Replicor announces publication of the REP 401 study achieving high rates of virologic control and functional cure in patients with chronic hepatitis B infection

Below, we are re-publishing with permission the press-release issued by Replicor Inc. on March 09, 2020

MONTREAL, March 9, 2020 – Replicor Inc., a privately held biopharmaceutical company targeting functional cure for patients with chronic hepatitis B and D infection, announced the publication of the final results of its latest REP 401 study in the prestigious journal Gastroenterology.

The article, entitled “Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy”, presents the analysis of the safety and efficacy of NAP therapy when added to a backbone of TDF and pegIFN in patients with treatment naïve chronic HBV infection.

The culmination of more than a decade of clinical investigation of NAPs, transitioning from REP 2055 to REP 2139-Mg, the REP 401 study achieved dramatic increases in the incidence of HBsAg loss and seroconversion during therapy (60%) and therapeutic transaminase flares (95%) compared to that observed with TDF + pegIFN alone. Importantly 78% of participants achieved virologic control of HBV of whom 39% further achieved functional cure. These outcomes dramatically improve those achieved by TDF + pegIFN alone and far exceed those observed with any other therapy currently in development in mono or combination therapy.

r. Andrew Vaillant, CSO of Replicor commented, “Our substantial body of published data clearly demonstrates that all NAPs using Replicor’s proprietary poly AC technology have very similar activity with similar doses required in humans. However, only NAPs formulated as magnesium chelate complexes such as REP 2139-Mg and REP 2165-Mg have the excellent tolerability and safety required for use with immunotherapy. This combination approach is essential to awaken an effective immune response capable of driving high rates of therapeutic transaminase flares essential for restoring virologic control and functional cure. The successful completion of the REP 401 study paves the way for the long-planned transition of REP 2139-Mg to subcutaneous administration and assessment in combination with other immunotherapies capable of driving HBsAg specific T-cell activation, an activity we believe is a critical component of achieving functional cure.”

The article can be accessed directly at the following link:

About Replicor
Replicor is a privately held biopharmaceutical company with the most advanced animal and human clinical data in the development of the cure for HBV and HDV. The company is dedicated to accelerating the development of an effective treatment for patients with HBV and HBV/HDV co-infection. For further information about Replicor please visit our website at

* The study is conducted by Clinical Accelerator

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Second Heart Assist Announces Successful Completion of Long-Duration Pre-Clinical Studies

Below, we are re-publishing with permission the press-release issued by Second Heart Assist Inc. on June 22, 2020

Salt Lake City, Utah, June 22nd, 2020 /PRDistribution/ — Second Heart Assist Inc., inventors of the first, true, aortic stent-based circulatory assist pump intended primarily for use in heart failure patients, announces the successful completion of a series of long-duration preclinical studies in pulsatile mock loop and bovine models. Long-duration studies were completed using mock-loop apparatuses at the University of Louisville (Louisville, KY), ViVitro Labs (Victoria, BC, Canada), and Biomerics (Minneapolis, MN) as well as in large animal models at Q Test (Columbus, OH), APS (Minneapolis, MN) and the Texas Heart Institute (Houston, TX). These successful studies pave the way for upcoming, first-in-human clinical studies in diuretic resistant heart failure patients suffering from cardio-renal syndrome—to be performed in Tbilisi, Georgia in July 2020. It is planned that OUS first-in-human studies will be followed by a US-based Early Feasibility Study (EFS).

“The recent successful completion of these long-duration in vivo studies, utilizing the percutaneously delivered Second Heart Assist circulatory assist pump within a true aortic stent, demonstrates the desired durability needed to address an increasing patient population suffering from advanced heart failure.” stated Alex Richardson, Chief Technology Officer and Vice President of Engineering Second Heart Assist, Inc. who was present and actively participated in all preclinical studies. “These preclinical studies demonstrated position stability and robust blood flow improvement provided by our system. We are particularly excited about the excellent outcomes we saw during long-duration studies where we noted minimal hemolysis and only minor clinically insignificant thrombus formation after over 40 hours of operation.” Richardson further stated, “These studies, again, give evidence to the advantages of the unique design for our catheter-based product. Furthermore, we have adapted this same mechanical stent and impeller pump platform for use in our chronic wireless device, which we are actively building and testing, to target additional therapeutic endpoints.”

“The Second Heart Assist product lineup introduces a unique solution for patients suffering from diuretic resistance resulting in cardio-renal syndrome by providing strong improvements to renal function, while offloading the heart. The strong radial force of the aortic stent minimizes risk of migration experienced by other available device designs.” stated Jeff Donofrio President, who was present for the Texas Heart Institute study.

Dr. Brett Burton, VP of R&D at Second Heart Assist, explained: “Our device is unique in that it not only occupies the entire aorta, but it is also designed to safely distend the vessel by about 2 mm. This design ensures that, once properly positioned and deployed, our device maintains a robust intervascular fixation within the aorta (just above the renal arteries).  In addition to secure device positioning, the large cross-sectional area produced by the open stent allows for the unimpeded flow of blood within the vessel and provides a space in which our impeller can operate safely, effectively, and, at low RPMs, to generate high flow to the renal arteries.”

