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.

Sources:

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-classification-database

https://clinicalaccelerator.com/clinical-trials-in-georgia/

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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.

 

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Clinical Accelerator collaborates with Thrombolytic Science International to study a tPA/mutant pro-urokinase dual regimen for thrombolysis in acute myocardial infarction

Clinical Accelerator, a full-service contract research organization, has entered into a collaboration with Thrombolytic Science International (TSI) to conduct a phase II randomised, multi-centre, open-label, parallel group mechanistic study using TSI’s dual treatment regimen in patients with ST elevation myocardial infarction (STEMI).

The purpose of this clinical trial is to affirm the safety and efficacy of sequential thrombolytic therapy with mutant pro-urokinase and low dose tissue plasminogen activator (tPA) as a potentially safe, simple and early reperfusion treatment for STEMI in comparison with standard of care percutaneous coronary intervention.

TSI’s thrombolytic treatment regimen is based on the endogenous human fibrinolytic system. It uses a low dose of tPA, the approved thrombolytic agent, followed by mutant pro-urokinase, a more stable and safer version of well-studied thrombolytic, pro-urokinase (proUK).

The dual regimen concept was validated in the phase II trial PATENT trial, which showed that a dual treatment of tPA and proUK was more effective and safer than either activator alone.

This novel treatment with mutant proUK is based on the pioneering work of Dr Victor Gurewich, Professor of Medicine at Harvard Medical School, a researcher and a TSI co-founder.

 

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Clinical Accelerator announces collaboration with Nasaleze International Ltd for a clinical study of Nasafort- a fast acting nasal spray for allergic rhinitis

Clinical Accelerator, a full-service contract research organization, is pleased to announce that it has entered into a collaboration with Nasaleze International Limited, for conducting a pivotal study for Nasafort: a nasally applied cellulose powder in seasonal allergic rhinitis (SAR) in adults with grass pollen allergy during 4 weeks of the pollen season. It will be a randomized, double-blind, placebo-controlled and multi-center medical device investigation conducted in Ukraine.

Allergic rhinitis is a very common chronic condition affecting 65 million people in the United States. Although the condition is minor medically, the symptoms are troublesome. A range of treatments and remedies are available on prescription and over the counter, but nasal steroid sprays are considered the most effective. There is however a need for greater palliative treatment of allergic rhinitis and better prevention.

Nasafort is sold in Europe as a Class 1 medical device for managing hay fever. It is applied in the nostrils via a patented puffer device. When the bottle is squeezed, a puff of fine cellulose powder (Hydroxypropyl methylcellulose (HPMC)) is released into the nose and reacts with moisture on the mucous membrane to form a gel layer. This layer acts as a barrier between the nose and allergy particle in the air, thus blocking them.

Previous studies have shown its efficacy in the absence of any clinically significant adverse effects. The purpose of this pivotal study is to obtain additional evidence of the efficacy and safety of Nasafort in adult patients with SAR aged 18 to 40 years old with SAR to grass pollen.

About Nasaleze Ltd.

Nasaleze International Limited is an Isle of Man based medical device company which has developed Nasafort (also known as Nasaleze and other trade names), a fast-acting nasal spray for the treatment of allergic rhinitis.  It is currently available in Boots, under the name of Boots Allergy Barrier in the United Kingdom, other countries where the product is sold, United States, Russia, China, France, Germany, Sweden, Netherlands, India, Korea and 15 + other countries.  Nasaleze is registered with FDA in the USA.

About Clinical Accelerator

Clinical Accelerator is an independent clinical trial management organisation operating principally in Central and Eastern Europe. The organisation offers a broad range of clinical trial services together with dedicated patient enrolment support to worldwide clients in the pharmaceutical, biotechnological and medical device industries.

Clinical Accelerator employs a cost-effective model of conducting clinical trials with a special focus on their accelerated implementation. The ultimate goal is to bring much needed pharmaceutical products and medical devices to the market faster.

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VisCardia Announces Completion of Enrollment and Three Month Follow-Up Visits for Its VisONE® Heart Failure Pilot Study

Below, we are re-publishing with permission the press-release issued by VisCardia Inc. on April 22, 2019

PORTLAND, Ore.–(BUSINESS WIRE)–VisCardia Inc., a privately held medical device developer, announced today it has completed enrollment and three month follow-up visits of the company’s VisONE® implantable system pilot for medical refractory heart failure patients with reduced ejection fraction and preserved ventricular synchrony.

