|Best of Both Worlds: SOPs for Device Trials in Europe, Part 1|
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Conducting clinical trials in Europe can be easier and can provide a faster route to market than conducting trials in the United States. However, the regulatory path can be tricky to navigate. European regulators recognize both ISO 14155, “Clinical Investigation of Medical Devices for Human Subjects—Parts 1 and 2,” and the ICH-GCPs, “The International Conference on Harmonization—Good Clinical Practice” (document number E6).1,2
For device manufacturers that decide to conduct their first-in-human trials in Europe, deciding which document to follow can be difficult. Following ISO 14155 is a more straightforward process and would likely bring a device to market faster. Following the ICH-GCPs imposes a more burdensome path and would probably take longer, but following this standard would be more likely to result in data that are usable in the United States.
So the dilemma for device manufacturers is which document to follow: ISO 14155 or the ICH-GCPs? The answer is not so simple: don't follow either ICH or ISO. Instead, write your own standard operating procedures (SOPs) for international trials using ISO procedures as a base and adding ICH-GCP components as necessary. If this is done methodically, the procedures will also meet FDA requirements but won't place additional burdens on European investigators. Whenever possible, it is best to meet all applicable standards—and the spirit and intent of the law.
It is important to note that ISO 14155 data may be of limited value for market approval in the United States. But by adding ICH-GCP components to the mix, you will come out with SOPs that meet and even exceed the requirements of 21 CFR 812.
This two-part article examines the feasibility of using the ICH-GCPs for device trials. It reviews the eight sections of the ICH-GCPs, comparing and contrasting them with ISO 14155 to determine whether the ICH document is relevant to medical device trials. Part 1 reviews the first four sections of the ICH-GCPs; Part 2 will review the last four sections.
ISO 14155: Medical Device Trials
ISO 14155 is clearly designed for clinically investigating devices.1 The standard was written by industry and regulatory experts from the United States, Europe, and Japan, but contributions were not limited; any ISO member country could have sent experts to assist in writing the standard. The most recent version was issued in 2003. The standard is under revision and may be reissued in about two years. However, some European countries have strongly objected to the revision, so it is by no means certain that a revised standard will be issued.
Unfortunately, the ISO standard is weak. Both Part 1 and Part 2 of the standard fall short of the current level of ethical and regulatory practices in medical device clinical trials. Both parts are silent on numerous critical issues. Moreover, FDA does not endorse ISO 14155. The U.S. vote on the 2003 version was a condemnation by faint praise: “yes, but with immediate revisions.” The Japanese vote was an outright “no.” It is encouraging to know that ISO mandates that a standard be revisited every three years to ensure that it keeps pace with current technologies and thinking.
ICH-GCPs: Pharmaceutical Trials
The ICH-GCPs are designed for clinically investigating pharmaceuticals.2 The guidance was written by industry and regulatory representatives from the United States, Europe, and Japan. Unlike ISO 14155, the ICH-GCP document is embraced by the FDA Center for Drug Evaluation and Research. FDA published it in the Federal Register and later proposed to adopt it as the basis for accepting foreign clinical drug data.3,4 The guidance set the standard for clinical research practices when it was released in 1996.
However, the ICH-GCPs have some drawbacks. They are now 10 years old. The committee that wrote them has disbanded, and most of the members have moved on to new jobs or have retired. Major areas are completely lacking in the ICH document. It lacks a comprehensive section on data management, particularly on managing electronic data. Although a mechanism for feedback to the Secretariat is provided, no new revisions of the ICH-GCPs are currently planned.
A Strategy for Developing Your SOPs
The following review is organized based on the sections of the ICH-GCPs. Within each section, correlating information from ISO 14155 is included. Subsections of the ICH-GCPs are skipped when they are consistent with standard medical device practices. Recommendations for preparing corporate SOPs are also included after each item within a section.
