We are pleased to introduce the collection Frontiers in Medical Technology – Highlights in Regulatory Affairs 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Regulatory Affairs section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research. Dr. Om Singh is a Senior Regulatory Consultant at TSG Consulting.

Johns Hopkins University

Guangzhou University of Chinese Medicine

Explore the diverse research conducted within Regulatory Affairs and discover its impactful studies.

. The development of effective vaccines against SARS-CoV-2 has been a major breakthrough in combating the COVID-19 pandemic. This research topic explores strategies to broaden the efficacy of monoclonal antibody therapies against variants of concern, as well as the concept of long-acting antibodies and non-intravenous routes of administration. It also looks into the use of anti-SARS-CoV-2 immunoglobulins produced from plasma of donors immunized with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine (VP-IVIg) and from plasma of COVID-19 convalescent donors (CP-IVIg). The research topic also examines the feasibility of using a web-based health app for post-concussion symptom management in an outpatient setting. Additionally, it analyzes the use of multi-criteria decision analysis (MCDA) and managed entry agreements (MEAs) to improve the health technology assessment (HTA) of innovative medicines and facilitate access to them, with a focus on safety data. <ul> <li>Major breakthrough in combating COVID-19 pandemic through development of effective vaccines</li> <li>Strategies to broaden efficacy of monoclonal antibody therapies against variants of concern</li> <li>Use of anti-SARS-CoV-2 immunoglobulins produced from plasma of donors immunized with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine (VP-IVIg)</li> <li>Feasibility of using a web-based health app for post-concussion symptom management in an outpatient setting</li> <li>Multi-criteria decision analysis (MCDA) and managed entry agreements (MEAs) to improve the health technology assessment (HTA) of innovative medicines and facilitate access to them</li> </ul>

Frontiers in Medical Technology

Regulatory Affairs

Highlights in Regulatory Affairs 2021/22

One of the major breakthroughs to combat the current Coronavirus Disease 2019 (COVID-19) pandemic has been the development of highly effective vaccines against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Still, alternatives are needed for individuals who are at high risk of developing severe COVID-19 and are not protected by vaccination. Monoclonal antibodies against the spike protein of SARS-CoV-2 have been shown to be effective as prophylaxis and treatment against COVID-19. However, the emergence of variants of concern (VOCs) challenges the efficacy of antibody therapies. This review describes the neutralization resistance of the clinically-approved monoclonal antibody therapies against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and the Omicron (B.1.1.529) variants. To guide the development of monoclonal antibody therapies and to anticipate on the continuous evolution of SARS-CoV-2, we highlight different strategies to broaden the antibody activity by targeting more conserved epitopes and/or simultaneously targeting multiple sites of vulnerability of the virus. This review further describes the contribution of antibody Fc effector functions to optimize the antibody efficacy. In addition, the main route of SARS-CoV-2 antibody administration is currently intravenously and dictates a monthly injection when used as prophylactic. Therefore, we discusses the concept of long-acting antibodies (LAABs) and non-intravenously routes of antibody administration in order to broaden the clinical applicability of antibody therapies.

One of the major breakthroughs to combat the current Coronavirus Disease 2019 (COVID-19) pandemic has been the development of highly effective vaccines against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Still, alternatives are needed for individuals who are at high risk of developing severe COVID-19 and are not protected by vaccination. Monoclonal antibodies against the spike protein of SARS-CoV-2 have been shown to be effective as prophylaxis and treatment against COVID-19. However, the emergence of variants of concern (VOCs) challenges the efficacy of antibody therapies. This review describes the neutralization resistance of the clinically-approved monoclonal antibody therapies against the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and the Omicron (B.1.1.529) variants. To guide the development of monoclonal antibody therapies and to anticipate on the continuous evolution of SARS-CoV-2, we highlight different strategies to broaden the antibody activity by targeting more conserved epitopes and/or simultaneously targeting multiple sites of vulnerability of the virus. This review further describes the contribution of antibody Fc effector functions to optimize the antibody efficacy. In addition, the main route of SARS-CoV-2 antibody administration is currently intravenously and dictates a monthly injection when used as prophylactic. Therefore, we discusses the concept of long-acting antibodies (LAABs) and non-intravenously routes of antibody administration in order to broaden the clinical applicability of antibody therapies.

