Good Clinical Practice for Medical Device Trials
Background
The medical device manufacturing industry is becoming a major player in health-care
delivery. Physicians treat many illnesses and conditions, such as cardiovascular and
neurological diseases, with medical devices as often as with medicine. In 2008, for the
first time, the FDA received more reports of adverse events from these devices than from
pharmaceuticals.
Medical device manufacturers can conduct clinical trials more easily in Europe where
currently regulatory barriers to clinical testing have less constraints. Consequently, new
innovative medical devices typically come to market in Europe first. Approval for
marketing these devices in the US follows in five to ten years, then an additional five to
ten years for Japan, which has the longest regulatory pathway.
A medical device clinical trial can cost between $5 and $10 million in the United States
or Western Europe and more in Japan. The cost of the same trial conducted in Eastern
Europe will be considerably lower, and in India, China, or Korea, it may be 1/10 as
expensive. Manufacturers are turning to Asian countries for their high-risk, first-in-
human studies and even for their pivotal studies because these countries contain a huge
available human population with limited alternatives for healthcare. Also, the regulatory
barrier to starting a device clinical trial in India, China, or Korea is almost nonexistent.
Problem
Regulations for conducting medical device clinical trials around the world have varied
widely. Complications that arise between trials conducted under different protocols make
bringing a device to market difficult in a stricter country. Data may be considered
questionable given different requirements. The time required to determine acceptability
and perhaps repeat trials may delay the device’s approval, frustrating patients as well as
manufacturers. In addition, the safety of human subjects participating in the clinical trial
and ultimately patients is in question in countries with lax regulations and resultant
uncontrolled clinical settings. Less rigorous studies cannot ensure consistent performance
quality thus potentially jeopardizing the health the devices are meant to protect.
Standards to harmonize these trials will ensure safety, effectiveness/performance, and
quality, as well as help to promote commerce, and may ultimately ease suffering.
Approach
In 1993, the European Committee for Standardization (Comité Europeen de
Normalisation, CEN) published standard EN 540, a precursor of the international
standard ISO 14155. Like the International Organization for Standardization (ISO), CEN
is an international nonprofit organization providing a platform for cooperating, volunteer
organizations to develop consensus standards. In 1996, ISO and CEN joined forces to
create the first version of ISO 14155, which repeated EN 540 standards. Almost
immediately, the two organizations formed parallel working groups (WGs) to expand the
standard. WG4 of ISO’s TC (technical committee) 194 developed more elaborate general
requirements in ISO 14155 part 1, while CEN’s WG elaborated part 2, requirements for
the clinical investigation plan. In 2003, the organizations published both.
ISO 14155 includes the following:
Step-by-step methodology, record-keeping, and reporting requirements
Ethical and legal approval requirements
Steps to construct a protocol
Risk assessment
Case report (data collection) forms
Instructions for preparing a final report
ISO 14155 defines procedures for conducting clinical investigations of medical devices
that will
Protect human subjects
Ensure proper scientific conduct in the clinical investigation
Assist sponsors, monitors, investigators, ethics committees, regulatory authorities,
and bodies involved in assessing medical device conformity
The requirements that ISO 14155 specifies ensure that the clinical investigation
establishes the medical device’s performance by mimicking normal clinical use. An ISO
14155 trial will reveal adverse events under normal use and allow researchers to assess
acceptable risks while considering the device’s intended performance.
In their last meeting before publishing ISO 14155 part 1, the TC 194 WG 4 members
documented outstanding points which they believed needed work in a revision.
Consequently, immediately after publishing the 2003 version, ISO voted a new work item
to continue evolving the general requirements.
ISO and CEN both work to make development, manufacture, and supply of products and
services safer, cleaner, and more efficient. Their standards also ease trade between
countries and make that commerce fairer. ISO 14155 confronts several ethical and fair
trade issues by leveling the playing field for all countries in conducting device trials.
In particular, medical tourism creates conflicts and safety concerns. Those countries
where devices become available because of more lax requirements benefit financially, but
with safety risks for their population. For example, many thousand American patients
with enough money to travel purchase a package tour to Europe or India that includes
surgery (for a spinal disc, for example), hospital stay, airfare, hotel stay, and follow-up
visits. Whether one argues that citizens of these countries benefit first from new,
innovative devices or that they serve as the proving ground for the rest of the world,
ethical issues abound.
Outcome
Experts from the United States, Europe, and Japan have agreed on a standard that, at
minimum, met the regulatory requirements that already exist in their respective countries.
This standard helped to level the field among countries. The standard raises ethical,
record-keeping, and reporting expectations to the level considered the norm in the
pharmaceutical industry, a related medical sector.
ISO 14155 standards will serve several groups involved in developing and regulating
medical devices:
Medical device manufacturers who sponsor clinical trials to gain human data
about the safety and performance of new devices
Physicians and other healthcare practitioners who serve as investigators and
implement and oversee trials
Hospital institutional review boards or ethics committees who review the trial
protocol (investigation plan) to protect the welfare of human subjects
Regulators such as the FDA who approve applications to conduct a clinical trial,
review the final data to assess safety and performance of a new medical device,
and approve or deny applications for commercialization
For patients, ISO 14155 helps provide access to innovative technology in a more timely
and safe manner.