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Applied Clinical Trials December 2020

The COVID-19 pandemic has affected different countries in different ways, but across the world it has had three common, defining characteristics: speed and scale (i.e., the disease spread quickly with potential to overwhelm the country's health systems); severity (an estimated 20% of cases are severe or critical, with increased risk in older age groups or those with underlying conditions); societal and economic disruption (particularly regarding shocks to healthcare systems and measures taken to control transmission.)

 Clinical research plays a crucial role in developing diagnostics and medicines to fight the ongoing COVID-19 pandemic, through rapid and accurate clinical trials, and collect robust and reliable outcomes, in a variety of different settings, on a large scale. Intensive global research collaborations among all stakeholders and industry involving all countries are necessary to enable identification and testing of effective treatments, vaccines and diagnostics.

The European CRO Federation, EUCROF, is a non-profit entity founded in 2005 and representing the interests of Contract-Clinical Research Organizations (CROs) in Europe towards regulatory bodies, the bio-pharmaceutical and medical device industry, healthcare professionals and patient’s associations. The Federation consists of Members (National CRO associations) from 12 countries, including Belgium with BeCRO, Czech Republic with ACRO-CZ, France with AFCROs, Germany with BVMA, Greece with HACRO, Italy with AICRO, the Netherlands with ACRON, Romania with ACCSCR, Slovakia with SACROP, Spain with AECIC, Turkey with SAKDER, UK with CCRA, and 15 Associate Members based in Albania, Austria, Bulgaria, Croatia, Denmark, Georgia, Serbia, Spain, Sweden, Switzerland (2), Ukraine (2), United Kingdom (2) as well as three Partner Members based outside Europe, in Algeria, Egypt and Israel. EUCROF is intensively engaged with its members and other involved stakeholders in the conduct of COVID-19 related clinical research. Through its large Network, represented by over 385 affiliated member-CROs and 25 countries, EUCROF contributes to have a wide perspective on the impact COVID-19 pandemic has having on ongoing and upcoming Clinical Trials.

The article provides the results of a brief survey conducted by the European CRO Federation (EUCROF) with the goal of collating data focused on COVID-19 research activities of its members. The survey was sent to all affiliated member-CROs to obtain an overview of the extent of contribution of EUCROF members to COVID-19 relatedresearch, and to collect information on pandemic impact on CTs, measuring the active participation to research activities planned to face coronavirus outbreak.

The online quick survey was developed through Google Forms and was distributed by email to all affiliated members-CROs, in March 2020. The survey included the following questions regarding the CROs' research activities:

Has your company been approached to participate in any research activities associated with COVID-19?

If yes, is your company actively participating in research activities now and scheduled to do so in the next 3 to 6 months?

Are the services provided on a national or international level?

If yes to either, please specify what activities you will be contributing to the research? Services provided by the CRO (tick all that apply)

Questions 1-2 of the survey were aimed to understand whether the pandemic had an impact on the clinical studies management activities, and if so, question 3 investigated to what extent the EUCROF affiliated member-CROs were to be involved in the next future (3-6 months). Questions 4 and 5 were aimed to qualify whether and how many respondents provided services at national or international level, and if respondent CROs were national or multinational. Finally, question 6 investigated which services were more frequently provided.

Results were collected from March 2020 to May 2020, analyzed electronically through Google Forms statistics and exported into graphs using Excel.

In total, 68 responses to the survey were received from affiliated member-CROs and analyzed electronically. The analysis of the results shows that 53 out of 68 of the respondent CROs (78%, as shown in Figure 1) were involved in COVID-19-related research activities, of which 48 (91%) expect to maintain and continue with this research for at least further 3-6 months.

respondent CROs who positively declared to be

Graph 1 describes globally the number of the single ongoing research activity associated with COVID-19 performed by the CROs and in detail if it involves only a potential therapeutic, and/or a vaccine, and/or a diagnostic or altogether the three research activities, Table 1 describes both the number and the percentage of each research activity.

In total 42 out of 53 (79%) respondent CROs are focusing their current research activities on a potential therapeutic, 24 (45%) on testing vaccines and 14 (26%) on testing diagnostics.

In details, the respondents who declared to be involved only in research activities on potential therapeutic are 19 (36%), while those who are involved only in research activities on vaccine and diagnostic are respectively 2 (4%) and 4 (8%). Furthermore, we analyzed the different combination of research areas and it resulted that the number of CROs whose research activities involved both in a potential therapeutic and a vaccine are 15 (28%); research activities involving both a vaccine and a diagnostic are 2 (4%); research activities involving both a potential therapeutic and a diagnostic are 3 (6%). The respondent CROs who are involved in all the three areas of research are 5 (9%).

As illustrated in Graph 2, the survey results show that 76% (52 out of 68) of the respondent CROs provide international services, whereas 24% (16 out of 68) provide national services. Regarding their legal forms, 65% (44 out of 68) are multinational CRO, whereas 35% (24 out of 68) are national CROs. We also analyzed the number of national CROs which provided services at International level, and these are 14 out of 24, while the number of national CROs which provide services locally is 10 out of 24. The multinational CROs who provide services at national or International level are respectively 6 and 38 out of 44.