Optimization of Anti-SARS-CoV-2 Neutralizing Antibody Therapies: Roadmap to Improve Clinical Effectiveness and Implementation

Despite vaccines are the main strategy to control the ongoing global COVID-19 pandemic, their effectiveness could not be enough for individuals with immunosuppression. In these cases, as well as in patients with moderate/severe COVID-19, passive immunization with anti-SARS-CoV-2 immunoglobulins could be a therapeutic alternative. We used caprylic acid precipitation to prepare a pilot-scale batch of anti-SARS-CoV-2 intravenous immunoglobulins (IVIg) from plasma of donors immunized with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine (VP-IVIg) and compared their in vitro efficacy and safety with those of a similar formulation produced from plasma of COVID-19 convalescent donors (CP-IVIg). Both formulations showed immunological, physicochemical, biochemical, and microbiological characteristics that meet the specifications of IVIg formulations. Moreover, the concentration of anti-RBD and ACE2-RBD neutralizing antibodies was higher in VP-IVIg than in CP-IVIg. In concordance, plaque reduction neutralization tests showed inhibitory concentrations of 0.03–0.09 g/L in VP-IVIg and of 0.06–0.13 in CP-IVIg. Thus, VP-IVIg has in vitro efficacy and safety profiles that justify their evaluation as therapeutic alternative for clinical cases of COVID-19. Precipitation with caprylic acid could be a simple, feasible, and affordable alternative to produce formulations of anti-SARS-CoV-2 IVIg to be used therapeutically or prophylactically to confront the COVID-19 pandemic in middle and low-income countries.

Despite vaccines are the main strategy to control the ongoing global COVID-19 pandemic, their effectiveness could not be enough for individuals with immunosuppression. In these cases, as well as in patients with moderate/severe COVID-19, passive immunization with anti-SARS-CoV-2 immunoglobulins could be a therapeutic alternative. We used caprylic acid precipitation to prepare a pilot-scale batch of anti-SARS-CoV-2 intravenous immunoglobulins (IVIg) from plasma of donors immunized with the BNT162b2 (Pfizer-BioNTech) anti-COVID-19 vaccine (VP-IVIg) and compared their in vitro efficacy and safety with those of a similar formulation produced from plasma of COVID-19 convalescent donors (CP-IVIg). Both formulations showed immunological, physicochemical, biochemical, and microbiological characteristics that meet the specifications of IVIg formulations. Moreover, the concentration of anti-RBD and ACE2-RBD neutralizing antibodies was higher in VP-IVIg than in CP-IVIg. In concordance, plaque reduction neutralization tests showed inhibitory concentrations of 0.03–0.09 g/L in VP-IVIg and of 0.06–0.13 in CP-IVIg. Thus, VP-IVIg has in vitro efficacy and safety profiles that justify their evaluation as therapeutic alternative for clinical cases of COVID-19. Precipitation with caprylic acid could be a simple, feasible, and affordable alternative to produce formulations of anti-SARS-CoV-2 IVIg to be used therapeutically or prophylactically to confront the COVID-19 pandemic in middle and low-income countries.

In vitro Characterization of Anti-SARS-CoV-2 Intravenous Immunoglobulins (IVIg) Produced From Plasma of Donors Immunized With the BNT162b2 Vaccine and Its Comparison With a Similar Formulation Produced From Plasma of COVID-19 Convalescent Donors

