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3
Cardiac Safety Biomarkers1
In the 1990s, reports of potentially fatal cardiac arrhythmias in adverse
event data focused attention on the potential of several drugs to cause car-
diac toxicity. One effect of these drugs was to prolong the interval between
the onset of the Q wave and the conclusion of the T wave in the heart’s
electrical cycle—which is known as QTc when corrected for heart rate.
This association with QTc prolongation and cardiac arrhythmias led to
the removal of a series of drugs from the market, including terfenadine in
1998, astemazole and grepafloxacin in 1999, and cisapride in 2000. QTc
is one of the oldest and best-known safety biomarkers used throughout
drug development. The effect of a drug on QTc is an important input to
regulatory decision making and has a major impact on how pharmaceutical
companies design and prioritize drug development programs.
Compared with the newer safety biomarkers discussed later in this
chapter, QTc has a number of strengths and weaknesses (Table 3-1). Among
its strengths are that the technology needed to measure it is established and
nearly universally available; a great deal is known about the molecular
mechanisms of the ion channels that affect ventricular repolarization; a
number of well-established in vitro and in vivo models exist; there is sub-
stantial clinical experience with patients who have a congenital prolonged
1 This chapter is derived from a white paper prepared by Daniel Bloomfield, Executive Di-
rector of Cardiovascular Clinical Research and Chair of the Cardiac Safety Board for Merck
Research Laboratories, and Norman Stockbridge, Director of the Division of Cardiovascular
and Renal Products for the FDA, with additional input from workshop discussions.
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
TAbLE 3-1 Strengths and Weaknesses of the QTc Interval as a Safety
Biomarker
Area Strengths Weaknesses
Biology • Knowledge of molecular • Weak links between experimental models
mechanisms and ion and clinical events
channels
• Cellular models
• In vivo models
Clinical • Genetic syndromes • Rare clinical events, multifactorial
experience (LQT), documented etiologies, unpredictability
and relevance clinical events • Insufficient data available to close gap
between signal and rare events
Measurable • Old technology, • Low-frequency and low-amplitude signal,
biomarker universally available resulting in difficult measurement and
poor signal-to-noise ratio
• Numerous methods of measurement
• Measured in static condition
Multisector • Interest from academia, • Lack of harmonization among
involvement clinical medicine, stakeholders
industry (technology, • Lack of infrastructure for a coordinated
diagnostics, pharma), collaborative effort (now addressed by
regulatory agencies Cardiac Safety Research Consortium)
QT (LQT) syndrome; and a wide array of stakeholders are interested in
advancing the understanding and use of this biomarker.
Despite these strengths, however, QTc also has several weaknesses as a
biomarker for safety. First, there is no consensus on the optimal method of
acquiring, measuring, and analyzing the QTc interval. This is due in part
to the nature of the signal, which has low frequency and low amplitude,
has a poor signal-to-noise ratio, is intrinsically variable, and is affected by
a number of important confounding factors. Second, the link between the
experimental models of QTc and the occurrence of rare and unpredictable
clinical events is weak, in part because insufficient data have been collected
to close this gap. Specifically, clinical epidemiology data have not been
collected that would define the probability of an episode of the ventricular
tachycardia known as torsade de pointes based on the QTc interval.
It should be noted that, while many biomarkers are used to under-
stand a wide range of cardiovascular conditions—such as hyperlipidemia,
inflammation, and ischemia—the scope of the discussion in this session of
the workshop was limited to biomarkers of electrophysiologic toxicity, in
particular, those related to QT interval prolongation.
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CARDIAC SAFETY BIOMARKERS
This chapter begins by describing the regulatory response to the recog-
nition that cardiac events were resulting from adverse reactions to drugs,
the responses of drug developers, and effects on physician decision making.
This is followed by a review of issues related to the development of poten-
tial cardiac safety biomarkers other than QTc, with a particular focus on
troponin, and the possible contributions to this work of the Cardiac Safety
Research Consortium (CSRC). Some lessons learned from experience to
date with the development of cardiac safety biomarkers are then summa-
rized. The chapter ends with highlights from the breakout discussion of key
steps necessary for further progress.
