Safety Put Into Practice

October 1, 2008

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-10-01-2008, Volume 0, Issue 0

From pre- to postmarketing, safety monitoring must be a priority that's handled with knowledgeable care.

Safety management in clinical trials is a process quite distinct from processes applied in postmarketing. It is regulated by a multitude of specific directives, guidelines, and regulations. These guiding and regulating documents have two important characteristics. First, they generally focus on individual aspects of safety management such as expedited regulatory reporting,1 patient exposure necessary to properly assess safety,2 and the set up of data safety monitoring boards (DSMB) as seen from the perspective of the FDA3 and the European Medicines Agency (EMEA).4 Second, they understandably deal with principles—none of them having an individual trial in their focus. The interpretation and implementation is left to trial sponsors.

Photography: Getty Images Illustration: Paul A. Belci

The Council for International Organization of Medical Sciences (CIOMS) is currently the world's leading think tank in the field of drug safety. Many CIOMS recommendations were subsequently incorporated into ICH guidelines. In addition to adhering to applicable regulations, it is wise to consider the current opinions of drug safety opinion leaders given in CIOMS working group publications.

This article will offer an approach on summarizing the current regulations, guidelines, and recommendations and applying them in practice at the level of a trial specific Safety Management Plan (SMP).

Defining roles

Serious adverse events (SAEs) require the most attention from a regulatory point of view, especially if subject to expedited reporting (considered related to the study medication and not observed before). Several parties are involved in clinical trials: sponsor, CRO, pharmacovigilance services or safety database provider, and potentially an additional party to handle the unblinding and regulatory reporting of unblinded expedited reports. Hence, the handling of the event among the involved parties should be defined.

For example, it should be defined who is the initial recipient of the report and how the receipt is documented, as the date of receipt determines the deadline for regulatory reporting. All subsequent steps like production of narrative, review, decisions regarding reportability, unblinding, and reporting should be linked with the responsible persons, back-ups, communication lines, documentation processes, and defined timelines for execution.

Investigators will most often need to be queried for additional information or clarification of an event. The sponsor may disagree with the investigator regarding the assessment of the event, most sensitively on the causality assessment, which often determines if the event needs to be reported on an expedited basis. Although justified to request clarification and thereby potentially imply disagreement with the assessment, this process should not include any attempts to unduly influence the reporting investigator. The incorporation of follow-up reports into event narratives or changes to previously reported information should be clearly presented and standardized, having in mind the purpose of an event narrative submitted for regulatory review.

Clinical trials offer the opportunity for sponsors to get early information on a reported SAE, frequently while it is still ongoing, and to be able to observe it developing and even suggest additional investigations. If the study involves pharmacokinetic sampling, the evolution of the event with respect to drug concentrations offers invaluable insights.

Pregnancy concerns

Pregnancies frequently occur unintentionally, particularly in trials involving young and moderately ill patients. The systematic and planned collection of information on outcomes from early phases of clinical development enriches the safety database. Even unwanted pregnancies provide valuable safety information on the product. They can be used to suggest the level of risk for future events. If the initial reported information shows no increased risk with the use of the drug in pregnancy, focused trials to support marketing claims for safe use in pregnancy can be considered.

Collection of data on unintentional pregnancies should be seen as a continuous process, from pre- to postmarketing. Trial sponsors should define the procedures to provide the potential parents with relevant information to allow them to make a free and informed decision. Consider designing a standardized supplementary information and consent sheet for follow-up after birth and consider a standardized approach to ethics committee notification.

The database used in premarketing should allow the transition into systematic collection of data in the postmarketing phase. This database can be essentially the same for all drugs within a company. Hence, a one time effort will benefit all developmental programs.

A great regulatory effort has been made to support development of treatment for pediatric and geriatric populations. In addition to ICH guidelines E7 and E11, major initiatives are underway at the EMEA5 and FDA6 for stimulating drug development for the pediatric population. The effort on supporting development of treatment in pregnancy is apparently disproportionate, with the exception of a recent guideline by the EMEA.7 The disproportion with respect to medical significance seems striking to the extent that one may ask if pregnancies should be classified as an orphan population.

Laboratory alerts

The use of central laboratories or central ECG, imaging, and other centralized evaluation facilities allows trial sponsors to review the results in real time. Sponsors may evaluate individual alert values and ongoing adverse events in individual patients. The questions are: How much should a sponsor be involved if the responsibility for patient safety lies with the treating investigator and how much valuable safety information can be obtained?