Dr. Leslie Miller, Chief Medical Officer (CMO) of Second Heart Assist commented, “We are thrilled to have reached this milestone, which further validates the safety and efficacy of our technology, particularly in preclinical settings, and supports our intent to now move into longer duration clinical studies.”

Dr. Mark Cunningham, Chief Cardiac Surgery Advisor, Board Director, and Cardiac Surgeon at USC Keck Medical Center, and who also assisted in the recent 40+ hour Texas Heart Institute study, stated “I see patients every week, including those receiving ineffective inotropic support (of which decreased renal function is a characteristic). Many of these patients could benefit greatly from the Second Heart Assist circulatory assist pump, designed to deliver continuous and reliable renal support while maintaining consistent positioning through its aortic stent technology platform. The 2nd generation wireless powered chronic implant in development represents a potentially huge leap forward.”

Clinical Accelerator, Inc. has been engaged as the Contract Research Organization (CRO) to help implement the OUS cardio-renal syndrome heart failure clinical study including data collection and analysis –

In 2019 the Second Heart Assist team previously announced results from a positive short-duration pilot first-in-human clinical study – This clinical data has been presented at the Heart Failure Society of America, TCT Cardiology, Devices for Heart Failure and ASAIO Annual Meetings.

The team also announced recent progress on the development of its wireless powered chronic product-

About Second Heart Assist: 

Second Heart Assist, Inc. is a Utah corporation founded in 2016 focused on development of a circulatory assist pump within an aortic stent within the Leonhardt’s Launchpads innovation and startup accelerator(s). See for more information.

Disclaimer: Forward looking information is subject to change without notice. Product is not yet proven to be safe or effective. Product is still in early stage of development and pathway to commercialization. The company lacks sufficient resources at this time to bring product to commercialization. Patents pending may not be issued. Patents issued may be invalidated. Patents optioned or licensed may not be maintained. As an investment Second Heart Assist must be regarded in highest risk category for total loss. No other group has succeeded in developing a wireless power chronic circulatory assist device with success as the obstacles to doing so are tremendous. Available for investigational use only in locations where proper regulatory clearance has been granted.

* The study is conducted by Clinical Accelerator

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Clinical Accelerator collaborates with CroíValve on a study for Tricuspid Regurgitation


Clinical Accelerator has recently entered into a new collaboration with CroíValve – a medical device company from Ireland – who is developing a novel, easy to use percutaneous solution for treating patients with severe Tricuspid Regurgitation (TR).

Tricuspid Regurgitation is an unmet medical need that affects over 550 thousand new patients every year in the US and EU alone. It often occurs in heart failure patients due to tricuspid annular dilation. Prognosis is poor for those affected and less than 1% of patients can undergo surgical treatment due to co-morbidities. Even for patients who can receive treatment, the operative mortality rate is between 10% to 35%.

Croívalve is dedicated to bringing an innovative solution to this area with their minimally invasive device that repairs the tricuspid valve without requiring surgery. The device will be placed across the native valve assisting coaptation and is held in place by a non-penetrating anchoring system. The device intends to provide patients with improved and extended quality of life and physicians with safe and easy treatment.

Croívalve announced first successful human use of its technology in March this year. The procedure was carried out at St James’ Hospital (Dublin, Ireland) and involved delivery and retrieval of the device fully percutaneously, with the device delivered without complications in the space of five minutes. It was published that the patient who suffered from severe TR with reduced heart function, experienced positive cardiac response to the treatment (Innovator, 2020).

Clinical Accelerator is excited to be participating in a new clinical study by Croívalve assessing the feasibility, safety and performance of temporary implantation of the device in TR patients prior to surgical intervention.

About CroíValve

Croívalve is an early stage medical device company focused on developing a minimally invasive device for the treatment of tricuspid regurgitation. It is based in Dublin, Ireland and combines significant clinical, technical and commercial experience.

About Clinical Accelerator

Clinical Accelerator is a boutique academically oriented clinical CRO focused on the needs of emerging MedTech companies. The organization was founded by a heart failure cardiologist and performs many clinical investigations of cardiovascular medical devices, with a special focus on heart failure. Studies are mostly implemented in Central and Eastern Europe, a region with well-known advantages for clinical trials such as – fast start-up timelines and good access to patients. Clinical Accelerator aims to accelerate clinical development programs of international medical technology companies through early entry into the clinic and fast and efficient implementation of both feasibility and pivotal clinical investigations.