Objectives: To determine the feasibility of patients to use a web-based health app for management of post-concussion (mTBI) symptoms in an out-patient setting.Participants: Seven (7) patients who were referred to an outpatient specialist clinic (physiatry) with persisting symptoms following a concussion. Participants had to be 18 years of age or older and more than 3 months post injury.Design: This was a prospective cohort study using a web-based platform for chronic disease management to guide patients in managing symptoms based on individual clinical recommendations. Each patient received weekly Symptom Management Plans created by a health coach and a physician specialist, designed to reinforce positive progress with clinical recommendations.Main Measures: Adherence to tracking daily recommendations and symptoms (data collected through the web-interface), The Rivermead Post-Concussion Questionnaire (self report) and a Satisfaction Questionnaire (self report).Results: Adherence to assigned clinical recommendations was close to 100%. Pre-post results on the patient reported outcome measure (Rivermead Post Concussion Tool) showed improvement for most patients in their experience of symptoms. The Satisfaction Questionnaire showed high rates of satisfaction with the App and the intervention in general.Conclusions: Use of a web-based health app with a health coach is feasible in this patient population from both the patient and clinician perspective based on high adherence. There is also some evidence of improvement of symptoms with this intervention over time. Further exploration of the use of this type of intervention with post-concussion patients could potentially impact long-term outcomes.

Objectives: To determine the feasibility of patients to use a web-based health app for management of post-concussion (mTBI) symptoms in an out-patient setting.Participants: Seven (7) patients who were referred to an outpatient specialist clinic (physiatry) with persisting symptoms following a concussion. Participants had to be 18 years of age or older and more than 3 months post injury.Design: This was a prospective cohort study using a web-based platform for chronic disease management to guide patients in managing symptoms based on individual clinical recommendations. Each patient received weekly Symptom Management Plans created by a health coach and a physician specialist, designed to reinforce positive progress with clinical recommendations.Main Measures: Adherence to tracking daily recommendations and symptoms (data collected through the web-interface), The Rivermead Post-Concussion Questionnaire (self report) and a Satisfaction Questionnaire (self report).Results: Adherence to assigned clinical recommendations was close to 100%. Pre-post results on the patient reported outcome measure (Rivermead Post Concussion Tool) showed improvement for most patients in their experience of symptoms. The Satisfaction Questionnaire showed high rates of satisfaction with the App and the intervention in general.Conclusions: Use of a web-based health app with a health coach is feasible in this patient population from both the patient and clinician perspective based on high adherence. There is also some evidence of improvement of symptoms with this intervention over time. Further exploration of the use of this type of intervention with post-concussion patients could potentially impact long-term outcomes.

Feasibility of an Interactive Coaching App to Enhance Post-concussion Outpatient Care

Through the years, solutions for accelerated access to innovative treatments are implemented in models of regulatory approvals, yet with limited data. Besides efficacy data, providing adequate safety data is key to transferring conditional marketing authorization to final marketing authorization. However, this remains a challenge because of the restricted availability and transferability of such data. Within this study, we set up a challenge to analyze the answers of two questions. First, from regulatory bodies' point of view, we bring the question of whether multi-criteria decision analysis (MCDA) is an adequate tool for further improvement of health technology assessment (HTA) of innovative medicines. Second, we ask if managed entry agreements (MEAs) pose solutions for facilitating the access to innovative medicines and further strengthening the evidence base concerning efficacy and effectiveness, as well as safety. Elaborating on such challenges brought us to conclude that increasing the attention to safety in MCDAs and MEAs will increase the trust of the authorities and improve the access for the manufacturers and the early availability of safe and effective medicines for the patients.

Through the years, solutions for accelerated access to innovative treatments are implemented in models of regulatory approvals, yet with limited data. Besides efficacy data, providing adequate safety data is key to transferring conditional marketing authorization to final marketing authorization. However, this remains a challenge because of the restricted availability and transferability of such data. Within this study, we set up a challenge to analyze the answers of two questions. First, from regulatory bodies&apos; point of view, we bring the question of whether multi-criteria decision analysis (MCDA) is an adequate tool for further improvement of health technology assessment (HTA) of innovative medicines. Second, we ask if managed entry agreements (MEAs) pose solutions for facilitating the access to innovative medicines and further strengthening the evidence base concerning efficacy and effectiveness, as well as safety. Elaborating on such challenges brought us to conclude that increasing the attention to safety in MCDAs and MEAs will increase the trust of the authorities and improve the access for the manufacturers and the early availability of safe and effective medicines for the patients.

Efficacy, Safety, and Economics of Innovative Medicines: The Role of Multi-Criteria Decision Analysis and Managed Entry Agreements in Practice and Policy