Graph 3 and 4 in details illustrate the number of International and National services provided by respondent CROs involved in COVID-19 research, as well as whether they are national or International. Moreover, table 2 describes that 12 (23%) National CROs involved in COVID-19 research provide International services, whereas 8 (15%) provide national services; 6 (11%) multinational CROs likewise involved in coronavirus research activities declared to provide national services, while 27 (51%) answered to provide International services.

With reference to the type of services provided by the respondent CROs and the kind of activities they are or will be contributing to in the research on COVID-19, 69% (47 out of 68) declared to be involved in Clinical Monitoring, 68% (46 out of 68) in Project Management, 63% (43 out of 68) in Data Management, 54% (37 out of 68) in Regulatory Affairs, 54% (37 out of 68) in Statistics and 53% (36 out of 68) in Medical Writing. In detail, considering only the 53 CROs involved in COVID-19 research activities, we found that 40 out of 53 (75%) are mainly involved in Clinical Monitoring, 41 (77%) in Project Management and 37 (70%) in Data Management. Also, 32 CROs out of 53 (60%) are involved in Regulatory Affairs, 33 (62%) in Statistics, 32 (60%) in Medical Writing.

Answers to questions 3a, 3b and 3c are considered in total, as single choice and in combination. They are reported as numbers and in percentages (out of the Total of 53 CROs involved in COIVID-19 Research).

. Answers to questions 3a, 3b and 3c. The participation in research on potential therapeutic, vaccine and diagnostic is provided by all combinations among research activities. On the left Y-axis, it is reported the number of positive responses calculated on the total number of CROs participating in COVID-19 research.

. Answers from questions 4 to 5. Graph 2 describes the number of CROs providing National or International services, the National or Multinational CROs and National CROs proving International Services, out of a total of 68 CROs respondents.

Graph 3 describes the total number of National and International services provided by the respondent CROs which are involved in COVID-19 research. Graph 4 describes the total number of National and Multinational EUCROF CROs, involved in COVID-19 research

National and international CROs, involved in COVID-19 research, providing International or national services were counted.

The survey has been successful in identifying among the respondents how many EUCROF affiliated members-CROs are involved in research related to COVID-19 and are at the forefront of the fight against this challenging pandemic. It is envisaged that EUCROF, through its affiliated members-CROs, and other researchers, would continue to work together to accelerate research activities related to COVID-19 and diagnostics. Leveraging tools, resources and knowledge would give the greatest chance of success against this difficult threat and provide an opportunity for collaborative (rather than competitive) clinical research in a way that is unprecedented. The opportunity of surveys and the dissemination of their data at European and pan-European level is intended to contribute to build large datasets. The potential integration of these large datasets would result in valuable insights to help tackle any subsequent SARS-COV-2 like outbreaks. The impact of COVID-19 on day-to-day activities as well as on the health of people across the world and the global economy is considerable enough to have evidently warranted coordinated and focused initiatives to circulate and share knowledge and expertise. Examples of this are represented by the nationally targeted effort, UK Coronavirus Immunology Consortium (UK-CIC),

 intended to understand immune responses to the virus SARS-CoV-2 that causes Covid-19 and to tackle some key questions and deliver real benefits to patients and public health. The UK-CIC focuses on five key research themes: 

, to characterize the primary immune response to COVID-19 and how this relates to clinical outcome of individual patients; 

, to identify how effective immunity is established and maintained to prevent re-infection; 

 to understand how the immune system can damage tissue while fighting COVID-19 and how this can be stopped; 

 to examine if immunity to other mild ‘seasonal’ coronaviruses (that cause common colds) can alter the outcome of SARS-CoV-2 infection; and 

 to reveal how SARS-CoV-2 can ‘evade’ the immune system. Also, innovation hubs such as NESTA

 are mobilizing collective intelligence to face the COVID-19 threat. NESTA promotes the exploitation of collective intelligence to predict, monitor, and find solutions to the COVID-19 pandemic. For instance, responding to concerns about lack of access to testing for COVID-19, Nesta Collective Intelligence grantee 

 is behind an effort to develop a cheap, quick coronavirus test to be possibly used anywhere in the world. The initiative is crowdsourcing ideas from Do-It-Yourself biology communities,

 with the ambition to open source and share designs so that certified labs can easily produce test kits for their communities.

This pandemic also represents an example of increased collaboration among industry and authorities such as the European Commission and the European Medicines Agency (EMA), where an easing of competition rules and flexibility shown by authorities has helped pharmaceutical companies and medical device manufacturers, cooperate to overcome problems that threaten the security of supply of vital medicines and equipment during the COVID-19 pandemic.

EMA has established dedicated task forces to deal with the scientific, regulatory and operational challenges created by the COVID-19 pandemic and initiated its business continuity plan. The COVID-19 EMA pandemic Task Force (COVID-ETF) has the role to help EU Member States and the European Commission to take quick and coordinated regulatory actions on the development, authorization and safety monitoring of medicines and vaccines intended for the treatment and prevention of COVID-19.