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Clinical Accelerator continues its collaboration with Sequana Medical, a medical device company developing the alfapump DSR System for the treatment of Diuretic Resistant Heart Failure

Clinical Accelerator, a full-service contract research organization with a strong focus on medical device investigations, is pleased to report that despite the global disruption caused by Covid-19, work has been continued in the Republic of Georgia on RED DESERT – Repeated Dose alfapump DSR study for Treatment of diuretic-resistant heart failure patients. The study is sponsored by Sequana Medical, an innovator in the management of fluid overload in liver disease, malignant ascites and heart failure.

Sequana Medical was founded in 2006 with the initial aim of finding a better way to manage ascites patients. The company has developed and commercialised the alfapump in Europe, a fully implantable, programmable, wirelessly-charged, battery-powered system that is CE-marked for the treatment of refractory ascites due to liver cirrhosis and malignant ascites. In the U.S., the alfapump received Breakthrough Device designation for recurrent or refractory ascites due to liver cirrhosis and Sequana Medical is currently running the North American pivotal POSEIDON study to support FDA approval. Over 750 alfapump systems have been implanted to date.

The company is now extending the application of its unique technology to a new indication – management of volume overload in heart failure patients. The new device is called alfapump DSR (Direct Sodium Removal). This innovative therapy is being developed in collaboration with Dr Jeffrey Testani, Associate Professor at Yale University. The results of the FIH single dose DSR study, conducted by Dr Testani were presented at the Heart Failure 2019 Congress and published in Circulation.

Sequana Medical’s alfapump DSR system involves the use of the peritoneal cavity for the removal of excess sodium via diffusion. The system comprises of i) the alfapump a fully implanted subcutaneous device with a rechargeable battery that moves fluid from the peritoneal cavity to the urinary bladder where it is eliminated and ii) an implantable peritoneal catheter port. The DSR System is used in conjunction with the DSR infusate (zero sodium peritoneal solution, 10% dextrose in sterile water), which is instilled into the peritoneal cavity and left to dwell for a period of 2 hours.

The ongoing study is a prospective, single-arm, repeated dose study and is expected to include up to 10 heart failure patients, who are on high dose diuretics, across two centres in Belgium and Georgia. The primary safety endpoints include the rate of device, procedure and/or therapy-related serious adverse events after two and six weeks. The secondary endpoints include the feasibility of alfapump DSR to remove excess sodium and fluid from the body, thereby eliminating the need for daily high dose diuretics during the six-week treatment period. Additional exploratory endpoints to measure the potential impact of DSR therapy to restore response to diuretics will be evaluated through week six.

About Sequana Medical

Sequana Medical is a commercial stage medical device company developing the alfapump platform for the management of fluid overload in liver disease, malignant ascites and heart failure. Fluid overload is a fast-growing complication of advanced liver disease driven by NASH (non-alcoholic steatohepatitis) related cirrhosis and a common complication in heart failure. The U.S. market for the alfapump resulting from NASH-related cirrhosis is forecast to exceed €3 billion annually within the next 10-20 years. The heart failure market for the alfapump DSR (Direct Sodium Removal) is estimated to be over €5 billon annually in the U.S. and EU5 by 2026. Both indications leverage Sequana Medical’s alfapump, a unique, fully implanted wireless device that automatically pumps fluid from the abdomen into the bladder, where it is naturally eliminated through urination.

Sequana Medical is headquartered in Ghent, Belgium. For further information, please visit

Important Regulatory Disclaimers

The alfapump® system is not currently approved in the United States or Canada.  In the United States and Canada, the alfapump® system is currently under clinical investigation (POSEIDON Study) and is being studied in adult patients with refractory or recurrent ascites due to cirrhosis.  For more information regarding the POSEIDON clinical study see .

The DSR therapy is still in development and it should be noted that any statements regarding safety and efficacy arise from ongoing pre-clinical and clinical investigations which have yet to be completed.

The DSR therapy is not currently approved for clinical research in the United States or Canada. There is no link between the DSR therapy and ongoing investigations with the alfapump® system in Europe.

About Clinical Accelerator

Clinical Accelerator is a boutique academically oriented clinical CRO focused on the needs of emerging MedTech companies. The organization was founded by a heart failure cardiologist and performs many clinical investigations of cardiovascular medical devices, with a special focus on heart failure. Studies are mostly implemented in Central and Eastern Europe, a region with well-known advantages for clinical trials such as – fast start-up timelines and good access to patients. Clinical Accelerator aims to accelerate clinical development programs of international medical technology companies through early entry into the clinic and fast and efficient implementation of both feasibility and pivotal clinical investigations.

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Clinical Accelerator and BetaGlue Technologies to conduct First in Human Medical Device Investigations in Breast Cancer and Liver Cancer

Clinical Accelerator is pleased to announce an exciting new collaboration with BetaGlue Technologies SpA. Two studies will be conducted, one on radio-ablation of surgical margins following resection of breast ductal carcinoma in situ (DCIS), in 20 patients and one of radio-ablation of malignant liver lesions – hepato-cellular carcinoma (HCC) – followed by surgical resection, in 10 patients.

