irb review of adverse events in investigational drug studies

IRB Review of Adverse Events in Investigational Drug StudiesAuthor(s): Ernest D. Prentice and Bruce GordonSource: IRB: Ethics and Human Research, Vol. 19, No. 6 (Nov. - Dec., 1997), pp. 1-4Published by: The Hastings CenterStable URL: http://www.jstor.org/stable/3564433 .

Accessed: 12/06/2014 20:40

Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at .http://www.jstor.org/page/info/about/policies/terms.jsp

.JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact [email protected].

.

The Hastings Center is collaborating with JSTOR to digitize, preserve and extend access to IRB: Ethics andHuman Research.

http://www.jstor.org

This content downloaded from 195.78.109.54 on Thu, 12 Jun 2014 20:40:37 PMAll use subject to JSTOR Terms and Conditions

http://www.jstor.org/action/showPublisher?publisherCode=hastings

http://www.jstor.org/stable/3564433?origin=JSTOR-pdf

http://www.jstor.org/page/info/about/policies/terms.jsp


A Revew o

H u

Researc

Volume 19, Number 6 November-December 1997

IRB Review of Adverse Events in Investigational Drug Studies by Ernest D. Prentice and Bruce Gordon 1

Ethical Considerations in Human Investigation Involving Paradigm Shifts: Organ Transplantation in the 1990s by Kenneth F. Schaffner 5

ANNOTATIONS 11

CALENDAR 12

IRB Review of Adverse Events in Investigational Drug Studies

by Ernest D. Prentice and Bruce Gordon

Introduction

I RB review of adverse events (AEs) that occur in investigational drug studies is nec-

essarily part of the process of continuing review. Both HHS and FDA regulations for the protection of human subjects (45 CFR 46; 21 CFR 56) require the IRB to perform continuing review of research at intervals appropriate to the de- gree of risk but not less than annually. The primary purpose of this review is to ensure that the risk-benefit relationship of the research remains acceptable and that the consent document contains all information necessary for valid informed consent. While most IRBs perform a scheduled continuing review no more often than annually, IRBs also have an

obligation to perform a more or less continuous, ongoing assessment of AEs. Unanticipated AEs may alter the risk-benefit relationship of the research or they may precipitate disclosure requirements where current and even previously enrolled research subjects must be advised of a hereto- fore unknown risk. The purpose of this paper is to discuss the responsibility of the IRB to review adverse event reports (AERs), the difficulties generally encountered by IRBs located at institutions with a large clinical trial base, and the system of review utilized by the University of Nebraska Med- ical Center (UNMC) IRB.

Regulatory Requirements for Reporting Adverse Events to the IRB

The IRB is required by 45 CFR 46.103(b)(5) and 21 CFR 56.103(b)(5) to establish a procedure for "prompt reporting to the IRB, appropriate institutional officials, and the department or agency head, of any unanticipated problems involving

risk to the subject or others ..." FDA Notice of Claimed Investiga- tional Exemption for a New Drug (IND) regulations also require the investigator to "assure that he or she promptly report to the IRB ... all unanticipated problems involving risk to the subject or others..." (21 CFR 312.66).

In consideration of the criteria "unanticipated" and "involving risk" it would seem that any AE not previously reported or noted in the investigator's brochure (and presumably in the consent document) that poses any risk, however small, should be promptly reported to that IRB. Therefore, in the ab- sence of any criteria based upon level of risk, even a minor new drug reaction should be reported to the IRB without delay. While the regulations do not specify a reporting time frame in terms of days, it is appropriate for an IRB to establish notification requirements according to the seriousness of the AE. For example, the sud- den, unexpected death of a subject while on protocol should be reported within a short time period such as 24 hours, whereas a minor side effect such as a limited skin rash could reasonably be reported within 48 hours or even later.

The section of the IND regulation that addresses investigator reports to the sponsor contains AE reporting criteria which are broad- er in that there is no requirement for the AE to be "unanticipated." Section 312.64(b) requires the investigator to "promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately." When complying with this regulation, investigators may also submit a copy of the AER to their IRB, though it is not specifically required.

