Managing Adverse Events and Effects during Clinical Trials

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI July 1999 Column

A clear understanding of the requirements can help manufacturers plan a successful reporting strategy and facilitate decision making during a device study.

Controlled experiments involving human subjects, clinical trials are perhaps the most useful methods for determining the safety, effectiveness, and performance of medical devices. As such, they are required for certain types of new products entering the U.S. or European Union (EU) marketplaces.

The design and conduct of device trials involve many complex issues, including patient protection and the minimization of undue risk. Among the processes that manufacturers must plan carefully are the recording and reporting of adverse events and effects, tasks which many companies find confusing and labor intensive. The FDA reporting regulations are unclear, U.S. requirements are different from those of most other countries, resource-conscious sponsors want to do what is right without burdening investigators unnecessarily, and no company wants to draw unflattering attention to itself needlessly. The review of U.S. regulations and international standards presented here is intended to help clinical trial sponsors establish a wise adverse event and effect policy.

WHAT ARE ADVERSE EVENTS AND EFFECTS?

As used in the healthcare field, the phrase adverse event is a broad-based term that is applicable to many types of medical situations, including research. A guide to pharmaceutical clinical trials, for example, defines adverse events as "unwanted effects that occur and are detected in populations . . . whether or not there is any attribution to a medicine or other cause."¹ Another definition often used by researchers is that adverse events are undesirable deviations in health away from baseline.

In the United States, clinical trials of medical devices are covered by the investigational device exemption (IDE) regulations at 21 CFR 812, which do not include a definition of adverse event. This lack has been a source of confusion for many American manufacturers, who have struggled to understand their reporting responsibilities based on the related words that are defined.

The comparable European and international standards do contain definitions. According to EN 540, "Clinical Investigation of Medical Devices for Human Subjects," an adverse event is "any undesirable clinical occurrence in a subject, whether it is considered to be device related or not."² A similar, but broader, definition is given in ISO 14155, "Clinical Investigation of Medical Devices," which uses the wording "any undesirable clinical occurrence in a subject" without mentioning devices.³

EN 540 goes on to identify adverse effects and the synonyms adverse device effects and undesirable side effects as "device related adverse event[s]."⁴ In other words, an adverse device effect occurs when there is a causal relationship between the device and an adverse event. ISO 14155 provides a similar definition,⁵ but, as for adverse events, 21 CFR 812 does not specifically define adverse device effects. The phrase is used several times throughout the regulations, however, in a manner consistent with the European usage. Section 812.38(c), for example, states that "Upon request or on its own initiation, FDA shall disclose to an individual on whom an investigational device has been used a copy of a report of adverse device effects relating to that use."⁶

The U.S. regulations and European standard also differ in their word usage regarding the severity of an event. EN 540 states that an adverse event or an adverse device effect may be "mild, moderate, or severe and [is] usually unexpected."⁷ The standard then explains that if, as a result of an adverse event during a clinical investigation, a subject has died, or has had to be hospitalized, or has had his or her hospitalization unduly prolonged because of potential disability or danger to life or because an intervention has been necessitated, the adverse event or adverse device effect should be classified as severe. For example, an adverse device effect would be considered severe if it caused a fetal death or resulted in a congenital anomaly or malignancy.

The U.S. IDE regulations use the word serious, rather than severe, and combine serious and unanticipated adverse device effects in one category of requirements. Accordingly, many U.S. companies use the word severe only as a measurement of an outcome, such as "a mild, moderate, or severe headache," and use the word serious in relationship to adverse events and effects. In the United States a serious adverse device effect is one that has a serious adverse effect on health or safety, or causes any life-threatening problem or death, while unanticipated adverse device effects are those "that have not been previously identified in nature, severity, or degree of incidence in the investigational plan or [IDE] application."⁸ (The regulations do not specify in which element of the investigational plan or IDE application anticipated adverse events should be mentioned, but the protocol and consent forms are appropriate places.)

Another phrase related to adverse device effects for which there is no definition in the IDE regulations is unreasonable risk. If a study sponsor determines that adverse device effects present an unreasonable risk to the participating subjects, the regulations specify that the sponsor must terminate the clinical trial within five days.⁹ FDA also has the authority to withdraw its approval of an IDE if it disagrees with the sponsor's determination of the level of risk.