Currently, surgery is the standard of care for resectable solid tumours. Loco-regional approaches combined with chemotherapy and/or radiotherapy are the standard therapy either before surgery to reduce tumoral mass or after surgery to reduce the risk of recurrence. Unfortunately, local recurrences and other complications are still a problem that needs to be remedied. BetaGlue, focusing specifically on these unmet needs and has developed a proprietary internal radiotherapy platform, composed of a 90Y β-emitting radioactive hydrogel matrix which has several clinical applications. Several administration devices have also been engineered or are in development for precise delivery and administration of this radio-active matrix.

The administration of β-emitting radionuclides has several advantages over external radiotherapy. There is improved efficacy, low impact on blood vessels, limited side effects and low surrounding tissue penetration. On the basis of the clinical experience accumulated in over 15 years of treatments based on trans-arterial infusion of 90Y-coated microspheres (Selective Internal Radio Therapy, SIRT, called also Trans Arterial Radio Embolization, TARE), it is reasonable to assume that the intra-tumoral injection of a personalized activity dose of 90Y, entrapped inside the matrix and directly into the hepato-cellular carcinomas, is expected to effectively ablate them and to reduce drastically the chances of local recurrence. Similarly, the administration of the appropriate activity of 90Y in the surgical bed of resected breast tumours should overcome the limitation of other radiotherapy techniques (intra-operative and/or external beam radiotherapy) and reduce drastically their chance of local recurrence, which occurs in the area of tumor resection in 95% of the cases.

The upcoming studies have the potential to pave the road for confirming the efficacy and safety of these applications. In breast cancer, after the cancerous region is removed, residual tumour cells are often left behind in the surgical bed. As part of the DCIS study, BetaGlue’s technology will be uniformly applied over the tumour bed, expectedly killing any residual tumoral cells through beta radiation. In the liver cancer study, once the tumour is identified, an introducer will be placed percutaneously into it and, through a proprietary delivery system, BetaGlue’s radioactive compound will be injected into the hepatic lesions, killing the tumoral cells. In both applications, once the radioactive charge is exhausted, the body will slowly reabsorb the bio-compatible matrix over time.

 About BetaGlue Technologies

 BetaGlue is a medical device company, founded in 2017 in Milano, Italy. Dr Antonino Amato CEO, Dr Pier Luigi Carriero, VP Clinical Operations and their team are dedicated to providing an innovative approach to fighting cancer with their proprietary β-emitting bio-compatible matrix, delivered through dedicated delivery systems. The company is supported by a highly qualified Scientific Advisory Board, and national/international consultants on intellectual property, product development and regulatory expertise.

  About Clinical Accelerator

Clinical Accelerator is a boutique academically oriented clinical CRO focused on the needs of emerging MedTech and Biotech companies. The organization conducts clinical trials in all main indications, with oncology being an important therapeutic area. Clinical Accelerator works with many excellent sites and investigators in Central and Eastern Europe, experienced in international clinical trials in the oncology field. The company offers clients a range of clinical trial services, including designing essential study documents, regulatory and ethics submissions, site selection and monitoring, safety reporting and medical monitoring, data management and biostatistics, medical writing and quality assurance.

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Clinical Accelerator collaborates with Axon Therapies on a First-In-Human Feasibility Study for Heart Failure

Clinical Accelerator, a full-service contract research organization is pleased to report on its continuous collaboration with Axon Therapies, an early-stage, US-based medical technology company. Axon Therapies has developed a novel device – the Axon System – with a neuromodulation approach to treating heart failure. The First-In-Human study is specifically focused on endovascular ablation of the greater splanchnic nerve in patients who have chronic heart failure with preserved ejection fraction (HFpEF).

Heart Failure is a major public health issue with more than 5 million cases and 600,00 new cases per year in the United States. Almost half of these patients have HFpEF. At this moment in time, there are no therapies for this other than diuretic control for fluid overload and standard treatments for comorbidities. In addition, the 5-year mortality rate has been reported to be as high as 50-65%. This unmet medical need is what Axon is trying to treat with their novel medical device.

In patients with HFpEF, sympathetically driven mobilization of blood from the splanchnic reservoir to the central circulation leads to an increase in venous return with subsequent hemodynamic deterioration. This causes congestions, diuretic resistance, acute decompensations leading to rehospitalization, dyspnea and intolerance to even mild exercise, and progressive diastolic dysfunction. The Axon Endovascular GSN Ablation System is to be used to perform unilateral GSN ablation which should selectively block sympathetic signalling to the splanchic circulation. The system is made up of the Axon Catheter, Axon Generator, Axon Pump, Axon Cable and Axon Tubeset. Beneficial outcomes to this approach include but are not limited to:

  • Lower pulmonary pressures at rest upon exercising
  • Improved capacity to exercise
  • Reduced mortality
  • Improved responsiveness to diuretics
  • Reduced re-hospitalizations for heart failure

The study is a prospective, multi-center, single-arm, non-blinded feasibility clinical study. The purpose of this study is to assess the safety and efficacy of the Axon System when performing catheter-based unilateral ablation of the greater splanchnic nerve (GSN) in patients with Heart Failure. Clinical Accelerator is pleased to be able to make a contribution to this exciting study in the Czech Republic and in the Republic of Georgia.