Moreover, the European Commission proposed a new Pharmaceutical Strategy for Europe which has been largely fostered by the crisis Europe is facing also due to the coronavirus pandemic. It has been acknowledged that 

the unprecedented coronavirus pandemic further demonstrated how important it is to have a crisis-resistant system and ensure availability of medicines under all circumstance.

 The Pharmaceutical Strategy for Europe aims to fulfil unmet needs and ensure accessibility and affordability for patients and health systems sustainability. Therefore, the strategy will establish a future proof of regulatory framework and support industry in promoting research and technologies that actually reach patients and fulfil their therapeutic needs while addressing market failures.

Due to the current pandemic, EUCROF is also developing a second survey to be submitted to all its affiliated members, aimed at collecting information on the economic impact the coronavirus pandemic is causing on CROs research activities and Clinical Trials.

In summary, our data reveal that the majority of EUCROF affiliated member-CROs responders to the survey are dedicated to supporting clinical research activities aimed at developing effective and safe medicines, vaccines, and diagnostics for COVID-19. Since the pandemic outbreak, European clinical research has aimed to address challenges from the SARS-CoV-2 infection and disease, and many innovative initiatives, involving industry, academia, policy makers, patient associations and society at large, have been started with the intention, of delivering useful and effective solutions to face this and possible future pandemics. Our findings show how promptly the respondent CROs have oriented towards research activities to fulfil the current needs which have arisen from the COVID-19 pandemic. Successful collaborations between Pharma/Biotech/Device industry and CRO'S, as well as the ability to leverage knowledge and resources between all of them, will play a key role in an effective and efficacious fight against the global COVID-19 pandemic and are desperately needed in order to overcome such a tremendous challenge. Projecting the preliminary results of this survey on a larger scale, we may deduct how constructively critical is the role of CROs in implementing research projects in every field the community may identify as strategic for the rising needs, particularly in difficult times when the maximal flexibility and a fast reaction represent a substantial requirement.

, MSc, EUCROF Communication Working Group;

, EUCROF Associate Member, Richmond Pharmacology Ltd;

, PharmD, EUCROF Code of Conduct Task Force;

, MEcon, EUCROF Events and Training Working Group Chair;

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Articles

Successful collaborations between Pharma/Biotech/Device industries and CROs will play a key role in an effective fight against the global COVID-19 pandemic.

The Current Status of European Research Related to COVID-19: The EUCROF Perspective

Cognizant’s Shared Investigator Platform (SIP) has integrated with Oracle Health Sciences. Cognizant and Oracle have combined the SIP solution and study startup offerings to address site challenges and aim to deliver value in the initialization of studies, collaboration, and management.

“Being able to stay connected, reduce administrative work, and stand-up clinical trials quickly is paramount, especially as the world faces the pandemic and must maneuver around social distancing guidelines,” said Srinivas Shankar, Global Head of Life Sciences, Cognizant. “Since 2016, Cognizant’s Shared Investigator Platform has over 130,000 users across 100 countries. This digital solution, in collaboration with Oracle, is helping bridge digital technology and life sciences.”

Oracle and Cognizant Aim to Accelerate Study Startup in Trials

Calyx has announced a new partnership program for Clinical Research Organizations (CROs). The program, “ACTIVATE Solutions for CRO Partners,” is designed to provide alignment between Calyx and its CRO partners.

Those who qualify to participate in ACTIVATE operate under a personalized governance and reporting structure that provides access to technology, decision-making, and issue resolution aiming to generate faster trial execution.

Calyx ACTIVATEs CRO Partnership Program 

Clinical research as a multi-stage multitasking complex of necessary targeted actions basically requires the involvement of patients or volunteers. (ICF GCP E6(R1) Step 4 version dated November 9, 2016). An important component of conducting a clinical trial is the time spent on the research. Increasing the duration of the study increases the financial cost of the study sponsor DiMasi (2016) and each additional day of research cost the sponsoring companies 37 thousand US dollars and, at the same time, losses from an unsold product were two or three orders of magnitude higher—from 0.6-8.0 million US dollars to USD 23 million.

 The total duration of the study is constantly increasing, in particular due to the complexity of the protocols and, as a consequence, the amount of information required from the site. In particular, PhRMA in 2015 provides data on the number of pages of registration cards and criteria for inclusion of patients in protocols from 2000 (55 and 31, respectively) and from 2011 (171 and 46), which corresponds to an increase of 227% and 58%, respectively.

The recruitment of patients occurs at the very beginning of the study of any phase - during the recruiting period. The activity of research sites during this period affects the duration of this period, and ultimately the cost of research and the duration of the entire research. IGEA Pharmaceutical club (2018) regards the recruiting period as one of the barriers to clinical trials.

The purpose of this analysis was to retrospectively review the enrollment of patients at various sites participating in international multicenter clinical trials, taking into account various factors.

Analyzed 69 sites in Russia, Ukraine and Belarus for the period 2008 to 2017.

We took the methodology for determining the rate of gain by Eric B. Lynam and co. (2012) and modified it by dividing the number of patients included in the study and the number of actual months spent by the site on involving the patient in the study.