Arguably, the sponsor may be more familiar with the investigational drug than the treating investigator, who may not have meticulously studied the Investigators Drug Brochure, or the reported alert value may be outside of the specialty of the investigator. For example, the sponsor may need to have in-house expertise on ECG interpretation if the investigator also needs to seek cardiology consultation. This could support the investigator and contribute to a good sponsor–investigator relationship, in addition to being in the patients' safety interest.

In addition, investigating a lab finding event in real time has better chances of linking it to a clinical event, thereby leading to a proper diagnosis. It would enable earlier association of the event to similar reports and earlier reaction to a potential safety signal, rather than at the time the clinical study report is written. Importantly, it may help in ruling out the relationship to the study drug if suspecting laboratory artifacts.

Rechallenge issues

Following a suspected reaction, it is extremely informative to confirm or rule out the suspected drug/event relationship. Taking the risk by rechallenging one study subject would decrease the risk to all other study subjects. If rechallenge confirms causal relationship, the safety information could be distributed to all involved investigators (or prescribers) and additional measures could be taken to prevent or appropriately treat the reactions. The sponsor may make the early decision to halt development if a safety concern is confirmed. This will prevent unnecessary further expenditure and prevent the drug from causing further harm. On the other hand, the rechallenge may confirm no relationship between the study drug and the event.

CIOMS working group V8 considers intentional rechallenge justifiable only if it may be in the interest of the particular subject. Looking at it from the ethical perspective, the well-being of an individual subject is one of the pillars of ethics in clinical trials as laid down by the Declaration of Helsinki. It should never be placed above the interest of science or the pharmaceutical industry.9 In most decisions regarding re-challenge, it is believed that the likelihood of the drug causing the event is low and that the event, if it reoccurs, will be mild and reversible. However, there is no guidance on delineation between low and high risk.

Several points to consider regarding rechallenge decisions include:

  • Subjects's documented informed willingness to accept the risks.

  • Investigator's assessment that the risk is justifiable by the expected benefit and the suspected reaction reversible and treatable.

  • Availability and risk/benefit ratio of alternative treatments.

  • Ethics committee notification or other necessary local approval. Ideally, a brief informed consent may be prepared for ethics committee approval. This consent could be an addendum to the initial consent signed and would detail the evolving individual risk in case of reoccurrence.

If actually going ahead with rechallenge, close observation and even hospitalization may be necessary to identify the reoccurring reaction as early as possible. All precautions should be taken to treat the reaction if it were to reoccur in a more severe form following repeated dosing. This is particularly sensitive if allergic mechanisms are suspected, which may be more dramatic following prior sensitization. All of the above points considered, is it worth the effort and risk?

Outside expertise

Data Safety Monitoring Boards (DSMBs) are increasingly used in clinical trials. They give credibility to safety monitoring as an external independent body and thereby may facilitate ethics and regulatory approval. In many cases, this is enough to decide to employ a DSMB. The key role is review of data from blinded trials where the sponsor has to remain blinded to treatment allocation in the interest of validity of trial data.

The FDA3 and EMEA4 both issued guidelines on DSMBs. What these guidelines do not say or maybe suggest only indirectly is that working with a DSMB requires effort, cost, and that receiving feedback from a DSMB may be slow. However, a DSMB may also be used for purposes other than periodic safety data review. If an effort has been made by the sponsor to set up a Board and format and prepare the data for their review, and if the Board members have taken the time to familiarize themselves with the study drug and trial data, it would be a pity to limit their function to merely periodically stating "no significant safety concerns have been identified and the study may continue according to plan," if all is fine.

For example, consultation may be sought regarding required safety assessments while developing the study protocol. A DSMB may also look at the safety data at the time of clinical study report writing. DSMB members must be experienced trialists who also support review of efficacy data. Safety and efficacy are inseparable, and the responsibility of a DSMB is to evaluate the balance. However, a line should be drawn with the extent of involvement of a DSMB in order to not compromise their position as external to the company. A DSMB does not replace the function of company expert consultants who may support the company in activities other than evaluation of the safety profile of the drug. A separate expert group must be set up for strategic development, promotional or other decisions.