About Axon Therapies

Axon Therapies is an early stage medical device company with a dedicated focus on Heart Failure. Founded in 2014 in New York, the company is led by CEO Dr Howard Levin – a veteran in the field of biomedical engineering and cardiology, with a specialty in heart failure and transplantation. Axon Therapies is a portfolio company of Coridea, a New-York based incubator, founded by Howard Levin and Mark Gelfand – two prominent experts in device development and serial entrepreneurs.


About Clinical Accelerator

Clinical Accelerator is a boutique academically oriented clinical CRO focused on the needs of emerging MedTech companies. The organization was founded by a heart failure cardiologist and performs many clinical investigations of cardiovascular medical devices, with a special focus on heart failure. Studies are mostly implemented in Central and Eastern Europe, a region with well-known advantages for clinical trials such as – fast start-up timelines and good access to patients. Clinical Accelerator aims to accelerate clinical development programs of international medical technology companies through early entry into the clinic and fast and efficient implementation of both feasibility and pivotal clinical investigations.

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VisCardia Announces Its Novel Heart Failure Therapy Receives Breakthrough Device Designation From the FDA

Below, we are re-publishing with permission the press-release issued by VisCardia Inc. on April 23, 2020

PORTLAND, Ore., April 23, 2020 ( – VisCardia Inc., a privately held medical device developer, announced today it has been granted Breakthrough Device Designation from the U.S. Food and Drug Administration (FDA) for its implantable VisONE® system designed for the treatment of moderate to severe heart failure with reduced ejection fraction and preserved ventricular synchrony.

The FDA Breakthrough Device Program is a two-phase process intended to help patients receive more timely access to breakthrough technologies. VisONE has now completed the first phase of the Breakthrough Devices Program by being designated to provide for more effective treatment of a life-threatening or irreversibly debilitating disease. During the second phase of the program, the FDA will expedite pre-market reviews of VisCardia’s IDE(s) as well as the subsequent Pre-Market Approval (PMA) application to request approval to commercialize the device in the U.S.

Gregg Harris, VP of Clinical & Regulatory Affairs, stated, “We are very excited that the FDA recognizes the great potential for this novel therapy and are looking forward to a productive collaboration with the FDA to ensure this technology can begin improving patients’ lives as soon as possible.”

The VisONE technology recruits the diaphragm by applying stimuli synchronously with the cardiac cycle which improves the blood flow through a weak heart by modulating the pressures within the chest. A recent European, multi-center, pilot trial demonstrated that patients improved their Quality of Life, physical performance and hemodynamic measurements when implanted with a VisONE device and followed for one year. VisCardia believes that expanding the size of the patient population studied to date will further illustrate the clinical benefit of this technology and lead to a minimally invasive therapy that will make this underserved patient population feel better and remain physically independent longer.

Peter Bauer, Ph.D., CEO of VisCardia, said, “As we continue to support scientific presentations at international meetings, this partnership with the FDA will expedite our entrance into the U.S. medical device market through the design and implementation of an initial IDE study. We are proud to have Dr. Lee Goldberg, Section Chief of the Advanced Heart Failure Program at the University of Pennsylvania, to serve as our U.S. Principal Investigator and Dr. Michael Mirro, Chief Academic Research Officer at Parkview Health and Clinical Professor of Medicine at Indiana University, as our Medical Director to assist us in identifying future clinical sites and implementing the next phase of our clinical research.”

About VisONE® SDS Therapy

The VisONE implantable system delivers VisCardia’s proprietary Synchronized Diaphragmatic Stimulation (SDS) therapy for improving cardiac function. By electrically stimulating the diaphragm in an imperceptible manner, transient intrathoracic pressures synchronized to cardiac activity are modulated, improving both cardiac filling and output. The therapy is non-invasively adjusted and programmed using an external programmer to improve hemodynamic benefit and optimize stimulation parameters.

* The study is conducted by Clinical Accelerator

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The effects of the New FDA Rule for medical device investigations conducted outside the United States


On February 21, 2019 the new US FDA rule on medical device clinical investigations conducted outside the United States (OUS) became effective. In this post, we would like to discuss the difference between the old and the new regulation and what is now required of sponsors by the FDA.