THE REGuLATORy RESPONSE
The recognition that cardiac events were being caused by adverse
reactions to drugs led to a variety of regulatory responses. In 1997, the
FDA and the International Conference on Harmonisation (ICH) issued
Guidance for Industry: S Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals (FDA, 1997). This was followed in 2001 by
Guidance for Industry: SA Safety Pharmacology Studies for Human
Pharmaceuticals (FDA, 2001). Both of these documents stated that cardio-
vascular safety testing should be performed on new drugs, but provided
no specific guidance on how this testing should be conducted. In 2001,
the FDA announced that in fall 2002, it would begin collecting raw
electrocardiogram (ECG) data from sponsors, and in 2002 a “points
to consider” document was jointly authored by the FDA and Health
Canada (FDA, 2002). This was followed by FDA/ICH guidance docu-
ments providing more specific recommendations regarding clinical (E14)
(FDA, 2005a) and preclinical (S7B) (FDA, 2005b) testing approaches. The
E14 guidance called for “thorough QT” (TQT) studies of new drugs to
assess their potential for causing torsade de pointes. Even prolongation
of QTc by just a few percent was considered to be clinically relevant. The
FDA then established an interdisciplinary team to handle the review of
QTc-related protocols and studies, to ensure a uniform response, and to
accumulate experience in this area.
As the regulatory response was being crafted, the FDA made a public
appeal for the development of standards for digital ECG data. This action
was based on the idea that it will be critical to review the ECGs from TQT
studies. Such a data standard was developed in 2002 and formally adopted
by the Health Level 7 (HL7) standards organization in early 2003.2
2 See http://www.hl7.org/search/viewSearchResult.cfm?search_id=17061&search_result_url=%
2FLibrary%2FCommittees%2Frcrim%2Fannecg%2FaECG%20Release%201%20Schema%20
and%20Example%2Ezip.
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0 DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
As the data standard was being finalized, the FDA entered into a Coop-
erative Research and Development Agreement with Mortara Instruments
to develop a web-accessible repository for conforming digital ECG data.
This repository came online in 2005 and now hosts more than 2.5 million
digital ECGs collected from more than 150 clinical studies.
RESPONSES OF DRuG DEvELOPERS
As the ICH S7B and E14 guidance documents were being developed,
responses from the pharmaceutical industry were mixed. In general, industry
appreciated clarification of the standards for preclinical and clinical assess-
ments of the effects of a drug on ventricular repolarization. In particular,
industry was pleased that E14 created a clear definition of a compound with
no QTc risk and made it clear that no further evaluation of QTc would be
necessary for these compounds.
However, industry representatives raised two concerns related to the
E14 guidance. First, E14 specified that every systemically available small
molecule would require a clinical TQT study even if the results of the
extensive preclinical studies related to ventricular repolarization outlined
in S7B were completely normal. Second, E14 set an extremely high bar for
declaring that a compound posed no QTc risk: at supratherapeutic expo-
sures, a compound had to demonstrate an increase in QTc of less than
5 milliseconds (ms) (mean) or 10 ms (upper confidence limit) in a study that
demonstrated assay sensitivity by detecting an increase in QTc of a similar
magnitude with a positive control (usually moxifloxacin).
These two concerns were focused primarily on a fear that very small
signals in QTc would be identified in compounds when there was no theo-
retical risk, when no preclinical evidence suggested future problems, and
when early clinical evidence showed no signs of QTc prolongation. The
initial lack of understanding of what it means when a compound demon-
strates a 5–10 ms increase in QTc generated considerable uncertainty in
drug development. In particular, drug developers asked questions such as
the following:
• What was the clinical significance of such a small increase in QTc?
• What additional studies would be necessary in later phases of drug
development to clarify the clinical significance of an increase in
QTc of this magnitude?
• How would these additional studies affect the timelines and costs
of drug development?
• What is the likelihood that these additional data would be able to
offset the perceived risk associated with a small but clearly docu-
mented increase in QTc from a TQT study?
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CARDIAC SAFETY BIOMARKERS
• How should a company weigh this potential increase in risk against
the potential benefits of a drug?
• How would these issues be described on the drug label?
Because of the uncertainty surrounding these questions, some pharma-
ceutical and biotechnology companies avoided developing compounds with
any potential for this liability. In the process of prioritizing compounds in
a portfolio, companies began looking for ways to kill compounds with any
potential QTc liability. Any increase in QTc in preclinical studies gener-
ated the perception that the compound would face enormous hurdles in
drug development. Some companies began to discontinue compounds in
development solely because of in vitro studies demonstrating an interaction
with the hERG channel (a potassium ion channel involved in ventricular
repolarization), even in the absence of evidence of prolonged QTc during
in vivo animal studies. In addition, as compounds advanced through devel-
opment, companies feared being penalized for evaluating supratherapeutic
exposures and attempted to minimize this risk by limiting the maximum
doses studied.