Because the first section of the ICH-GCPs is a glossary, it is not reviewed separately. Instead, important terms are discussed throughout the remaining sections.
Section 2. This section of the ICH-GCPs covers the general principles of trial design.
Item. “Medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist,” states the ICH-GCPs (2.7). By contrast, ISO says that investigators should be appropriately qualified practitioners legally entitled to practice (ISO 14155-1, 10.2.a). In the device world, investigators may be optometrists, acupuncturists, osteopaths, enterostomal therapists, or other medical specialists.
Recommendation. Specify in your corporate SOPs that the trial investigator must be trained and licensed to use the investigational device. Then, ensure that the investigator is trained to use the device correctly by conducting a training program. Include a statement in the protocol that all medical needs outside of the trial are available to the subjects and that it is each subject's responsibility to seek appropriate medical care.
Item. “Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice” (2.12). Neither ISO 14155 nor 21 CFR Part 812 ask for investigational devices to be made per GMPs because it would make the investigation of early-developmental devices impossible.
Recommendation. Many first-in-human devices do not comply with good manufacturing practices. Always follow the ISO 14155 practice, where the emphasis is placed on an assurance of safety as well as an extensively prepared medical risk assessment and investigator's brochure.
Section 3. Institutional review boards (IRBs) and independent ethics committees (ECs) are covered in this section.
Item. Most of Section 3 of the ICH-GCPs deals with the organization and functionality of IRBs. IRBs are referred to as ECs in ISO 14155. ISO is mostly silent on the issues of how IRBs or ECs should organize and conduct themselves. ISO 14155 views this as a country-specific regulatory issue that cannot be dictated by a standard.
The ICH-GCP suggestions are similar to FDA's requirements, and in fact, these suggestions were largely incorporated into Europe's Clinical Trials Practice Directive of 2001.5 This directive applies to clinical trials on medicinal products, but the consensus in the device community is that the EC rules for pharmaceuticals will ultimately dictate the rules for medical devices.
Recommendation. Expect the ethics committee rules in the Clinical Trials Practice Directive to become the standard across Europe. Write your corporate SOPs accordingly, but be prepared for possible country-specific variations.
Item. The ICH-GCPs (in 3.1.4) ask for continuing review of ongoing clinical trials, a requirement that is consistent with FDA procedures and U.S. regulations for medical devices. But ISO 14155 is silent on the issue of continuing review, and this is an important weakness of the standard.
Recommendation. Plan to ask the ECs to perform annual reviews of longer trials because the ongoing reviews will help both with ethical conduct issues and with later FDA acceptance of the trial data. It may require some investigator education to accomplish the ongoing reviews because European device investigators will question the necessity and the challenge to their authority.
Section 4. In section 4, the ICH-GCPs examine the role of trial investigators.
Item. The ICH-GCPs remind investigators that “clinically significant laboratory values” are also adverse events, and medical care should be provided if they are trial related (4.3.2). ISO 14155 doesn't mention laboratory values as potential adverse events.
Recommendation. If a clinically significant change in values is device related, such an event should be recorded, reported, and medically addressed. It is essential that investigators report serious adverse events to the sponsor immediately, and this should be clear in your SOPs.
Item. Investigators are instructed to “make a reasonable effort to ascertain the reason(s)” a subject may have prematurely withdrawn from a trial (4.3.4). ISO 14155 is silent on this topic.
Recommendation. Compliance with the requirement is not a great burden, and the information as to why a subject decided to withdraw from a trial may be of great value for further protocol or product development. Your SOP should follow the ICH-GCP strategy.
Item. The ICH-GCPs say that subject-recruitment procedures (e.g., advertisements) must be reviewed and given approval by the IRB/EC (4.4.1). ISO 14155 does not address this topic, and it is a weakness of the standard.
Recommendation. The global convention is to treat all information that may arrive in the hands of the subject as part of the consent form. Write your SOPs to follow the ICH-GCP strategy.
