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Applied Clinical Trials December 2020

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

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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

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Articles

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.

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

The latest industry news, all in one place.

People and Business News — 1/21

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.

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Applied Clinical Trials December 2020