With regard to drug development, the ultimate success of the E14 and
S7B guidance documents will be realized when there is a shared under-
standing between pharmaceutical companies and regulatory agencies of
the clinical significance of a small increase in QTc interval in the context
of the possible benefits of a new molecular entity. Excessive focus on this
biomarker in the absence of true clinical risk could stifle innovation and
lead to an unfortunate decision to discontinue the development of a drug
that could offer patients benefits outweighing the actual risk.
One solution to this potential conundrum is to create an environment
in which regulatory agencies, academics, and industry scientists can col-
laborate to better understand the link between the safety biomarker (in this
case QTc) and the event it is intended to predict (in this case torsade de
pointes). All parties involved would benefit from improved clinical epide-
miology and greater understanding of how to measure and use this safety
biomarker. If successful, this type of collaboration would likely result in
better decision making that would place the risks of a drug in the context
of its benefits. The potential of this approach is demonstrated by the CSRC,
discussed later in this chapter.
EFFECTS ON PHySICIAN DECISION MAkING
The regulatory guidance discussed above has important effects on
physician behavior and decision making. The provision of information to
physicians on a product insert or label regarding how a drug might affect
the QTc interval raises a number of important questions:
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
• How do physicians use the information on the label?
• How successful are physicians in measuring the QTc interval when
instructed to do so by the label?
• How do physicians make risk/benefit decisions for an individual
patient?
• Are physicians avoiding potentially beneficial medications because
of the fear of a small increase in QTc?
• What is the impact of including new warnings on the labels of drugs
that have been used for a long period of time (e.g., methadone)?
OTHER CARDIAC SAFETy bIOMARkERS
The recent developments related to QTc provide insight into the com-
plexity facing the development of other cardiac safety biomarkers. Some
examples of biomarkers that might merit further attention because of their
link to cardiac morbidity and mortality include
• heart rate,
• blood pressure,
• lipids,
• troponin,
• C-reactive protein (CRP),
• brain or B-type natriuretic peptide (BNP),
• ex vivo platelet aggregation, and
• imaging biomarkers (cardiac magnetic resonance imaging).
It is beyond the scope of this chapter to discuss all of these potential
cardiac safety biomarkers in any depth. However, examination of one
example highlights both the challenges involved and the potential path
forward.
Troponin is a protein complex involved in contraction in cardiac mus-
cle. Subtypes of troponin can be sensitive indicators of damage to heart
muscle caused by myocardial infarction or other cardiovascular conditions,
and these uses are well established and supported by considerable research.
Cardiac troponin also has been recognized as a potential biochemical marker
of subclinical myocardial injury. Much less is known, however, about
the use of troponin to identify drug-induced cardiotoxicity. For example,
troponin has been studied as a potential biomarker of cardiotoxicity asso-
ciated with two chemotherapeutic agents—the anthracycline doxorubicin
and the humanized monoclonal antibody trastuzumab. Since the toxicity
associated with anthracyclines varies considerably among individuals, the
use of cardiac troponin has been suggested as potentially important in plan-
ning and monitoring treatment to allow maximum anthracycline dosages
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CARDIAC SAFETY BIOMARKERS
without causing severe cardiac damage, and in developing preventative
strategies to limit cardiomyopathy in later life. A complicating finding is
that the early left ventricular dysfunction associated with doxorubicin may
be reversible in the short term, even though clinical heart failure may not
appear until much later.
Trastuzumab is an example of a drug whose use could be optimized by
employing an appropriate biomarker. Trastuzumab has been used to pro-
long the lives of women with advanced breast carcinoma who have over-
expression of the HER2 oncogene. Preclinical animal studies on mice and
monkeys did not reveal cardiac toxicity for this drug; however, subsequent
clinical trials demonstrated an unexpectedly high incidence of such toxicity.
Despite the reversibility of trastuzumab-induced cardiac changes in most
cases, this toxicity frequently leads to discontinuation of antibody therapy.
If cardiac troponin were shown to be a reliable biomarker of patients at risk
for this toxicity, it could help optimize the use of trastuzumab.
A number of important questions are raised by this approach:
• When should cardiac troponin be measured, and how should it be
quantified?
• Which cardiac troponin assay should be used?
• What is the appropriate threshold to establish that an increase in
cardiac troponin will be clinically significant?
• How will that threshold be determined in the context of the poten-
tial benefits of the drug?
• What should be done about events that are biochemically detect-
able but below that threshold and therefore may be clinically
insignificant?
• How should investigators manage elevations in troponin in clinical
studies?
• Which compounds need to undergo a cardiac troponin evaluation
preclinically?