The new rule was triggered by the increasingly global nature of clinical research. Today, many clinical investigations of medical devices are conducted in locations OUS and the data produced is submitted to the FDA to support an IDE (Investigational Device Exemption), device marketing application or submission.  The FDA wishes to accept such data from well-designed and well-conducted clinical investigations performed OUS but wants to make sure that they were conducted in a manner similar to studies conducted in the US under FDA guidance. The agency wants the studies to be conducted in accordance with GCP, for the supporting information provided to be applicable, and for the FDA to be able to validate the data from the investigation through an onsite inspection if necessary. Under this new rule, the FDA’s intention is to achieve more uniformity since it wants to accept quality data from both clinical investigations conducted within and outside the United States equally, for whatever the application or submission type.

The new FDA rule applies to all regulatory pathways applicable to medical devices, including an investigational device exemption (IDE) application, a premarket notification (510(k)) submission, a request for De Novo classification, a premarket approval (PMA) application, a product development protocol (PDP) application, or a humanitarian device exemption (HDE). By having the requirements for acceptance of data from clinical investigations conducted outside the United States the same for all device marketing applications and submissions, greater assurance of the quality and integrity of the data from investigations OUS can be achieved.

The previous version of the regulations stated that investigators located OUS were expected to conduct clinical studies of medical devices in accordance with the “Declaration of Helsinki” or the laws and regulations of the country in which the research was conducted, whichever accorded greater protection to the human subjects.

With the new rule, entitled “Human Subject Protection; Acceptance of Data From Clinical Investigations for Medical Devices,” the Agency amended its regulations on the acceptance of clinical data arising from clinical studies of medical devices conducted both inside and OUS with the purpose of ensuring quality and integrity of the data obtained from these investigations and the protection of human subjects.

For investigations conducted in the US, the rule requires applicants and sponsors to state whether the investigation complied with 21 CFR, parts 50, 56, and 812. These regulations address data quality, integrity and human subject protection and are considered part of the FDA’s GCP regulations.

For clinical investigations conducted OUS, the US FDA requires that these investigations are conducted in accordance with good clinical practice (GCP). Supporting information must be submitted to the agency which proves the conformance with GCP and the data should be available for possible FDA inspections.

Compliance with GCP

Compliance with GCP should be demonstrated by obtaining and documenting the review and approval of the clinical investigation by an independent ethics committee (IEC) and obtaining and documenting freely given informed consent of subjects. This includes individuals whose specimens are used in investigations of medical devices. The new FDA rule imposes obligations on sponsors of medical device studies to make statements and provide information describing in detail how their investigations comply with GCP.

Further requirements vary however depending on whether the investigation is for a significant risk device or a nonsignificant risk device (classification must be done by the clinical study sponsor, but the FDA does not expect foreign IECs to necessarily make such differentiation).

For clinical investigations of significant risk medical devices, the FDA must be supplied with information on the incentives offered to participants. For clinical studies of nonsignificant risk devices, this information should be collected and provided to the FDA only on request. However, information on incentives should be included in the ICFs, reviewed and approved by IECs for both kinds of investigations.

Greater Flexibility

A certain degree of flexibility has been granted by the new FDA rule. In cases of non-complete GCP compliance, sponsors of clinical trials may submit a statement to the FDA justifying the reasons for non-compliance or requesting a waiver. This may be required, for example, when the investigation was conducted in a location where the applicable rules and regulations do not completely cover the provisions of GCP. The statement should explain the reason for not conducting the investigation in accordance with GCP and a description of the steps taken to ensure that the data and results are credible, accurate, and that the rights, safety, and well-being of subjects have been adequately protected.

Which GCP standard to follow?

The new rule states that clinical investigations OUS should be conducted in conformance with GCP. However, the FDA did not specify the GCP standard which should be followed. This is related to the fact that currently there is no one harmonized, international GCP standard for clinical studies of medical devices. ICH E6 – mostly applicable to clinical studies of pharmaceutical products – and ISO 14155:2011 are the two best known international GCP guidelines.

As a result, the FDA has allowed some flexibility when choosing the GCP standard. However, it has officially recognized the ISO standard for medical device investigations as the acceptable standard for clinical studies conducted OUS, and therefore OUS studies conducted in compliance with ISO are deemed to be in compliance with GCP. The FDA stated that sponsors and applicants who follow ISO 14155:2011 in the conduct of clinical investigations will be able to meet the requirement in § 812.28(a)(1) of the new rule as well as the local laws and regulations of the countries where the investigations are conducted.

The application of GCP standards in the conduct of clinical investigations OUS is in addition to the local laws and regulations, to the extent that the local laws and regulations do not incorporate such a standard.

Supporting information

The information which should be submitted to the FDA by sponsors of clinical investigations conducted OUS should include:

The names of all the investigators, and the names and addresses of all facilities that took part in the investigation, such as the investigational sites, laboratories, and specimen collection sites and where records relating to the investigation are maintained.

Information confirming investigator qualifications (typically in the form of CV or other similar document) confirming that the investigator is qualified to serve as an investigator based on his or her training and experience specifically related to the clinical investigation

Description of the research facilities including sufficient information for the FDA to make a judgement about the adequacy of the facilities to execute the investigation and meet its requirements (e.g., whether the site is appropriately staffed and equipped to conduct the investigation and is able to provide the appropriate emergent or specialized care, if required).