 The sites were divided into four categories depending on the rate of recruitment of patients per month (30 days):

Silence sites—rate of recruitment—0 patients per month;

Low recruiting—rate of recruitment by 0,01 to 0,19 patients per months;

Middle recruiting—by 0,20 to 0,89 per months;

High recruiting—by 0,90 to 3 patients per months.

Fig.2. Breakdown of sites on rate of recruitment

Figure 2 shows that the number of centers in which there were no patients throughout the study was 37%. Our data is comparable to the NCBI data for 2010, where the percentage of sites who did not recruit patients reached 50%.

 This high percentage affects the duration of the study.

The distribution of ranked centers by recruitment rate in different countries is shown in Figure 3.

Fig.3. Breakdown of sites on rate of recruitment in countries.

The data in Figure 3 show the absence of silent sites in some countries, which, in our opinion, is associated with the total number of international multicenter studies. According to clinicaltrial.gov, 2,744 studies were conducted in Russia from 2008 to 2017, in Ukraine—1143 and in Belarus—135 studies.

The distribution of studies in centers by nosological units is shown in Figure 4

The data in Figure 4 show that oncology prevailed in research during this period, which is comparable to the general growth trend in research in the field of oncology.

Figure 5 shows that researchers are faced with the absence of patients for research in all pathologies and the percentage of such centers ranges from 15 to 40%. Obviously, this percentage of silent sites directly affects the recruitment duration. It can also be seen that in the case of rectal cancer, a high percentage of silent sites (33%) is compensated by a higher percentage of highly recruited sites (44%), however this is an exception and the general trend is a large percentage of silent sites and a small percentage of highly recruited sites.

Potentially stated patient enrollment plan at the beginning of the study.

According to the researcher's experience, the site was divided into three categories

with work experience up to 4 years—beginners

with work experience from 4.1 to 6.9 years—experienced

with more than 7 years of work experience—with extensive work experience

The analysis reveals a picture of double the percentage of silent sites (43%) in centers with more than seven years of Principal Investigator experience. This fact can be interpreted as a great activity in the search for patients of young researchers earning a reputation for themselves, but this percentage of activity goes into low recruiting. The number of highly recruited sites is approximately the same in all groups.

Sites that potentially had patients and were planning to recruit a certain number of patients are divided into four groups:

up to 1 patient—low patient recruitment potential;

1 patient to 10—moderate patient recruitment potential;

from 11 patients to 23—average patient recruitment potential;

more than 23 patients—high potential for patient recruitment.

Fig.7. Breakdown of sites depending on patients to be planned involved to study.

An analysis of the data in Figure 7 shows that centers that planned average patient enrollments generally met their plans. Centers that initially underestimated recruitment plans did not strive to fulfill them and, as a consequence, had a high percentage of complete absence of recruitment and lack of high recruitment. Centers that initially overestimated their recruitment plans had the highest percentage of complete absenteeism, but this percentage was partially offset by the presence of high recruiting (8%).

Experiences of Principal Investigators in relation to recruitment plans are presented in Table 1.

Site allocation by patient recruitment plans and researcher experience

Analysis of the data in Table 1 is primarily necessary for silent sites that have not recruited a single patient. Among the silent sites that initially assess their potential for recruiting patients as high, there are no researchers with up to four years of experience.

Among the silent sites, all groups of researchers who rated the potential as low participated in the study on thrombocytopenic purpura, a rare disease.

Silent sites with seasoned lead investigators and extensive experience overestimated potential patient recruitment, requiring further analysis.

Among the highly recruited sites, researchers with different experience of participation in research do not have sites that initially assess the potential for recruiting patients as low.

Thus, the analysis of the rate of recruitment of patients to international multicenter clinical trials revealed some possibilities of the site for conducting a given study, taking into account the initial data of the researcher's experience and the planned recruitment of patients, which will allow in the future to predict the duration of the recruitment of patients.

A Randomized, Multi-center, Double-Blind, Placebo-Controlled, Single/Multiple Dose Escalation Phase Ib/IIa Clinical Trial to Investigate the Safety and Efficacy of Recombinant Human Soluble Fc-gamma Receptor IIb (SM101) for Intravenous Application in the Treatment of Patients with Chronic Adult Primary Immune Thrombocytopenia (ITP). EudraCT Number: 2009-014842-28. https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-014842-28/DE

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DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics, 47, 20–33.

Efficacy and Safety Study of Leukocyte Interleukin,Injection (LI) to Treat Cancer of the Oral Cavity (IT-MATTERS). ClinicalTrials.gov Identifier: NCT01265849.

, Pharm.D. A Patient Focused Solution for Enrolling Clinical Trials in Rare and Selective Cancer Indications: A Landscape of Haystacks and Needles // 

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Kalinovskaya Elena. In Russia, the number of approvals for clinical trials has decreased by more than 20%. Pharmaceutical BulletinВ России более чем на 20% снизилось количество разрешений на клинические исследования. Фармацевтический вестник. 6 Octоктября 2017 // 

https://pharmvestnik.ru/content/news/v-rossii-bolee-chem-na-20-snizilosj-6-10-17.html

List of life-threatening and chronic progressive rare (orphan) diseases leading to a reduction in the life expectancy of citizens or their disability Перечень жизнеугрожающих и хронических прогрессирующих редких (орфанных) заболеваний, приводящих к сокращению продолжительности жизни граждан или их инвалидности . //report of Russian MoH. https://www.mzsocial-rk.ru/dejatel-nost/organizacija-lekarstvennogo-obespechenija/orfannye-zabolevanija/.