Approaches to managing DSMBs greatly vary. Some DSMB charters detail the data to be reviewed, including statistical aspects, whereas others limit themselves to responsibilities and meeting organization. The rights of DSMBs in decision making, the extent of unblinding, and the way they communicate recommendations are equally subject to variation. A standardized approach significantly facilitates DSMB management across studies. It may be applied to issues likely applicable to all DSMB, including data format, unblinding, review of external data (data relevant to study subjects reported outside of the study itself), and other issues.

Routine safety data review and signal detection remains the sponsor's responsibility irrespective of the periodic review by a DSMB. In clinical trials this review should encompass nonserious as well as serious adverse events and also imaging, ECG, and corresponding safety labs cross checked with pharmacokinetic and pharmacodynamic parameters. In postmarketing, statistical evaluation of spontaneous reports would complement the reviews that have been performed in premarketing.

The procedures for routine safety data review should describe the process for documenting the reviews and any actions required as a result of the review. If a safety signal is discovered during the routine review, this should be appropriately followed up.

Safety signals

A safety signal is defined by CIOMS as a report or reports of an event with an unknown causal relationship to treatment that is recognized as worthy of further exploration and continued surveillance.10 The definition itself dictates appropriate exploration. It is advisable to set up a Signal Exploration Plan (SEP) to describe the procedures, responsibilities, and timelines. This may mean additional assessment of available data (e.g., assessment of covariates and confounders, risk to subpopulations of trial subjects), an amendment to the protocol or initiation of additional preclinical or clinical trials.

An SEP is based on the known or suspected mode of action of the study drug(s) and suspected mechanism of adverse effect. It evaluates based on the known and suspected properties, if there is a plausible mechanism by which the study drug(s) may have caused an adverse effect. However, even if no mechanism of adverse effect is fully clarified and confirmed, immediate measures based on preliminary assessment to minimize the risks to study subjects must not be delayed.

A company's safety unit takes the leading role but collaboration with other units, such as data management and regulatory affairs, is necessary (see Table 1).

Safety signal detection in clinical trials, particularly premarketing trials, is a process quite distinct from postmarketing. In postmarketing it is mainly statistical and quantitative, based on disproportionality in adverse reaction reporting.11 In premarketing clinical trials it is rather qualitative with early involvement of medical evaluation. Statistical significance does not need to be reached and early trends or even individual events may warrant attention and exploration. While assessment of clinical trial safety signals is rather qualitative, some will argue that it is in fact more scientifically or statistically robust because there is a denominator, the subject pool. The numerator is also available, as reporting of adverse events is mandatory (see Table 2).

Drug safety monitoring practices are essentially continuous in pre- and postmarketing, with subtly different approaches. The approach depends on the amount of known and suspected drug properties and the possibility and responsibility of the trial sponsor to more tightly control and more quickly get access to the clinical trial adverse reaction information. While they are different, both serve their purpose of describing the safety profile of a drug and should be seen as two points within a spectrum. They are complementary and one cannot exist without the other.


1. International Conference on Harmonization, Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting,

2. International Conference on Harmonization, Guideline E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions,

3. Food and Drug Administration, Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring Committees,

4. European Medicines Agency, Guideline on Data Monitoring Committees, Doc. Ref. EMEA/CHMP/EWP/5872/03, www.

5. European Parliament and the Council, Regulation (EC) No 1901/2006 on Medicinal Products for Paediatric Use,

6. Congress of the United States of America, Best Pharmaceuticals for Children Act,

7. European Medicines Agency, Guideline on the Exposure to Medicinal Products During Pregnancy: Need For Post-Authorisation Data,

8. Council for International Organizations of Medical Sciences, "Current Challenges in Pharmacovigilance: Pragmatic Approaches" (Report of CIOMS Working Group V), Geneva, 2001.

9. World Medical Association Declaration of Helsinki,

10. Council for International Organizations of Medical Sciences, "Benefit–Risk Balance for Marketed Drugs: Evaluating Safety Signals" (Report of CIOMS Working Group IV), Geneva, 1998.

11. S.J. Evans, P.C. Waller, S. Davis, "Use of Proportional Reporting Ratios (PRRs) for Signal Generation from Spontaneous Adverse Drug Reaction Reports," Pharmacoepidemiology and Drug Safety, 10, 483-486 (2001).

Vid Stanulovic, MD, MSci, is head of the drug safety unit at Accelsiors CRO and Consultancy Services, Budapest, Hungary, +36 1 299 0095, email:

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