Getting to First-in-Man Studies

Last month I had the opportunity to attend the CRT2011 meetings in Washington, DC. My purpose was to report on the March 1 "Workshop with the FDA" on device development in the US. My whitepaper today is to combine the cardiovascular message from "Workshop with the FDA" with significant findings published by AdvaMed in a November 2010 publication titled "FDA Impact on US Medical Technology Innovation." I hope to take a deeper look into the why behind the what, and then hopefully propose a way forward.

The Device Development 'Ecosystem'
When I talk about innovation, I am referring to either the conception and invention of new devices or to incremental improvements to existing devices. When I talk about development, I am referring to the bench, animal safety, pre-clinical and clinical studies that occurs before FDA clearance or approval or EU certification. When I use the adjective "clinical" in this paper, I am referring to human studies. By the way, the 'ecosystem' is the new buzzword for global device development, including regulatory, economic, and resource availability effects.

  
While the US is still the leader in medical device innovation, development has largely fled to other continents. Most first-in-man studies are done in Europe, Asia, Latin or South America. The reasons are a ready patient population, modern hospital facilities, and English-speaking physicians trained in Western medicine and good clinical practices.

But all of this begs the question, how is it that it is easier to get first-in-man trials approved in countries outside the US?

First-in-Man Approval in the US
In the States, first-in-man trials require the same review process as any other clinical trial, which means you must get an IDE from FDA if the device is significant risk. While FDA reports an average of 27 days to get IDE approval from time of IDE submission, and six months if you count from first communication, Advanced reports an average of 14 months to get an IDE approval from the time of first communication with FDA. The long lead-time results in costs and delayed revenue stream that venture capital firms are becoming unwilling to fund.

  
First-in-Man Approval in the EU
In many European countries the Ethics Committees (ECs) have the real control over approval for clinical trials; the National Authority is only notified of the trial's initiation but doesn't take an active review role. The Notified Body serves as the inspection arm and reviews certification sometime after the device is commercialized. This means the level of review for first-in-man studies rests in the hands of the Ethics Committees, which are usually local and most certainly not funded or trained to the level of FDA.

I can't find any figures for the time required from first EC submission to initiating the first-in-man study, but AdvaMed reports that a 510k-level device requires an average of only seven months to certification. When you compare the benefits of earlier revenue stream with the inconvenience of implementing studies on the other side of the ocean, it is small wonder that American manufacturers have moved their development process to Europe.

 

The Global Harmonization Task Force
As an aside, the Global Harmonization Task Force (GHTF) has attempted to close the gap between continents but it lacks regulatory teeth. Its documents are written with more hope than how-to, (Medical devices should be designed and manufactured in such a way that...they will not compromise the clinical condition or safety of the patients....), and an Australian report says GHTF is closing shop and will reopen as "regulators only."

The Flight of Device Development
Both the speakers at CRT2011's Workshop and the report from AdvaMed draw a disturbing picture of the flight of medical device development to Europe. Sean M Salmon of Medtronic (VP and General Manager, Coronary and Peripheral) said he does 95% of his clinical trials outside the US, "why bother with FDA?" He acknowledged that US investigators feel left out and that he, too, is frustrated with the US system. But exceptional competencies exist around the world and there is no reason to restrict clinical studies to the US.

As device development moved to Europe and to other countries, US investigators fall increasingly behind the curve. One trend is the development of international relationships between US and outside-US hospitals (example) whereby American physicians can participate in international clinical trials by practicing outside the country.

So if manufacturers have found a way to go to Europe and elsewhere, and investigators are finding a way to go to Europe and elsewhere, where does that leave the American patient? According to the Medical Tourism Association, medical tourism is one of the fastest growing industries within healthcare. Traveling to another country to receive healthcare is the pathway of choice for many Americans seeking leading-edge care. Many insurance companies, such as Aetna, the Blues, WellPoint, and others, have implemented medical tourism pilot programs to support such care.

The workshop with the FDA can be summarized in a few simple statements:
[1] Device development has moved to Europe.
[2] US investigators are following.
[3] Device availability is delayed two-to-five years in the US.
[4] Medicare reimbursement doesn't necessarily follow FDA clearance/approval.
[5] Patients are following the new technologies through medical tourism.
[6] As development leaves the US, innovation and jobs will follow.
[7] The device industry is struggling under Healthcare Reform's federal excise tax on sales.

FDA's Response
Next at the workshop it was FDA's turn to speak. Dr. Ashley Boam (Branch Chief, Interventional Cardiology Devices, CDRH, FDA) summed FDA's position up simply: "Bring us better pre-clinical data."

Pre-clinical Strategies
In addition to ISO 10993 biocompatibility testing, preclinical animal testing to investigate potential harms to humans before doing first-in-man studies may be necessary. Such testing is often done in large animals in order to mimic clinical use of the device. You need to select a species whose anatomy can receive the device or provide reasonable feedback regarding human use.

There is no single, prescribed protocol for preclinical studies. Instead the intended use of the device is reproduced as best as possible. The potential harms from the device are identified from the literature or prior experience, including biological harms, mechanical harms, electromagnetic harms, software harms, harms from human error, or harms from any other source. Finally a protocol is developed to investigate the device's safety and performance. The species of animal, sample size, endpoints and pathology must all be justified. The protocol should be approved by an Animal Care and Use Committee and implemented in conformance with ISO 10993-11 "Systemic toxicity" Section 6. FDA favors the involvement of an experienced toxicologist in the development of the protocol and the final report.

For example, an embolization system was evaluated in a rabbit model, a thrombectomy device was evaluated in porcine whose arteries had been injected with fribrin-laden thrombi, a robotic spinal surgical system was evaluated in a porcine model, but I could find no accepted animal model for evaluating joint surface repair or osteonecrosis.

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CDG Can Help with Pre-Clinical Strategies

Dr. Dan McLain, convener of ISO 10993-11, is available to assist with pre-clinical strategies for your device. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

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Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Comments

[Russell Roiko]

What is the typical path for devices approved in Europe to get approved in the US?

[Philip Needham]

Hi Nancy,
I'd treat the "average 7 months in Europe" with caution. Here in the UK the local ethics committees now come under an overarching national body, making involvement of local clinicians difficult and resulting in extended timescales. Other States in mainland Europe seem to have a more pragmatic approach to trials.

[MeneResearch]

I found this paper very useful, and agree all of them, many thanks, Sule Mene