U.S. RECORDING AND REPORTING REQUIREMENTS

Investigator Requirements. The upper diagram in Figure 1 shows the reporting responsibilities of investigators conducting clinical trials in the United States under the IDE regulations. The outer box represents the universe of adverse events; the three inner circles represent those adverse events that are device related, that are serious and unanticipated, and that present an unreasonable risk to subjects, respectively. As the arrows indicate, investigators must record and document all device-related adverse effects, and report device-related adverse effects that are serious and unanticipated to the sponsor and their institutional review board (IRB) within 10 days. In practice, many sponsors establish even shorter reporting deadlines.

Figure 1. Requirements for adverse effect reporting during clinical trials conducted under the U.S. IDE regulations.

Sponsor Requirements. The lower diagram in Figure 1 shows the reporting responsibilities of sponsors for clinical studies conducted under the IDE regulations. The outer box again represents the universe of adverse events, and the three circles represent those adverse events that are device related, that are serious and unanticipated, or that present an unreasonable risk. After receiving a report from an investigator or otherwise learning of an adverse event, sponsors must record all device-related adverse effects, report serious and unanticipated device-related adverse effects to FDA, other IRBs, and participating investigators within 10 working days; and terminate the study within five working days after making a determination that continuing the study presents an unreasonable risk to subjects.

Because clinical trials involving non-significant-risk (NSR) devices can be initiated without submission of an IDE application to FDA, sponsors of such studies are sometimes uncertain about whether to report serious, unanticipated device-related adverse effects to the agency. FDA does expect such adverse effects to be reported to it in writing and receives approximately one such report each month.¹⁰ The Office of Device Evaluation (ODE) reviews the reports to determine if a device should be reclassified as significant risk or if any additional safeguards should be added to a study design. The reports are placed in a file labeled "AEs for NSR Studies" and retained at FDA.

EU REPORTING AND RECORDING REQUIREMENTS

Investigator Requirements. The upper diagram in Figure 2 shows the reporting responsibilities of investigators for studies conducted under European standard EN 540. The outer box represents the universe of adverse events, and the two inner circles represent those adverse events that are device related or severe. All investigators participating in a trial must have (and follow) procedures to record and document all adverse events, with separate files for device-related adverse effects. They must also report all severe adverse events and all device-related adverse effects to the sponsor. All adverse effects that are both severe and device related must also be reported to the reviewing ethics committee.

Figure 2. Requirements for adverse effect reporting during clinical trials conducted under European standard EN 540.

Sponsor Requirements. The lower diagram in Figure 2 shows the reporting responsibilities of sponsors for studies conducted under EN 540. The outer box represents the universe of adverse events; the two inner circles those adverse events that are device related or severe. In consultation with the reporting investigator, sponsors must consider all adverse events and report them to the competent authorities as required by each EU member state. Device-related adverse effects are reported separately. Sponsors also must report all device-related adverse effects and all severe adverse events that have been reported to them to other investigators within 10 days.

ADVERSE EVENT COLLECTION

In addition to receiving (and submitting) the required adverse effect reports described above, sponsors must plan the collection of adverse event information in study protocols. Such data should be collected at predetermined intervals throughout the clinical trial and follow-up period, and at unplanned intervals whenever an adverse event becomes known to an investigator.

The form used to collect adverse event data might include a list of anticipated adverse events and must include a list of those important adverse events for which the sponsor is required to gather incidence data. Each investigator should ask the same question in the same way and should be trained to query subjects about possible adverse events in a neutral manner so as to minimize bias. For example, "How are you doing?" is a less biasing question than "Has anything gone wrong?" Subjects would be more likely to answer the latter question in a negative manner because they think the investigator is seeking information about problems and wish to please him or her. It's a good idea to make up several mock adverse event examples that might arise and then work with the investigators to complete the data forms.

There are two primary models for adverse event and effect collection forms. In the first model, there is space to list several adverse events on a single sheet and a small comment field for each. In the second, there is space for only one event per form and a large comment field. The two models can be combined, with all adverse events listed on a multiple-event form and each device-related adverse effect detailed on a single-event form. Whichever format is chosen, for each adverse event recorded, the following information should be collected on the form:

The top of each form should identify the study, investigator, and subject and include the date the data were collected.

OTHER TERMS FOR UNDESIRABLE EVENTS

Sponsors frequently try to use words other than adverse events to describe undesirable clinical occurrences in order to exempt such events from the recording and reporting requirements. Understanding these terms does little to clarify sponsor responsibilities, but may have some utility in helping manufacturers to assess the complexity of adverse events.