It should be noted that the Na- tional Cancer Institute (NCI) and cooperative research groups have their own reporting requirements that influence when an investigator reports an AE to the IRB. The NCI requires investigators con- ducting clinical trials involving in-

Ernest D. Prentice, PhD, is associate dean for research and vice-chairman, IRB, University of Nebraska Medical Center; Bruce Gordon, MD, is associate professor of pediatrics and chairman, IRB, University of Nebraska Medical Center, Omaha.

A publication of The Hastings Center, Garrison, NY 10524-5555 ? 1997



::::_ ::::::::: :i:iiiiiiiid3i'ii:: :i-iiii'iii:iii?i:i-ilil?:~i~.i~l:i:i _:ilii-iii:iil;ii:i:i:ii~:~'::l-_-ji : i i:i:i:l~iiili:iiiii i:i::-i i::.i-i- li:i::i-"S-:-i~::::: : ::'::::':::::::::' :::::::"'" ii:i-i'~i-i-:-i:i-iii-i-i --?i::i-i-i-i-ii?-i-ii-iiJ~-i-ii-i i- i-i-i-iiil~::-i-ii:i--i-i--: :_ :---i:i:i-;i:i-iiii:i~~i:_i - :?-\::?:??:? ::?:?:?:i i'i'iii~-i.iii-n~:-i-i '-:: :::::::::: ::::::::-::;~::::::: :: :':':' ; : ::: : ::ii:-:-i ::':::':~~: :

:-: :': :::::"'::: ::: i;i-;~j:~-iiiii-_:::_

-i-ii-iii~~l:i:i-i _ i i:i.~j~ii?ri:i ii-i-i-i-i-ici-i i-i.i:r~--i-i i::_ i--i-i'.ia:ie'i~'i ::::a~:::: :"-::::::;:: i?i:i:iii-~j~:~.i~i:i: l-i-i-i:i:i-i ?i:iiii:i~-. -i i :::----- ii:i:i:i-ii i?i iii:i:i'i~-.i--e i-?::::::?:?::--_ : _

IRB vestigational anticancer agents sponsored by the Division of Can- cer Treatment (DCT) to promptly report to the DCT and their IRBs any "previously unknown toxicities and life threatening or fatal toxicities regardless of whether previously unknown."' Some oncology cooperative research groups require investigators to route AERs to the DCT through the group's operations office, while other groups ask investigators to report AEs directly to the DCT and also send a copy to the operations office.

Reporting Adverse Events to FDA and OPRR

The IRB is responsible for en- suring that unanticipated problems involving risk are reported to department or agency heads. IRBs, however, rarely report such inci- dents directly to FDA or OPRR unless they are part of serious or continuing noncompliance with federal regulations. AE reporting is usually accomplished through the normal reporting channel, i.e., the investigator to the sponsor to FDA. OPRR does not have the staff or the clinical safety data necessary to be able to review effectively a large volume of AEs. Thus it is not surprising that IRBs do not rou- tinely forward AERs to OPRR. In- deed, OPRR has encouraged institutions to develop rational deci- sionmaking criteria on when to report unanticipated problems that are based upon unusual circumstances and substantial risk.2 For example, a serious AE involving a normal healthy subject enrolled in a phase I drug study should obvi- ously be reported.

Sponsor Responsibilities in Reporting Adverse Events

Section 312.32(c) of the IND regulation requires the sponsor to notify "all participating investigators in a written IND safety report of any adverse experience associated with use of the drug that is both serious and unexpected" within 10 working days. While this regulation does not require the sponsor to notify IRBs at participating study sites, it is routine for

sponsors either to instruct investigators to provide their IRB with a copy of the safety report or to send a copy of the report directly to the IRB. It should also be noted that unlike the regulations cited previously, the criteria in this section include a risk-reporting threshold, i.e., the AE must be "serious." Sec- tion 312.32(a) defines a "serious adverse experience" as

any experience that suggests a significant hazard, contra- indication, side effect, or pre- caution. With respect to human clinical experience, a serious adverse drug experience includes any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospital- ization, or is a congenital anomaly, cancer, or overdose.