“VisONE provides an innovative and unique approach for improving cardiac performance in medical refractory heart failure patients who currently have no alternative treatment options”

The VisONE Heart Failure pilot is a prospective open label, single arm, multi-center study conducted in select European countries to evaluate the safety of VisCardia’s novel VisONE implantable system for delivering Asymptomatic Diaphragmatic Stimulation (ADS) as a novel heart failure therapy. “Our objectives are to demonstrate that the promising and consistent evidence of therapeutic efficacy observed to date with the VisONE implantable system can be delivered on a safe and chronic basis. We look forward to sharing our study results over the next upcoming months in peer reviewed scientific conferences,” said VisCardia’s Director of Medical Affairs, Dr. Michael Mirro. The primary measures of the study are safety of the minimally invasive laparoscopic surgical implant procedure and implanted system, with secondary endpoints of heart failure therapeutic efficacy, including acute hemodynamic parameters, cardiac function and heart failure status.

“VisONE provides an innovative and unique approach for improving cardiac performance in medical refractory heart failure patients who currently have no alternative treatment options,” said Dr. Michel Zuber, the principal investigator at the University Hospital in Zurich, Switzerland. “Our expectations are that the chronic improvements to clinically accepted endpoints will mirror those observed during our early proof of concept studies.”

Dr. Tamaz Shaburishvili, from the Heart & Vascular Clinic in Tbilisi, Georgia, one of the study centers, stated that, “While patient enrollment is an accomplishment in any clinical study, we believe the rapid enrollment rate for VisONE can be attributed to the promising evidence to date, the minimally invasive implant procedure, combined with the lack of options for these patients in our center.”

About VisONE® ADS Therapy

The VisONE implantable system delivers VisCardia’s proprietary Asymptomatic Diaphragmatic Stimulation (ADS) therapy for improving cardiac function. By electrically stimulating the diaphragm in an asymptomatic manner, transient intrathoracic pressures gaited to cardiac activity are applied against the cardiac walls, improving both cardiac filling and output. The therapy is non-invasively adjusted and programmed using an external programmer to improve hemodynamic benefit and eliminate undesired stimulatory side effects.

About VisCardia

VisCardia, based in Portland, OR, is developing a novel implantable device therapy for treating heart failure, a condition that afflicts 10 million patients in the U.S. and Europe. To learn more about VisCardia, visit: http://www.viscardia.com.

* The study is conducted by Clinical Accelerator

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Clinical Accelerator announces collaboration with Archivel Farma in a phase IIa Clinical Trial for RUTI®: a therapeutic vaccination against Multi-Drug Resistant Tuberculosis

Clinical Accelerator, a full-service contract research organization, is pleased to announce that it has entered into a collaboration with Archivel Farma, for conducting a phase IIa clinical trial for their therapeutic vaccine RUTI® against multi-drug Resistant tuberculosis. The double-blind, randomized and placebo-controlled trial will take place at several specialist tuberculosis sites in the Ukraine alongside with Groningen University Medical Centre in the Netherlands, and will be testing the vaccine’s safety and immunogenicity.

The RUTI® vaccine stimulates host immune effectors directed at bacilli that persist under antibiotic therapy of tuberculosis. It works in tangent with standard antibiotic treatment, improving the efficacy of the standard antibiotic treatment and reducing the chance of recurrence. Clinical safety and immunogenicity has already been proven in healthy volunteers and in individuals with latent tuberculosis infection, both HIV +/ in phase I and II studies. The purpose of the current study is to show that it is safe in patients with multidrug-resistant (MDR-) TB at two different time points of vaccination.

With this study, Archivel Farma aims to evaluate the safety and immunogenicity and to explore the efficacy as the reduction of bacillary load in the sputum of the novel anti-TB vaccine RUTI®, and collect data that could potentially assist in pin-pointing the optimal time to administer RUTI®.

About Clinical Accelerator

Clinical Accelerator is an independent clinical trial management organisation operating principally in Central and Eastern Europe. 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.

About Archivel Farma

Archivel Farma is an R&D biotech company that develops immunotherapeutic agents to tackle unmet medical needs. The company was founded in 2005 and has ever since been committed to fighting tuberculosis which affects 10 million people every year.

The Director of Clinical Accelerator, Nik Nikitin MD, PhD says, there are significant unmet medical needs in the management of multi-drug resistant tuberculosis (MDR-TB). A large proportion of MDR-TB cases occur in Central and Eastern Europe where Clinical Accelerator runs its clinical studies. The novel anti-TB vaccine RUTI, which is being developed by Archivel Farma can make an important contribution to the fight against MDR-TB in our region of operation and globally. On behalf of Clinical Accelerator, we will be making every effort to make sure that the study is implemented within compact timelines and with high quality.

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