Phase 3 Trial of Litx™ Plus Chemotherapy vs. Chemotherapy Only Treating Colorectal Cancer Patients With Recurrent Liver Metastases. ClinicalTrials.gov Identifier: NCT00440310

Study of Ganetespib (STA-9090) + Docetaxel in Advanced Non Small Cell Lung Cancer (GALAXY). ClinicalTrials.gov Identifier: NCT01348126

The complete analysis of the costs and barriers to drug development in 2018. All the expenses to conduct clinical trials and the split by disease areas // https://www.igeahub.com/2018/08/28/evaluation-of-clinical-trial-costs-and-barriers-to-drug-development/.

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The success of a clinical study depends on the possibilities to involve the patient in the study. 

Rate of Patient Recruitment to International Multicenter Clinical Studies in Eastern Europe Countries

overview of its key recommendations in 2020

 on the authorization and safety monitoring of medicines for human use.

In 2020, EMA recommended 97 medicines for marketing authorization. Of these, 39 had a new active substance which had never been authorized in the European Union before. The Agency recommended one vaccine and one treatment for COVID-19. The infographic includes figures on the authorization of medicines and a selection of new treatments that represent significant progress in their therapeutic areas.

EMA Publishes Human Medicines: Highlights of 2020

Prime Global and Raremark have announced a partnership aiming to transform solutions for patients with rare diseases.

The partnership will combine Raremark’s Xperiome platform for patients with Prime Global’s 23 years of medical communications experience aiming to uncover insights into the entire patient journey that will allow the creation of a patient-centric drug development and commercialization programs.

Prime Global and Raremark Partner for Patients with Rare Diseases

Nexelis, a portfolio company of Ampersand Capital Partners, has signed an asset purchase agreement with GSK to acquire its GCLP-certified clinical bioanalytical laboratory located in Marburg, Germany.

The Clinical Laboratory Science (CLS) team in Marburg, consisting of approximately 80 scientists and analysts, will be transferred to Nexelis. The CLS team in Marburg will continue to keep a strong relationship with GSK and support the development of future GSK vaccine candidates through a 5-year agreement.

The transaction with GSK will be effective at the end of January 2021. Nexelis intends to expand the Marburg site, initiating collaborations with other vaccine development companies as well as with the company’s other North American and European sites.

Nexelis Acquires GSK Vaccines Clinical Bioanalytical Laboratory

Bioclinica has announced the addition of Image Redact AI to its portfolio. The new product supports redaction of sensitive patient information from videos, photos, and PDFs in clinical trials.

Bioclinica Image Redact AI safeguards sensitive clinical trial data by redacting sensitive patient identifiers from videos, photos, and PDFs. Research that utilizes video or other image formats for studies on vision loss, gait or other movement analysis, dermatology, dental, or behavioral research are especially prone to issues with current products that blur a patient’s entire face.

Bioclinica Announces Addition of Image Redact AI 

Ongoing COVID-19 lockdowns and requirements of social distancing have swiftly pushed healthcare provision and patient monitoring towards remote options. Even though remote patient monitoring (RPM) was already being used before the start of the pandemic, the uptake of the technology was relatively low, primarily used to ensure better post-acute care and management of chronic conditions. However, now the technology is uniquely positioned to lead to a fundamental change in healthcare services delivery and clinical trials, says GlobalData.

Their latest report, ‘The State of the Biopharmaceutical Industry 2021’, reveals that RPM is expected to become the industry trend with the most impact on the pharmaceutical industry in 2021, as confirmed by 20% of 198 pharmaceutical industry professionals.

Urte Jakimaviciute MSc, Senior Director of Market Research, commented, “Despite much lower uptake in previous years, RPM got off to a strong start and witnessed a massive uptake in the life-sciences sector in 2020. With more patients, payers, and physicians getting accustomed to virtual interactions, RPM will continue to transform healthcare delivery and accelerate adoption of decentralized/virtual clinical trials. The COVID-19 outbreak provided a unique opportunity for RPM to gain widespread acceptance, demonstrate value, and subsequently become a ‘new normal’ across healthcare and pharmaceutical fields.”

With increasing numbers of patients, clinical practices and pharmaceutical companies getting hands-on experience with RPM, the adoption of remote monitoring tools is on course to remain solid even after COVID-19 recedes. 

Remote Monitoring will Continue in 2021, says GlobalData

Although there was much analysis over the past year about the difficulties and challenges in distributing millions of doses of new vaccines across the nation, the process so far has been much less effective than anticipated. Since FDA authorization of two innovative mRNA vaccines to combat COVID-19 late last year, 30 million doses have been distributed, but only four million people were vaccinated in December 2020, and just 13 million have received shots so far.