"Unexpected adverse experience" means

any adverse experience that is not identified in nature, severity or frequency in the current investigator brochure; or, if an investigator brochure is not required, that is not identified in nature, severity, or frequency in the risk information de- scribed in the general investigational plan or elsewhere in the current application ...

Beginning in the 1990s, IRBs at major academic medical centers have been increasingly inundated with safety reports from sponsors that are not restricted to a descrip- tion of AEs which are serious and unexpected. Indeed, many of the reported AEs are not serious according to the FDA definition, not related to the study drug, or represent anticipated side-effects of the drug. Since FDA has no specific regulation-based requirement for IRB review of any AE that does not occur at the study site served by the IRB, it would appear that the pharmaceutical industry, with encouragement and/or tacit en- dorsement from FDA, has decided that IRBs should at least be noti- fied of reported AEs regardless of the nature of the event. One rea-

son may be the pharmaceutical industry's fear of litigation. AE reports to sponsors are potentially discoverable in litigation in some states3 and involvement of the IRB in review of the AE may offer some legal protection.

View from the IRB

IRB review of AEs is largely driven by FDA, sponsors, NCI, and cooperative research groups. In consideration of the variability in AE reporting requirements, it is not surprising that many IRBs are confused about their responsibilities. Unless an IRB adopts a comprehensive approach to the review of AEs there will be inconsistency across the institution's clinical trials in terms of what kinds of AEs are reported to the IRB. In other words, a comprehensive approach demands that the IRB review all AEs which involve any risk if the AE is thought to be related, or possibly related, to the drug. This review would be performed regardless of where the AE occurred, i.e., the study site, and whether the adverse effect was unanticipated or not.

In an idealistic sense, not tem- pered by administrative, economic, or medical reality, it would appear reasonable to have the IRB review all AE reports. Since IRBs are responsible for continuing review of ongoing research, it would seem important for the IRBs at participating study sites to be apprised of all reported AEs associated with a given drug. Certainly, FDA and OPRR have made it clear that IRBs are responsible for valid ongoing assessment of research, al- though it would be helpful if regulatory consistency and definitive guidelines for IRB review of AEs existed. However, it should be rec- ognized that the relatively new practice of the sponsor forwarding all safety reports to IRBs has cre- ated a major additional workload that few IRBs are able to handle effectively. Many AEs represent complex clinical scenarios, clarify- ing data are often simply not available, and blinding is not bro- ken. The problem is further com- plicated by the fact that the AE



November-December 1997

has occurred at a study site dis- tant to the reviewing IRB. Under these circumstances, an IRB may not have the broad-based medical and scientific expertise necessary to perform a valid review.

To cope with a virtual flood of safety reports, some IRBs are forced to expend the time, effort, and expense necessary to use ex- pert consultants. Other IRBs may perform cursory reviews that offer little if any protection for the human subjects enrolled in the research. Conversely, an IRB may devote an inordinate amount of full board time to the review of AEs. This level of detailed review, however, is often unjustified in light of the fact that both the sponsor and investigators should be thoroughly assessing the significance of AEs in terms of protection of human subject issues. The sponsor is required by 21 CFR 312.56 to "evaluate evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator" and to discontinue any study that presents "an unreason- able and significant risk to subjects." In large-scale clinical trials, this evaluation is performed by data safety monitoring boards (DSMBs). While investigators and IRBs are not privy to the delibera- tions of DSMBs, it is, nevertheless, comforting to know there is inde- pendent, ongoing monitoring of data. Also, FDA reviews the data. Thus AEs are often subject to mul- tiple reviews in addition to the one performed by the IRB. This necessarily raises a question about the extent to which IRBs should be reviewing AERs. In our opinion, FDA should encourage sponsors to limit the safety reports given to IRBs to only those AEs that are both serious and unexpected and are judged to be related or possibly related to the drug. This action would certainly help reduce the workload of many IRBs.