Item. The ICH-GCPs allow the protocol to substitute for an investigator agreement (4.5.1). This possibility is contrary to the expectations of ISO (and FDA), which require a separate and distinct agreement between the investigator and sponsor. In addition, the investigator agreement is expected to contain additional elements beyond those in the protocol itself.
Recommendation. Obtaining an investigator's signature on the protocol to confirm that the investigator has read the protocol and agrees to implement it is fine. But don't assume this step will substitute for an agreement in which the investigator confirms his or her qualifications and agrees to follow IRB and EC requirements and his or her country's regulatory requirements.
Item. The ICH-GCPs identify four separate transactions that should be documented for investigational product accountability: records of the product's delivery to the site, inventory at the site, use by each subject, and product returns to the sponsor. These records should include dates, quantities, batch and serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records that adequately document that the subjects were provided the doses specified by the protocol and should reconcile all investigational product(s) received from the sponsor (4.6.3).
ISO 14155 is not as specific in its accountability requirements. Sponsors should “ensure accurate device accountability and traceability systems” (Part 1-8.2.o) and investigators should “ensure that clinical records [are] clearly marked to indicate that the subject is enrolled in a particular clinical investigation” (Part 1-10.3.r). ISO 14155 is remiss in that it does not require accountability of comparator devices or records of device exposure.
Recommendation. Ultimately, you want to be able to track every device as it changes custodianship during a trial—from sponsor to site, site to subject, subject consumption or return to site, and site return of unused devices to sponsor. This is required by FDA in 812.140(b)(1), which states that sponsors shall keep records of device shipment and disposition. The tracking process will be different for disposable, reusable, or implantable devices. It will be different for items that can be partially consumed, such as a bottle of liquid or a dressing that can be cut into pieces. It will be different for capital equipment, such as imaging equipment or IVD systems, for which exposure to or use of a device, rather than consumption, is tracked. It will be different for devices for which each device is given a serial number as opposed to being tracked by lot. And don't forget, comparator devices must be inventoried too. Your SOPs should reflect the types of devices you develop.
Item. The person who conducts the informed-consent discussion is required to sign and date the informed consent (4.8.8). A witness may sign and date the consent if neither the subject nor the subject's representative can read (4.8.9). These statements seem odd to device people. ISO 14155 requires the clinical investigator to sign and date the consent, and the concept of delegating this responsibility never comes up (Part 1-6.7.e). ISO 14155 also does not provide for the possibility of a witness, nor does it require one.
Recommendation. Your SOPs can allow anyone to sign a consent form if the IRB or EC approves, but the meaning of every signature should be clearly stated in the form. If the trial discusser signs, the fine print should read “I verify that I explained the trial as described in the protocol, gave the subject an opportunity to ask questions, and answered those questions.” If the investigator signs the consent but didn't discuss the trial, the fine print could read, “I verify that I trained the trial discusser in the process of obtaining informed consent and in the details of this protocol.” If you have a witness sign the consent form, the fine print could read, “I verify that I observed the trial discusser explain the trial and answer the subject's questions.” Thinking about what a signature means will help you decide whether it is necessary.
Item. Trial subjects are sometimes paid for participation, and the ICH-CGPs provide for the possibility of prorating subject payments in the event that a subject withdraws from a trial early. The possibility of prorating payments should be included in the informed-consent form (4.8.10.k). ISO 14155 also allows for the possibility of financial compensation for participation (Part 1-6.7.3.f.2), but does not consider the possibility of prorating payments.
Recommendation. Although many device trials are short in duration, the follow-up period for some trials can be several years. Subjects who fail to keep follow-up visits deprive the sponsor of needed data. It is fair that subject payments be prorated, so long as it is disclosed ahead of time. Write your SOPs to reflect the practice you intend to follow.