While the Trump administration’s Operation Warp Speed (OWS) deserves kudos for supporting the accelerated development and production of safe and effective anti-COVID vaccines in record time, its plan for distributing and administering the preventives has been marred by political infighting and conflicting messages. State health officials have complained loudly of the lack of resources to support a massive new vaccination program and on limited information from Washington on the timing and size of anticipated vaccine distributions. The initial roll-out to health care workers and nursing home residents were tricky to schedule and arrange, and federal vaccine prioritization guidelines proved cumbersome. Many states are moving on to include more elderly populations, acknowledging that efforts to target certain groups such as nursing homes, teachers and other front-line workers have been confusing and wasteful.

A main problem was the administration’s delay in authorizing the Centers for Disease Control and Prevention (CDC) to provide states with clear guidelines for updating existing local procedures for distributing vaccines that critical “last mile” to clinics and health centers, a challenge familiar to supply-chain experts. Uncertainty about vaccine shipments and supplies, at a time when hospitals were dealing with surges in COVID-19 infections and deaths, prompted medical centers to cancel inhouse vaccination activities. And there still is confusion about whether clinics should hold back supplies for second doses or administer all on hand.

Although vaccine manufacturing has been ramping up, and supply has not been blamed for current distribution failures, there remains concern about unanticipated production problems. Last November Pfizer rattled OWS by disclosing that it would provide only 50 million doses in 2020, instead of the 100 million doses initially expected. And just last week, Pfizer announced plans to reduce vaccine supplies in Europe as it moved to renovate production processes at its Belgium facility. At one point in December, Moderna had to discard 400,000 vaccine doses due a filtration issue during production, although the company maintained that it would still produce its promised doses. Pfizer agreed recently to increase U.S. vaccine deliveries by another 100 million doses in 2021, but that is linked to access to certain supplies and raw materials needed for production. There is great hope that Johnson & Johnson will gain emergency authorization soon for its one-shot COVID vaccine, which would greatly bolster supplies of a product much easier to deliver, store and administer.

Meanwhile, research is underway on strategies for extending the current vaccine supply. These include studies on whether smaller or less frequent doses of the Moderna vaccine provide sufficient protection. There’s a search for a certain kind of syringe that is able to extract an additional sixth dose from Pfizer five-dose vials. There also has been talk of delaying or dropping the second doses for current vaccines, but FDA officials oppose such an untested move.

Congress finally approved a $900 billion relief package in late December, which provides an additional $8 billion for state vaccine distribution and administration, and that is now beginning to trickle down to local operations. However, efforts by the Biden transition team to form a new vaccine distribution program were hampered by limited communication and information sharing by the Trump administration and OWS. In fact, current vaccine policy was further confused by the recent announcement by Health and Human Services (HHS) secretary Alex Azar that OWS would ship to states thousands of vaccine doses held in warehouses to provide second shots for patients, only to learn that there was little supply on hold to do this.

Meanwhile, President-elect Joe Biden released a new initiative for ramping up vaccine distribution to meet the goal of administering 100 million doses to Americans in the next 100 days.

 The plan calls for mobilizing the National Guard and the Federal Emergency Management Agency to establish federal vaccination centers, while also working with pharmacies, community health centers, and mobile vaccination clinics to reach broader populations. There’s a promise of more support and resources for states and plans to ensure that all entities know well in advance and understand vaccine allocations and timing of deliveries, including an assurance of second-dose availability, in keeping with current FDA recommendations.

The plan acknowledges the need for added access to critical vaccine components, such as vials, syringes, stoppers and needles, and may leverage the Defense Production Act to fill any gaps. And there’s support for boosting vaccine finish-and-fill and packaging operations, as well as for augmenting required cold chain systems needed for effective vaccine distribution and storage. The new administration furthermore backs efforts to “maximize the manufacture of vaccine,” but is vague on how to do this.

In looking to put a new stamp on its federal vaccine initiative, Biden named former FDA commissioner David Kessler to replace OWS leader Moncef Slaoui in directing continued development and production of vaccines and therapies to combat the pandemic. Kessler is best known for expanding FDA regulation of tobacco, establishing FDA user fees, and revising regulatory policies in the face of the AIDS epidemic. There is concern that he has little experience in vaccine research or distribution and has been away from federal health policy for the last 20 years. But now he will be key to the success of the new administration’s promise to vaccinate 1 million people a day to gain control of the pandemic and restore the nation’s health and economic well-being.

https://buildbackbetter.gov/uncategorized/fact-sheet-president-elect-biden-outlines-covid-19-vaccination-plan/

The process of distributing millions of doses of new vaccines across the nation has been much less effective than anticipated.

Vaccine Rollout Worse than Expected, Mars Research and Regulatory Successes

The Center for Information and Study on Clinical Research Participation (CISCRP) has announced that it is providing plain language communication consulting and services to companies involved in Operation Warp Speed vaccine studies.

Public, patient, and healthcare community demand for plain language information about the results of COVID-19 vaccine clinical trials is extremely high. At the same time, health officials and Operation Warp Speed vaccine sponsors believe that transparency and disclosure of clinical trials results and information is essential to engendering public trust and facilitating broad support for vaccination programs that are now rolling out globally.