• Are the preclinical models sufficiently predictive? If not, which com-
pounds warrant a cardiac troponin evaluation in clinical studies?
• How can a negative cardiac troponin evaluation be defined? Will a
positive control be necessary to determine assay sensitivity? How
would a positive control be used?
To examine the potential of QTc and other cardiac safety biomarkers,
the Health and Environmental Sciences Institute (HESI), the FDA, and
the CSRC hosted an open think tank forum on October 6–7, 2008, titled
“Integrating Preclinical and Clinical Issues in Cardiac Safety: Translational
Medicine Meets the Critical Path.” Experts from academia, industry, and
the FDA gathered to discuss key topics in cardiac safety assessment, with
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
a particular focus on the translational gaps between the preclinical and
clinical perspectives.
Plenary presentations titled “Collaboration, Critical Path, and Cardiac
Safety: The FDA View” and “How Can Collaborations in Cardiac Safety
Efforts Best Impact the Regulatory Landscape?” set the stage for examining
the value of the collaborations promoted by the HESI and CSRC consortia.
Organizational updates from HESI and CSRC summarized the challenges
of and solutions to data-sharing processes, and presented the first proof-of-
concept report illustrating the sharing of data from a number of companies
in the ECG warehouse. The forum’s agenda encompassed the exploration of
a number of potential biomarkers in addition to QTc, and included discus-
sion of the following questions:
• Cardiotoxicity and troponin: Where do they fit in drug development?
• Preclinical and clinical testing for QTc proarrhythmia: How do they
relate to one another and to the risk of life-threatening arrhythmic
events?
• QTc evaluation of non-QTc proarrhythmia: What is appropriate
preclinical and clinical testing?
• Biologics and large molecules: How should proarrhythmia and
myotoxicity be evaluated?
• Risks and benefits of developing drugs with safety signals: What
are the challenges?
• New horizons for cardiac safety programs: Do we need “thorough”
blood pressure, heart rate, platelet, and lipid studies?
THE CARDIAC SAFETy RESEARCH CONSORTIuM
As the ECG warehouse was coming online, the FDA and the Duke
Clinical Research Institute initiated the CSRC, a public–private partner-
ship, to “advance scientific knowledge on cardiac safety for new and
existing medical products by building a collaborative environment based
upon the principles of the FDA’s Critical Path Initiative as well as other
public health priorities.”3 This initiative brought together pharmaceutical
companies, clinical research organizations, and academic partners in an
effort to leverage the ECG warehouse and associated clinical data for
mutual benefit.
The implementation of the CSRC has faced many challenges related
to governance, infrastructure, resources (both funds and staff time), intel-
lectual property, antitrust and other legal issues, and how to get companies
to share data in a collaborative environment. Many of these challenges
3 See http://www.cardiac-safety.org/about_us.
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CARDIAC SAFETY BIOMARKERS
have been or are being overcome. Companies have begun to share data,
and CSRC research teams—including industry scientists, academics, and
regulators—have begun to make progress on a number of projects.
An important accomplishment of the CSRC has been enhancing com-
munication and education by promoting dialogue among scientists from
the pharmaceutical industry, academia, and regulatory agencies. The CSRC
has established common ground and an environment in which difficult
issues can be discussed outside of formal regulatory channels. These discus-
sions have included methods for evaluating the effects of chemotherapeutic
agents and large molecules (antibodies and biologics) on QTc, as well as
different statistical approaches to evaluating the effect of a drug on QTc,
including concentration–response (PK-QTc) modeling. Recently, a number
of pharmaceutical companies agreed to allow the FDA to share data from
the ECG warehouse to create a meaningful data set that will enable com-
panies and scientists to enhance the use of old measurements of QTc and
develop new measurements of ventricular repolarization. This data set will
also provide the opportunity to gain insight into the effect of moxifloxacin
(the most commonly used positive control in TQT studies), including a
better understanding of outliers and nonresponders. The potential will exist
for informative studies in pharmacogenomics that might not be possible in
a single company.
Combined with the technological and regulatory advances that have
been achieved over the past few years, the CSRC has the potential to gen-
erate significant improvements in the utility of QTc as a safety biomarker.
But it is not clear at this time whether the CSRC will be able to generate the
clinical epidemiology studies and data necessary to provide a more refined
link between drug-induced QTc prolongation and the risk of developing
torsade de pointes. The next few years will determine whether the collabo-
rations within the CSRC will generate the data sets necessary to provide
meaningful and relevant answers to questions that limit the use of QTc as
a safety biomarker.