Item. The informed-consent form should contain information about whom to contact in the event of a trial-related injury (4.8.10.q). It should state the approximate number of subjects in the trial (4.8.10.t), and subjects should receive a copy of their signed and dated written consent forms (4.8.11). None of these issues is discussed in ISO 14155.
Recommendation. Your SOPs should address each of these issues, specifying your expectations.
Item. The ICH-GCPs discuss nontherapeutic trials and require that the subject personally give consent, i.e., a personal representative cannot give consent on the subject's behalf (4.8.13). Nontherapeutic trials are not acknowledged in ISO, although they are commonly done in certain industry sectors such as dermal contact products or contact lenses. Even FDA acknowledged the use of healthy, employee volunteers as subjects of certain clinical trials in the preamble to Part 812.6
Recommendation. Write SOPs that make ethical sense for your particular products. If nontherapeutic trials are a part of your product development process, prepare SOPs to cover them.
Item. The ICH-GCPs state that written or electronic changes or corrections to case report forms (CRFs) should be dated, initialed, and explained (if necessary), and they should not obscure the original entry, to maintain an audit trail. Finally, they state that “sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented” (4.9.3). None of these elements are discussed in any detail in the ISO standard, but with the exception of sponsor representatives making changes, they are common industry practice.
Recommendation. Your corporate quality system should follow the ICH-GCP methods for CRF corrections, but don't let sponsor representatives write on the forms.
Item. For the ICH-GCPs, documents should be retained until at least two years after the last approval of a marketing application or two years after the clinical trial ceased (4.9.5). ISO 14155 is silent on this and all other time frames, bowing to local regulatory requirements.
Recommendation. Most sponsors keep their clinical records for as long as the device is on the market. When a device is replaced by newer versions of the model that underwent trials, records are kept indefinitely.
Item. Per the ICH-GCPs, financial aspects of trials should be documented in an agreement (4.9.6). ISO 14155 does not cover business matters.
Recommendation. Most companies follow the practice of contracting for financial remuneration to the investigational sites in financial agreements that were separate from the investigator agreement.
Item. Section 4.11 of the ICH-GCPs describes the adverse event reporting requirements of investigators. One notable provision is that trial documents may list certain serious adverse events as nonreportable (4.11.1). This is a continuing question among device companies: if an adverse event is absolutely expected (an incision, say, for an implantable device), does it have to be reported? The ICH-GCPs resolve the question by saying no, as long as you list the nonreportable events in the trial documents. The ICH-GCPs also say that investigators should write follow-up reports on reportable serious adverse events (4.11.1). ISO 14155 neglects to mention this common practice.
Recommendation. Write your SOPs to divide device-related adverse events into useful categories, such as the following:
The first of this two-part series has reviewed sections 1–4 of the ICH-GCPs and the corresponding topics in ISO 14155. In many instances, the guidance provided in the 10-year-old ICH-GCPs is useful for medical device trials in Europe. For areas of conflict, common device practice should define a company's SOPs, especially if the company is planning to use the data for future U.S. trials. For each case, appropriate policy and procedure strategies have been described that will allow medical device companies to meet the ethical and legal requirements. Part 2 continues the examination of ISO 14155 and sections 5–8 of the ICH-GCPs.
Nancy J. Stark is founder and president of Clinical Device Group Inc. (Chicago). She can be reached at firstname.lastname@example.org.
1. ISO 14155, “Clinical Investigation of Medical Devices for Human Subjects—Parts 1 and 2” (Geneva: International Organization for Standardization, 2003).
2. ICH-GCPs, “Harmonized Tripartite Guideline, Guideline for Good Clinical Practice—E6” (Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1996).
3. Federal Register, 62 FR:25692–25726, May 9, 1997.
4. Federal Register, 69 FR:32467, June 10, 2004.
5. Directive 2001/20/EC, “Clinical Trials Practice Directive,” Official Journal of the European Communities, April 4, 2001.
6. Federal Register, 45 FR:3740, January 18, 1980.