CISCRP is assisting Operation Warp Speed vaccine sponsors in a variety of ways including sharing best practices; developing, producing, and distributing plain language trial results summaries; and preparing plain language content to be communicated in print and digital formats.

CISCRP Provides Plain Language Services to Support Operation Warp Speed

 to the position of Chief Executive Officer.

 has joined The IMA Group as Strategic Advisor in the Clinical Research division.

 has become the Non-Executive Chair of PHASTAR.

 announced it provided clinical trial services to the Pfizer and BioNTech investigational COVID-19 vaccine program.

 will become a public benefit corporation on Feb. 1, 2021

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As the Biden administration readies to take over the reigns of government, top administration officials continue to rush through new rules and decisions that appear to challenge the independence and effective operations of FDA. One new requirement could revise oversight and review for prescription drugs and certain medical devices. This follows adoption of a broader new rule to “sunset” many established regulations and programs in the Department of Health and Human Services (HHS) unless they can justify their continuation. And in another area, the administration has tried to push through a new plan blocking FDA oversight of genetically modified animals despite strong objections from agency leaders.

The task of dealing with these issues may fall to Janet Woodcock, who appears poised to serve as acting FDA commissioner until the Biden administration selects and gains confirmation of a new leader for the agency. Woodcock was recently named medical advisor to commissioner Stephen Hahn and has been director of the Center for Drug Evaluation and Research (CDER) for many years but was detailed to head up development of anti-COVID-19 therapeutics under Operation Warp Speed.

A sign of FDA’s difficult position is the recent White House move to block Hahn from selecting a replacement for departing chief counsel Stacy Cline Amin. Just as the commissioner named experienced attorney Mark Raza to fill the job during the administration’s final days, HHS announced that political appointee James Lawrence would become FDA’s chief counsel, where he could continue the administration’s deregulatory campaign.

A late surprise from the Trump administration is the plan for FDA to publish new information on drug approval timelines and to explain and justify when reviews exceed 180 days. Touted as a “transparency” measure, the new policy instructs FDA to provide data on each approved application for new drugs and generics stating dates filed and approved and number of days over the statutory 180-day timeframe. CDER currently has user fee review goals of 10-months for most new drugs and generics and 6 months for priority therapies, but change would require the agency to collect and report data on review time frames using different metrics. The larger fear is that this policy could lead to more onerous requirements; at a minimum it’s seen as a meaningless distraction at a time when all hands are overloaded with initiatives to address the pandemic.

A related HHS policy would waive FDA premarket review for certain medical devices. This extends the current review exemption under the COVID-19 health emergency for items such as gloves, personal protective equipment, ventilators, and infusion pumps. Not a critical change, but regarded as another challenge to FDA internal policy making.

In addition, the battle over FDA authority to regulate laboratory developed tests (LDTs) continues to create problems. A contentious issue for several years, HHS revoked FDA’s authority over such tests in August in response to pressure from private labs for reduced regulation. However, in November, HHS reinstated FDA’s authority to issue Emergency Use Authorizations (EUAs) for lab tests in order to provide companies with liability protection for erroneous results during the pandemic. By then, however, FDA staff claimed a lack of resources to handle this activity, prompting a shift to outsourcing the EUA reviews.

The most contentious challenge to FDA’s authority, though, involves a late move by the Trump administration to shift oversight of genetically modified animals to the Department of Agriculture, a move backed by industry working in this area. Commissioner Hahn evidently refused to sign an HHS memorandum of understanding authorizing the change, claiming that it required further analysis of the legal and health repercussions.

On another front, FDA staff has had to accept administration efforts to limit utilization of prescription drugs to induce an abortion. In March 2020, FDA was able to relax in-person dispensing requirements for many drugs, including certain controlled substances to reduce the risk of spreading COVID-19. However, the Trump administration left in place the specific rule requiring women to make in-person visits to a clinic or doctor’s office to obtain mifepristone, one of two drugs required for a medication abortion. Even though a U.S. District Court judge suspended the in-person pick-up rule during the health emergency, the administration continued to fight for its reinstatement and recently gained a ruling to that effect from the Supreme Court.

Many of these recently issued regulations and policies can be rescinded or dropped by the Biden administration under established transition practices. However, these efforts by the Trump administration to limit FDA’s authority have rekindled calls for FDA to become an independent regulatory agency, separate from HHS. 

As he prepared to exit the agency amidst all the political infighting, commissioner Hahn joined with Anand Shah, deputy commissioner for medical and scientific affairs, in issuing a 

 outlining FDA’s important achievements in combatting the “devastation and turmoil” wrecked by the COVID-19 pandemic. The report highlights the agency’s accomplishments and offers recommendations for continuing to address the still-evolving public health emergency. To improve FDA’s emergency response and ability to sustain innovation, it calls for strengthening the EUA process, government partnerships, innovation in clinical trial conduct, and supply chain surveillance, among many other strategies. Hahn and Shah emphasize that FDA decisions are based on rigorous science and aim to protect and promote the health and safety of American patients.