Once an IRB receives either an in-house AER from one of its own investigators or a safety report originating from the sponsor, it ob- viously incurs an obligation to review the report. The type of IRB review, i.e., full board or expedited, should be dictated by the na-

ture of the AE. While the regulations do not address the kind of IRB review required for AEs, it is logical for IRBs to follow the dic- tates of 46.110(b) and 56.110(b) that allow the IRB to use an expedited review procedure in perform- ing continuing review of no more than minimal risk research and minor changes. Therefore, if the AE is minor in terms of clinical significance it would seem appropriate to use expedited review, particularly if the AER is provided by the sponsor, as opposed to an event that occurs at the institution served by the IRB. On the other hand, all serious, unanticipated AEs should be reviewed by the full IRB.

UNMC IRB Review of AEs

The UNMC IRB has never adopted a comprehensive approach requiring all AEs to be reported. Despite existence of the aforemen- tioned inconsistency, we do not feel such an approach is cost-effec- tive or justified from a human subject protection perspective. Accord- ing to our guidelines, nonfatal, unanticipated AEs that occur at UNMC must be reported to the IRB within 48 hours. Fatal AEs that are unanticipated must be reported within 24 hours. AEs judged by the investigator to be completely unrelated to the drug and the result of progressive dis- ease or other factors, such as acci- dents, need not be reported to the IRB unless required by the sponsor, NCI, or a cooperative group. Sponsor-generated safety reports must be submitted within 5 working days after the investigator receives the report.

The following are the questions the UNMC IRB asks investigators on our forms when submitting either a report of an AE that occurred at UNMC or a safety report from the sponsor. If the necessary information is contained in the safety report, it can be referenced.

SWhat is the medical nature of the AE and the relevant clinical history?

* Is the AE related, possibly related, unknown, or not related to the drug, or is the relationship unknown? Provide a brief rationale including laboratory results, if appropriate. Ad- dress whether or not the same AE has occurred previously and provide incidence data.

* What medical treatment did the subject receive for the AE?

* Risks must be minimized to the greatest extent possible. Is a change in protocol necessary to reduce or eliminate risk? If the answer is no, provide a brief rationale.

* Are any changes required in the informed consent/assent form(s) to better inform and protect the rights of the subjects? If the answer is yes, submit a revised consent/assent form(s). If the answer is no, provide a brief rationale.

* Is it necessary to repeat the informed consent discussion with subjects who have already agreed to participate in the study? If the answer is yes, submit a copy of the notification, consent/assent form, or amendment. If the answer is no, provide a brief rationale.

* Have you complied with all ap- plicable requirements of the sponsor, NCI, or FDA?

Upon receipt of the report, the IRB chair and/or vice-chair will perform an administrative pre-review to determine whether any further review by subcommittee is necessary and if any action(s) should be taken immediately in order to protect the rights and welfare of subjects. For example, an AER could, if warranted, require a change in protocol and/or the consent document before the next subject is enrolled. In extreme cases, the protocol may even be suspended. Since time may be critical, it is often not appropriate to wait until the full IRB meets. The full board does, however, review and must endorse all such actions after the fact.

i _i--,iiiii-i:8-'i:i?i?i'i? ?-: ?::ii-iiiiis iii?ii~i~~iii: i;: i: :E-`?:iiiriil-~:::::-- ::I -:: :::-:-: : iii;ii~~'l::: :::: .::-:::::::

I':-iii:i:-'ii''i'i i:i i:i~: :::..:::,

i~i-iii:ii% i:i-iii?iiii:iii :i;m:i?:-i:iii:ii:ii :ii-::: ::~:::-: -:-:-::_:-:::: -:-~::::: ?::::-?::~-~:?-:::



IRB Once the administrative pre-

review is completed, the AER may be reviewed by an IRB subcommittee that meets weekly. Any reported AE related or possibly related to the drug is automatically sent to subcommittee. The subcommittee reviews the complete protocol file as necessary and determines if additional information or clarifica- tion is required and whether the AE must be reviewed and discussed by the full board. AERs generally referred to the full board include (a) any event that is serious, unanticipated, and related or possibly related to the drug, or (b) any event where the investigator and/or the sponsor has determined that a significant change in protocol or the consent form is necessary.