Complications. A medical dictionary defines complication as "an added difficulty, disease, or accident superimposed upon another without being specifically related, yet affecting or modifying the prognosis of the original disease, i.e., pneumonia is a complication of measles and is the cause of many deaths from that disease."¹¹ The complications that arise in medical device clinical trials may not need to be reported to the study sponsor or FDA. For example, an allergic reaction to the anesthesia given during a surgical procedure to implant an investigational heart valve would be a serious complication, but because it is not device related, it would not be reportable. (If, however, there is any doubt as to what substance caused the reaction, the investigator should consider reporting the event.) In another example, a failure of the lead wires for an investigational pacemaker might necessitate a follow-up surgical procedure to replace them. Again, this is clearly a serious adverse event, but it is not related to the device being studied. The lead wires are a separate, commercially available product so the investigator's reporting responsibility is to their manufacturer rather than the study sponsor. Note that both complications are reportable events in Europe.

Underlying Illnesses. Another category of undesirable clinical occurrence is the worsening of an underlying illness. In one case, a manufacturer was evaluating a urinary catheter in women with multiple sclerosis. Subjects were to use the device three to six times daily (as needed) for six weeks to drain their bladders. During the course of the study, several subjects experienced a relapse of their underlying illness. While these occurrences were serious adverse events (many of the women required hospitalization), they did not seem to be related to use of the investigational catheter, so would not be considered device-related adverse effects.

Events Related to Compassionate Use. Under the FDA Modernization Act of 1997, FDA can grant permission to a manufacturer to make investigational products available to single patients or small groups of subjects on the basis of compassionate use.¹² Compassionate use requires prior FDA approval, and the usual rules for reporting adverse events apply. Some U.S. clinical trial sponsors have been unaware of the correct use of this provision and have justified a failure to report adverse effects for investigational products by declaring, in retrospect, that a particular subject was a compassionate use patient, assuming, erroneously, that adverse events associated with compassionate use are not reportable.

Investigator-Related Events. Because many medical devices require a high degree of skill to be used properly, adverse events may result from an investigator's lack of training or practice. For example, a subject may have suboptimal vision as a result of overcorrection during radial keratotomy with an investigational laser. Although the investigator is the primary cause of such adverse events, generally speaking, they should be considered adverse device-related effects. Another example involved the evaluation of a muscle stimulation unit to treat female urinary incontinence. When the device was being inserted into the vagina of one subject, she ran out of the doctor's office screaming that she was being raped. This adverse event was probably related to the investigator's lack of skill in manuevering the device and his lack of rapport with the patient, but it should be reported as a device-related adverse effect since it demonstrated the reaction some women may have to the device.

For trials of some devices requiring a particularly high user skill level, FDA has agreed to allow the first one or two subjects to be considered "practice" subjects. Adverse events that occur with these subjects are reportable, but efficacy data from their experiences need not be included in the final data analysis.

Treatment or Device Failures. A trickier category of adverse event is treatment or device failures. Suppose a subject was given electromagnetic radiation to promote bone healing but the bone failed to heal and even deteriorated. The treatment outcome is a serious adverse event, but investigators may argue that it was not device related because the device did not cause the bone to deteriorate. On the other hand, it could be maintained that it was the failure of the device that led to this result.

In another example, when an ostomy pouch seal opened unexpectedly, the digestive contents of the subject's upper intestine were released onto the skin. The intestinal enzymes caused painful wounds, which were characterized by weeping and oozing. This adverse event was not serious (hospitalization was not required), and it might be argued that it was not device related because the wounds were caused by the digestive enzymes, not by the device. However, it was a failure of the device seal that released the enzymes, so FDA would most likely consider the event a device-related adverse effect. Investigators and sponsors should carefully consider reporting any incidents involving treatment or device failures. Of course, if such failures are occurring frequently, the risks may outweigh benefits to the subject, and it may be unethical to continue the trial.

OTHER REPORTABLE EVENTS

The events that occur during clinical trials may involve multiple reporting requirements. In instances such as the examples described below, it is important for the sponsor to determine the status and reporting requirements of each element of the event.

