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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.

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