It should be noted that the UNMC IRB requires the investigator not only to analyze the AE in terms of its relationship to the study drug, but also to address minimization of risks and adequa- cy of the consent/assent document. With regard to the latter, prior to 1995 the IRB asked investigators only whether a change in protocol or of the consent form was necessary. Investigators rarely an- swered in the affirmative and the board often raised questions about issues such as subject eligibility, monitoring, withdrawal, and disclosure of risk in the consent document. With the current review system, however, negative answers must be accompanied by the rationale. This has facilitated IRB review of AEs by forcing investigators to justify why changes are not necessary. In some cases it is obvious, but in others it is not clearcut and investigators have sought advice from colleagues and the sponsor in order to complete their report to the IRB. Over the last two years, we have seen more changes in protocol and, in particular revised consent/assent forms resulting from our review system. It would appear that the need to provide a rationale has caused investigators to consider more critically the significance of the AE in terms of human subject protection. It is

surprising to us that sponsors have not mandated many of the same changes in advance of IRB review.

Conclusion

The UNMC IRB system for reviewing in-house AE reports and sponsor-generated safety reports relies upon the investigator to provide critical information not easily obtainable by the IRB. Granted, our system has increased the workload of UNMC investigators. However, we believe it is the investigator who bears the ultimate responsibility for protecting his or her patients enrolled in clinical research and for appropriate conduct of the study. Therefore, our system of review relies heavily on the expertise and decisions of the investigator, who is required to analyze the AE in terms of protection of human subject issues. Our experience indicates that investigators respond thoughtfully and appro- priately if they understand the rationale for the information requirements of the IRB. Without doubt, UNMC investigators have helped facilitate this IRB's review of AEs.

As mentioned previously, the UNMC system for reviewing AEs is more or less driven by FDA, sponsors, NCI, and the various cooperative groups to which we be- long. Like many other IRBs, we are deluged with AERs, particularly those that have occurred at ex- ternal sites. AERs, together with an ever-expanding volume of new protocols, amendments, and docu- mentation requirements has creat- ed an enormous workload. Again, like many other IRBs, we have be- come increasingly concerned about the future integrity of our entire system of human subject protection, which necessarily relies upon the willingness of qualified and motivated faculty members to serve on the IRB. As Robert Levine explains, faculty members in the past were highly motivated to serve on IRBs. Now, however, there is generally less interest in becoming an IRB member in the

face of new federal regulations and more stringent interpretations of existing regulations that, in turn, has produced a staggering workload for already overburdened faculty who must now operate under the constraints of managed care. As Levine explains further, "The bottom line is money. Universities are pressed to evaluate their faculty members on the basis of how much revenue they generate through their teaching, research and patient care .. ."4

IRBs generally agree that the entire system could be made more efficient and that their workloads could be decreased without com- promising human subject protection. To that end, Levine goes on to suggest that we must decrease excessive and nonproductive pa- perwork associated with the current practice of forwarding to the IRB reports of all AERs that occur anywhere in the world in connec- tion with studies of investigational drugs.4 We concur with Levine and it is safe to say that IRBs at other major medical centers also agree.

References

1. National Cancer Institute, Division of Cancer Treatment, Adverse Drug Reaction (ADR) Guidelines, October 1993.

2. Personal communication with T. Puglisi, Office of Protection From Research Risks (OPRR), 10 April 1996.

3. Newsome v. Breon Lab., Inc., 709 S.W. 2d 559,560 (1986).

4. Phillips DF: Institutional review boards under stress: Will they ex- plode or change? JAMA 1996; 276:1623-26.

Back issues of IRB are available with discounts for large orders. For information on rates write to:

Pauline Bowles The Hastings Center Garrison, NY 10524-5555

TEL: (914) 424-4040 FAX: (914) 424-4545



irb review of adverse events in investigational drug studies

Documents