in cases where protocol changes are made to directly eliminate hazards to patients, these may be implemented without IRB approval. Finally, alarming projections indicate that social-distancing countermeasures may need to be in place well into 2021

, which means that biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.

is a manager in ZS’s San Francisco office; 

is a manager in ZS’s Los Angeles office; 

is ZS’s global clinical lead, based out of the company’s Princeton office; 

is an associate consultant in ZS’s San Francisco office

https://www.jdsupra.com/legalnews/the-global-impact-of-covid-19-on-72027/

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic

https://continuumclinical.com/blog/covid-19-live-updates

https://www.science37.com/wp-content/uploads/2020/03/12161417/Navigating-Clinical-Trials-in-the-Coronavirus-Era_Science37.pdf

https://www.science37.com/blog/siteless-clinical-trials-changing-the-game-for-patients/

https://www.clinicalleader.com/doc/the-benefits-and-challenges-of-siteless-clinical-trials-0001

https://www.acrohealth.org/wp-content/uploads/2020/03/ACRO-Statement-on-Monitoring-Oversight-FINAL-3.13.20.pdf

https://info.zs.com/activeingredient/clinical-development-risks-and-issues-in-a-covid-19-world

https://www.washingtonpost.com/health/2020/03/19/coronavirus-projections-us/

Articles

Lockstep with regulatory guidance on conducting trials amid crisis, here are four key actions sponsors can take to minimize disruptions. 

Moving Clinical Operations Forward During Pandemic

	In accordance with recommendations from the FDA, there are four key actions that biopharmaceutical sponsors can take immediately to offset disruptions:

For clinical studies currently in flight, sponsors need to virtualize their trial operations

to avoid jeopardizing the safety of patients as well as site staff. In a purely virtual setting, patients are in contact with study teams and trial physicians through smartphone technologies

, and investigational products are shipped directly to patients’ homes. Patients can self-administer therapies if feasible. For more complex procedures and interventions, sponsors can collaborate with third-party home-trial vendors

or incorporate at-home nurse visits. Obviously, the feasibility and logistics of this approach need to be analyzed thoroughly. For example, does a protocol involve procedures that cannot be conducted outside of a hospital setting? 
		 

If clinical research associates are unable to access sites because of global travel restrictions or local quarantines, sponsors should enable remote monitoring and oversight as the FDA recommends. If not already in place, sponsors may need to enable virtual workspaces for sites to upload the necessary documents for centralized monitoring. The Association of Clinical Research Organizations (ACRO) recently laid out emergency guidelines

for sponsors, clinical research organizations and sites on conducting trial oversight during the pandemic. 
		 

Engage patients and investigators through proactive communication.

Developing a communication and remote engagement strategy with patients and investigators that can be sustained throughout the pandemic is vital to ensure motivation and reduce burden. Virtualizingtrials or monitoring sites will only be successful if sponsors frequently engage and empathize with patients and sites in order to assuage concerns caused by COVID-19.
		 

Assess the overall clinical portfolio and evaluate study design, feasibility and operations as the pandemic evolves. 

For each clinical trial in the portfolio, sponsors need to conduct a thorough assessment exercise aimed at answering key questions related to design, feasibility and operations in the immediate term, short term and long term. For example, in the immediate term, sponsors should determine which of their in-flight trials need to pause enrollment and which of their new planned trials need delayed starts. In the short and long term, sponsors should think through: 

		Protocol modifications to incorporate remote patient and site assessments or other virtual elements

		Patient visit requirements and anticipated data collection challenges

		Effective resumption of activities when the pandemic situation improves

		Improvements to risk management planning

		Overall impact on clinical trial and clinical program timelines (including time to approval) 

	These are just a few questions among many that need to be sorted out. To plan for the short- and long-term scenarios, sponsors should go back to the drawing board and reevaluate overall clinical study design, including patient eligibility, feasibility, enrollment, timelines and budgets against the evolving global landscape.

	Sponsors should note that these strategies may require amendments to study protocols, and the FDA guidelines urge sponsors to engage with institutional review boards (IRBs) as soon as possible. However, in cases where protocol changes are made to directly eliminate hazards to patients, these may be implemented

without IRB approval. Finally, alarming projections indicate that social distancing countermeasures may need to be in place well into 2021

 is a manager in ZS’s San Francisco office. 

 is a manager in ZS’s Los Angeles office. 

 is ZS’s global clinical lead, based out of ZS’s Princeton office. 

 is an associate consultant in ZS’s San Francisco office. 

	Editor’s Note: The full version of this article will be available in our April digital edition on April 13. 

Biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.

4 Key Actions ClinOps Can Take Now to Avoid Disruptions

	On March 14, outgoing FDA commissioner Scott Gottlieb chided pharmaceutical companies and clinical research organizations (CROs) for being slow to embrace innovations in clinical research, even when the FDA sanctions those innovations. “The business model adopted by the clinical trial establishment just isn’t compatible with the kind of positive but disruptive changes that certain innovations can enable,” he wrote 

	The data back him up. Use of innovative designs such as 

 for Phase II and III trials. These innovations can increase the likelihood of launch for new drugs 

	Why, after 15 years, is pharma still struggling to adopt innovative trial designs? There remain many obstacles, including:

		  Lack of sufficient investigator, site, and patient input

		  Poor operational standardization of data and protocols

 of pharma’s approach to innovation among payers and patients 

	FDA keeps churning out guidelines for innovation 

	To foster innovation, the FDA recently offered a slew of initiatives. The agency’s 

 (September 2018) allows for the evaluation of multiple investigational drugs, disease types, or patient populations under a single clinical trial structure. (This is not new: the first “basket” trial, conducted by Novartis, tested imatinib mesylate in five different types of cancer in 

 (August 2018) promotes the use of seamless trial designs, Bayesian models and other advanced statistical approaches. And Gottlieb’s March 2019 press statement was a rollout for the FDA’s new guidelines on clinical trial 

-both practices key to precision medicine.

	However, guidance documents are not the whole story. For example, the FDA’s Master Protocol guidance suggests that sponsors use independent data monitoring committees (IDMCs) to conduct pre-specified and ad hoc assessments of endpoints and recommend protocol modifications. However, 

 has shown that there no standards for IDMC operating procedures, qualifications, and training.

	How can pharma address obstacles to innovation?

	Despite operational obstacles and low adoption rates, the industry has chalked up a few successes with innovative approaches. Effective strategies strike a balance between adopting innovation and mitigating risk. Companies can: 

		 Adopt clinical trial data standards and agreements proposed by organizations such as 

		 Provide patients with a virtual simulation of the clinical trial experience and offer logistics support to facilitate access to clinical trial sites

 that combine on- and off-site data to boost patient compliance and engagement in the process

, especially if the development plan involves using novel biomarkers, non-traditional clinical endpoints, or other innovations

	For its part, the FDA can continue to support innovation by sharing concrete examples of how sponsors and industry have worked together to solve problems and striving for better cross-divisional collaboration, standardization, and communication on crucial drug development issues. 

Venkat Sethuraman, Sharma Ramanathan Deva Devesa, 

FDA commissioner Scott Gottlieb criticized pharmaceutical companies and clinical research organizations for being slow to adapt innovations in clinical research, claiming that the business model adopted just isn’t compatible with the kind of changes that certain innovations can enable.

Arvind Chavali

Articles

Moving Clinical Operations Forward During Pandemic

4 Key Actions ClinOps Can Take Now to Avoid Disruptions

How Pharma Can Work with the FDA to Embrace Innovation and Overcome Its “Adoptaphobia”