A detailed summary of the protocol and results of the investigation

Availability of data for inspections

One condition of the acceptance of data from investigations conducted OUS is that the FDA should be able to validate the data from such investigations through an onsite inspection, or through other appropriate means, if the agency deems it necessary.

Retention of records

Finally, the new rule specifies the period of retention of study records.

It requests that the sponsor must retain the required records of clinical investigations conducted OUS for at least 2 years after an Agency decision on that application or submission or, if the investigation is submitted in support of an IDE, for 2 years after termination or completion of the IDE.

In summary, the FDA recognizes the international nature of clinical research and wishes to accept data obtained in clinical investigations OUS in support of an IDE application, a 510(k) submission, a PMA application, a PDP application, or an HDE application. However, in its new rule, the FDA has updated the criteria for acceptance of data from clinical investigations to help ensure the quality and integrity of data obtained from those studies and the protection of human subjects. The new rule makes it clear that the clinical investigations should be conducted in conformance with a GCP standard such as ICH E6 or ISO 14155:2011 and will require the sponsors to make statements and submit the supporting information demonstrating conformity.


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The ongoing search for the better early-stage clinical trial location: a case study on Australia and Georgia

International biotech and medtech companies are constantly searching for optimal locations for their early stage and proof-of-concept clinical trials. An example of a location that has become increasingly popular is Australia. This is in large part due to the great promotional effort of the government and Australian CROs.

The well known advantages of Australia for clinical trials include a streamlined regulatory process under the Clinical Trial Notification (CTN) scheme under which only ethics approval is necessary and a simple notification to the regulatory authority. Another advantage are the tax credits offered by the Australian government which reduces costs but requires incorporation of a corporate entity in Australia.

Clearly Australia makes a strong case; however other potential locations should not be overlooked. For example, Central and Eastern Europe (CEE) boasts many of the advantages for clinical trial conduct that can be found in Australia and also offers its own unique characteristics which are very well suited. As a result, CEE has increasingly become a popular hotspot for clinical trial conduct over the last couple of decades.

Advantages of CEE

CEE is densely populated with its encapsulated countries ranging in population. On one end of the spectrum there is Estonia with 1.3 million people and 2 million people in Latvia. On the other end of the spectrum there is Ukraine with 42 million and 38.4 million in Poland. Depending on which countries are included into the calculation or not (Russia in particular, would make a major difference with is population of over 140M people) the total population of the region is in the range of 100-300 millions of habitants.

Large and available patient populations has always been a strong point for the CEE region attracting big and small sponsors of clinical trials looking for easier access to patients.

Coupled with centralized healthcare in many CEE countries, patients tend to be pooled together in higher numbers at larger and specialist hospitals which allows for a more efficient patient enrolment process with a smaller number of sites needed to reach the recruitment targets. The average reported recruitment rate in CEE is 10.3 patients per site compared to 7.5 site in Western Europe.

For various reasons, including some economic disadvantages (although these are diminishing), both the physicians and patients in the CEE region tend to be motivated and enthusiastic about their participation in clinical trials, creating a win-win situation for the sponsors of clinical trials. Good patient retention and low drop-out rates is another important advantage.

Fast rates of patient enrolment is one of the crucial advantages when considering the fact that the no. 1 cause of delays in clinical trials is inefficient patient enrolment. According to a TUFTS analysis, 48% of investigative sites either under-enrol or fail to enrol subjects. For Phase II and Phase III trials within the Western environment, 11% of sites fail to enrol even a single patient in a clinical trial. This leads to prolonged study timelines and significant financial and human resource losses.

Centralized systems of healthcare in CEE with large hospitals and effective patient referral pathways; motivated investigators with considerable experience in conducting clinical trials; patients usually enthusiastic about clinical trials and available in large numbers – all these factors form a good basis for effective patient recruitment. When these advantages are coupled with modest costs of clinical trials, CEE becomes a very strong competitor in the global clinical trial market.

Typically, all CEE countries share the advantages discussed but, in this article, we would like to focus on one particular location that is fast becoming a very popular choice for international clinical trials – the Republic of Georgia.

Spotlight on Georgia

Georgia is located in the Caucasus region, at the cross-roads between Europe and Asia. It’s a country of 69,700km squared and with a population of nearly 4 million people. It is also only 2 hours ahead of the Central European Time-Zone. In comparison, Australia is 8 hours ahead.

Let us review the clinical trial environment in Georgia. Like in Australia, the clinical trial approval process is very streamlined. Ethics approvals are granted by independent local ethics committees with typical approval timelines not exceeding 2 weeks. Approval by the special committee on clinical trials within the Ministry of Health which is needed for clinical studies of pharmaceutical products is granted within 21 days. This makes Georgia the fastest location for clinical trial start-up timelines in Europe.