Protocol Violation. In a clinical trial to evaluate the use of epoxy glue as a space-filling agent to treat arteriovenous malformations (AVM) in the brain, potential subjects were to be excluded if they had a concomitant aneurysm. However, an interventional radiologist cannot determine if an aneurysm is present until after the patient has signed a consent form, been anesthetized, been injected with contrast media, and has had the affected area viewed on a fluoroscope. Suppose that all this had been done and an aneurysm found before a subject's AVM was treated with glue. If the study protocol had made it clear to the investigator's IRB and the consent form had made it clear to the subject that a final determination of study eligibility could not be made until after the procedure had started, then no protocol deviation would have occurred, no adverse event would have occurred, and the subject could be treated using standard methods for AVM plus aneurysm. On the other hand, if neither the protocol nor the consent form discussed the inability of the radiologist to determine subject eligibility until after initiating the intervention, the event must be treated as a protocol violation and reported accordingly.

Suppose further that the ineligible subject had received a glue injection before the radiologist detected the aneurysm. Two protocol violations (enrolling the subject, delivering glue) would have occurred, but unless the glue caused an undesirable clinical occurrence, there would not have been an adverse event. And if the aneurysm had burst during the procedure, that would have been a serious adverse event (a complication) but not a device-related adverse effect. Thus, no adverse effect report would have been required.

Protocol Deviation. In another clinical trial, a subject being treated with an investigational wound dressing suddenly experienced cardiac palpitations and these symptoms were promptly treated, even though such treatment was not within the scope of the study protocol. It was later determined the palpitations were caused by the high potassium concentration in the dressing formulation. In this instance there was both a device-related adverse effect and a protocol deviation that would need to be reported. Although both U.S. regulations and the European standard allow an investigator to deviate from a protocol in order to protect the life or physical well-being of a subject in an emergency, such deviations are reportable.^13,14

Failure to Meet Selection Criteria. It's relatively easy for investigators to determine that subjects meet basic study inclusion criteria—they have the disease or condition under study, they have a particular symptom, etc. However, it can be more difficult to ensure that there are no reasons to exclude particular subjects. If the investigator is not a subject's primary physician, he or she may not be aware that the subject has an underlying illness, exhibits additional symptoms, or has received a prior treatment that makes him or her ineligible for the study. Suppose an investigator discovers that a subject who has responded well to treatment with an investigational device should not have been enrolled in the trial. No adverse effect report would be required since there had been no undesirable clinical occurrence, but the protocol violation of failing to meet selection criteria would need to be reported.

Failure to Obtain Informed Consent. Suppose a clinical trial monitor traveled to a site to observe the treatment of a subject and the investigator could not locate the consent form or the IRB approval. It's not mandatory that the monitor see these documents before a subject is treated, so treatment could proceed on the word of the investigator that the forms were just misplaced. In this situation, if the consent form and IRB approval were found later, no reports would be needed. If they were not, both the failure to obtain consent and the initiation of a study without IRB approval would be considered reportable protocol violations. However, although both events compromised subject safety and welfare, neither would be reportable as an adverse event unless an undesirable clinical occurrence had resulted from the treatment.

CONCLUSION

Developing a successful strategy for recording and reporting the adverse events and effects that may occur during a clinical trial requires careful planning. Although some U.S. companies only collect data on reportable device-related adverse effects, it may be wise to collect information for all adverse events, especially when a new technology is first being studied. FDA sometimes requires more information than what the regulations mandate because it feels such data is either important to ensuring subject safety or necessary to establish product efficacy. Sponsors also need to decide how to handle such issues as complications, underlying illnesses, investigator-related events, treatment failures, protocol violations and deviations, failure to meet selection criteria, and failure to obtain informed consent. Careful preparation up front will go a long way toward easing the decision-making process when adverse events occur later on.

REFERENCES

1. Bert Spilker, Guide to Clinical Trials (New York: Raven Press, 1991).

2. "Clinical Investigation of Medical Devices for Human Subjects," EN 540 (Brussels: European Committee for Standardization, 1993), sect. 3.13.

3. "Clinical Investigation of Medical Devices," ISO 14155 (Geneva: International Organization for Standardization, 1996), sect. 3.15.

4.EN 540, 3.14.

5. ISO 14155, 3.16.

6. Code of Federal Regulations, 21 CFR 812.38(c).

7. EN 540, note.

8. 21 CFR 812.3(s).

9. 21 CFR 812.46(b)(2).

10. Personal communication with ODE staff, CDRH, FDA.

11. Tabor's Cyclopedic Medical Dictionary (Philadelphia: F. A. Davis, 1981).

12. Guidance on IDE Policies and Procedures (Rockville, MD: FDA, January 1998).

13. 21 CFR 812.150.

14. EN 540, 5.5(c).

Nancy J. Stark is a principal, Clinical Design Group Inc. (Chicago).

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