Efforts by the Trump administration to limit FDA’s authority have rekindled calls for FDA to become an independent regulatory agency.

FDA Struggles to Fend Off Further Attacks from Trump Administration

Clinical Investigation for safety and performance evaluation of Medical Devices differ from the Clinical Development of other medicinal products. These differences are related to data and tenure. Data is majorly collected in post-marketing phase, unlike drugs, that have clinical development carried out in three phases. The data in drug clinical trials is majorly related to patient health, while for devices, this data is about patient, the device the use of the device, and the device deployment procedure. While the large number of clinical research for drugs is mandatory, in medical devices it is only to support clinical evidence when clinical evaluation does not suffice to establish compliance with general safety and performance requirements; as evident in table 1. 

Table 1: number of clinical studies logged for drugs and devices registered (as on Oct-2020 

Devices other than cosmetic and contraceptives cannot be tested in healthy human being. Hence, unlike drugs there are three types of investigations of the device depending upon the purpose of investigation i.e., pilot, pivotal and post-marketing. Pilot investigations are performed in a small population study to establish safety and performance of a product that is innovative or has critical risks. Commonly, this is the only clinical investigation performed for most devices before its marketing. A few devices require a Pivotal Clinical Investigation on a larger and diverse population, with end-point driven evidence generation. This investigation is performed for devices intended to treat critical diseases that has high risk associated with failure of the device. Major amount of data collection for such devices is generated in the Post Marketing environment. Regulatory Authorities are aware of this, and therefore there has been a significant surge in the number of Post Marketing Clinical Follow-up (PMCF) investigations after declaration of EUMDR-2017.

Medical device investigations are frequently compared with the drug development clinical phases( Phase I, II, and III). However, there is a wide difference between device and drug development. These differences percolate to all scientific aspects of clinical research including data collection, clinical data management (CDM), operations, statistics, and medical writing.

While the majority of CDM processes continue to be similar for all healthcare products, a few requirements are unique to the medical devices. Understanding these unique requirements for Case Report Form (CRF) designing and Electronic Data Capture (EDC) solutions is extremely important to successfully complete the clinical development process and market a safe and tested device.

There are two key challenges related to the design and implementation of a device EDC solution: 1: Regulatory requirements (Figure 1), and 2: Clinical aspects (Figure 2).

Medical devices must continually innovate. The products have to rapidly change and evolve to be more personalized and connected, leveraging AI and cognitive automation, robotics, and mobile technology. The constant changes and innovations on device developments, not only represent a big challenge for Life Science Industries and Manufactures, but also for Regulators.

New, evolving and complex regulatory requirements and government guidelines include changes pertaining to how manufacturers and distributors show the safety and efficacy of products (Medical Device Regulation, MDR, in Europe), demonstrate clinical evidence for all products as well as maintain systems and documents to remain compliant throughout the device lifecycle (Food and Drug Administration, FDA in the US). Both the U.S. FDA and Europe under MDR, demand more quality control processes throughout the device lifecycle including more audit trails.

Figure 1 regulatory requirements for CDM for medical devices

Device manufacturing organizations need to be responsive to regional and local Regulatory Authorities and government pre-requisites in an effective manner. Responding to the complex and dynamic regulatory environment requires the adoption of modern technology solutions for improved data capture, and safety process flexibility while maintaining compliance.

The complexity of clinical data collected for Medical Device is another challenge for Device Manufacturers and for the clinical development of the product. This complexity is reflected mainly on the design of the CRFs. CRF related challenges include need for multi-level forms, multiple repeating tables, capability to handle data of multiple investigational and supporting devices and procedural data. Another complexity is in the device details, which may include one or more investigational devices with different sizes or variation, different combinations of supporting and accessory devices, etc. Often, accurate capture of operative and post-operative data affects the definitions of population like screened, enrolled, intent to treat and treated etc. In addition, some in-patient follow-up until discharge may alter the definitions of the outcomes. The challenge is more pronounced for procedure visit in interventionally deployed devices. Hence, the CRF designing based upon the disease, therapy, procedure, outcome criticality, and discharge related follow-up requires thorough understanding of the domain as well as clinical data management. This data is often populated by technical persons or specialized doctors, nurses and technicians. Hence, creating an interactive, intelligent query-based, high performance EDC system ensures that data is captured right at first time.

Figure 2 Data oriented challenges in medical device Clinical Data Management

Mitigating challenges in clinical data management with platforms and technology advances

Medical Device CDM challenges and subsequent EDC requirements are unique and distinct from the perspective of:

device specific data: device identifiers, exposure, incidents, adverse events, tracking, device-subject interphase etc.

procedure related data: procedure steps, time, complications, outcomes, effect, and patient-operator-procedure-device relationship etc.

use of the device data: usability issues, instructions for use etc., and

patient data: adverse events, adherence to handle and use of the device, demographics etc.

The collection of data from these factors influence the design of the EDC platform for effective implementation of Medical Device investigations. Some of these challenges and their process-technology-method trio solutions are provided in table 2.

Table 2 EDC Challenges and strategy for mitigation

Benefits of business 4.0 approach in EDC in med-dev studies.

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Applied Clinical Trials December 2020