In addition, no import license is required in Georgia for the importation of investigational products. This means faster and easier study start-up; and the whole logistics process is very simple and cost-effective with no duties to pay on the imported clinical trial materials.

The cost of clinical trials is always an important consideration, particularly for smaller and mid-size sponsors. Although no tax credits are available in Georgia, the cost of clinical trials is modest and, in our estimates, the overall costs end up being significantly lower than in Australia.

The standard of the healthcare system is also of course a crucial factor. Visitors to Georgia are often very surprised by the high standard of the healthcare system. The majority of (the nearly 300) hospitals are very modern and have state of the art equipment. Many physicians received training in Western Europe and the United States and speak very good English. There are also many national key opinion leaders available who are extensively published and have participated in many international clinical trials. The two therapeutic areas that are the most popular and most advanced in Georgia for clinical trials are oncology and cardiology.

ICH GCP compliance was introduced in Georgia in 2008 and is fully integrated into national legislation. In general, it is a misconceived concern that CEE countries do not conform to the standards of data quality and GCP demonstrated in Western Europe, Northern America and Australia. Our own experience would prove the contrary, but FDA inspections– an excellent objective measure of the quality of clinical study data – prove this claim too.

On the FDA inspection database and in the figure below, you will find that Georgia has had 17 Bioresearch Monitoring FDA inspections, with 100% NAI (No Action Indicated) reports. To our knowledge, Georgia is the only country in the world to have achieved 100% NAI outcomes in FDA inspections. In comparison, 19 Bioresearch Monitoring FDA inspections have been carried out in Australia within the last decade, with 12 NAI reports and 7 VAI (Voluntary Action Indicated) reports.

The results of the FDA inspections in Georgia are impressive and credible proof that the quality of clinical trials and GCP compliance are both high and worthy of recognition. Evidence exhibits that Georgia is the new rising star location to watch for international clinical trials.

Figure 1:

In conclusion, there are multiple locations in the world competing for clinical trial business and being the top choice for early stage clinical studies. Australia is one of these competitors. More and more countries are now joining the rivalry, including Central and Eastern European countries such as the Republic of Georgia. The positive outcome of this is that there is now greater choice for biotech and medtech companies for clinical trial conduct. This leads to better and faster clinical trials and helps the growth of the entire lifescience sector.


Posted in Biotech, Central and Eastern Europe, Clinical Accelerator, FDA, Medical Devices, Patient Enrolment | Leave a comment

Clinical Accelerator announces collaboration with Reprieve Cardiovascular for developing a Cardiovascular system to treat Acute Decompensated Heart Failure

Clinical Accelerator, a full-service contract research organization, is pleased to announce that it has entered into a collaboration with Reprieve Cardiovascular, LLC for conducting a study aimed at optimally decongesting patients with Acute Decompensated Heart Failure (ADHF). The study will also identify and collect the parameters that can be used to develop the next generation of the Reprieve Cardiovascular System.

A US study showed that 1,000,000 annual admissions of heart failure are caused by fluid retention – a typical clinical feature of ADHF.[1] For such a significant condition, the treatment options remain suboptimal. The leading therapy is administration of furosemide and other diuretics but it has an unreliable impact on fluid loss. The problem is that, although ADHF patients have extra litres of fluid in their body, they may be intravascularly dehydrated. Injecting diuretics however only allows the loss of fluid from these already dehydrated intravasculature. This in turn causes ‘diuretic resistance’, whereby the kidneys attempt to retain the fluid lost after the diuretic in effort to compensate, causing fluid retention to increase and urine output to drop to sometimes even zero.  This can eventually result in so much fluid being retained that it builds up in the patients’ lungs, causing pulmonary edema and death. Clearly a change to the current standard of care needs to be made and this study is attempting to do just that.

About Reprieve Cardiovascular, LLC  

Reprieve is a pioneering medical device company from Massachusetts, United States, with a focus on improving the care and outcome of patients with Acute Decompensated Heart Failure.  Their aim is to provide clinicians with the ability to control patients’ fluid volume with precision which would in turn both improve cardiac care and aid decongestion of ADHF patients.

 About Clinical Accelerator

Clinical Accelerator is an independent clinical trial management organisation operating principally in Central and Eastern Europe, Russia, Ukraine and CIS countries. The organisation offers a broad range of clinical trial services together with dedicated patient enrolment support to worldwide clients in the pharmaceutical, biotechnological, nutraceutical and medical device industries. Clinical Accelerator’s model of operation is designed to achieve significant cost savings for its clients and to guarantee compact timelines for patient enrolment with a firm focus on the quality of clinical trial data.

[1] Costanzo M.R. Agostoni P, Marenzi G. Extracorporeal fluid removal in heart failure patients. Contrib Nephrol 2010;164:173-98. Epub 2010 Apr 20.


Posted in Central and Eastern Europe, Clinical Accelerator, Medical Devices | Leave a comment