The CSRC also hopes to foster collaborations among industry, aca-
demia, and regulatory agencies to further the development of new cardiac
safety biomarkers. These advances in biomarker development will require
investments in basic science to better elucidate the molecular mechanisms
of cardiac toxicity and in preclinical models and clinical data to allow
evaluation of the use of biomarkers. A coordinated approach to this effort
is important to ensure that scientific issues are addressed appropriately,
that regulatory strategies are crafted, that an infrastructure is developed to
collect industrywide experience, and that the proper public–private partner-
ships are forged to profit from the aggregate experience.
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
LESSONS LEARNED
A number of important lessons that may be applicable to the develop-
ment of other safety biomarkers have been learned from the development
of regulatory guidance on evaluating the potential of drugs to prolong QTc;
the technological advances that enabled the formation of the ECG ware-
house; and the healthy dialogue that has taken place among the pharmaceu-
tical industry, academia, and regulatory agencies through the CSRC. This
series of events has yielded a fairly complete (but still evolving) system for
addressing a public health issue through regulatory and technical develop-
ments. The historical account makes the endeavor look like a coordinated
response, but that is an inaccurate perception. Rather, individuals who
recognized what needed to be done next made sure those steps were taken.
The original “points to consider” document had its roots in a document
authored by Health Canada’s Collette Strnad. The effort to develop a digital
ECG data standard, which involved a team of people from pharmaceutical
companies, clinical research organizations, device manufacturers, and aca-
demia, was initiated and managed by Scott Getzin of Eli Lilly. The CSRC
came into being largely through the efforts of Christopher Cabell, then at
the Duke Clinical Research Institute. Had any of these individuals failed
to become involved when and to the extent that they did, the result would
most likely have been significant delay and a suboptimal response. There
is a pressing need to develop a quality-assured response to other perceived
biomarker-based health risks.
HIGHLIGHTS OF THE bREAkOuT DISCuSSION
The breakout group on cardiac toxicity identified several key steps
necessary for progress on both the enhanced use of QTc as a biomarker and
other biomarkers that can supplement the information provided by QTc.
In the plenary session following the breakout, Alastair Wood described the
group’s main conclusions.
Standardization
The collection, annotation, curation, and submission of data need to be
standardized across the entire research spectrum, including NIH, the FDA,
and academia. Annotation and curation of data are especially important so
that data will be usable, standardized, and accessible.
Without standardization, it is impossible to look across databases or
even different studies and make comparisons or compare outcomes against
biomarkers. In addition, patient data need unique identifiers, since fre-
quently it is difficult to identify a patient who took part in more than one
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CARDIAC SAFETY BIOMARKERS
study or developed toxicity after an event. Even drug names need to be
better identified, since the trade names of drugs can change.
Identifying Mechanisms
It is important to relate biomarkers to mechanisms of toxicity. Mecha-
nistic understanding can be used to generate hypotheses that can then be
tested experimentally. Identifying a biomarker can help clarify a mechanism
and vice versa. And understanding mechanism can provide information on
long-term clinical outcomes and on biomarkers that do and do not correlate
with these outcomes.
Access to Data
Access to data held by the FDA and by private companies would be
valuable for those involved in the development of biomarkers. For example,
noncompetitive access to old drug data would benefit multiple stakeholders.
Removing restrictions on access to FDA data would require legislation.
In general, broader access to compounds and past data associated with
those compounds could improve productivity. For example, compounds
that were abandoned because of toxicity concerns could yield data that
relate to potential biomarkers currently being studied. Such data could
reveal correlations or their lack and would allow for comparisons across
studies.
Responsibilities for Future Actions
A variety of organizations need to assume or be assigned responsibility
for bringing stakeholders together and arranging for funding to advance
the development of cardiac safety biomarkers. Among the issues that need
to be resolved is who will support the needed research, what mechanisms
will drive the research, and what is the proper balance of incentives and
requirements to foster participation.
As part of this allocation of responsibilities, NIH’s role in biomarker
development needs to be rethought and redefined. If NIH interprets its role
too narrowly, it may not be willing to support clinical research that can
have a major impact on patient outcomes. One option would be to convene
a standing group including representatives of the National Heart, Lung, and
Blood Institute, the FDA, industry, and academia to identify and prioritize
high-impact opportunities in terms of public health and to recommend spe-
cific targets for research funding. Topics that NIH should consider include
technology and animal model development aimed at translation to human
studies; development of biomarkers through detailed studies of human
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DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
genomics, proteomics, and metabolomics; human studies to validate bio-
markers in adequately sized longitudinal studies; and definition of appropri-
ate institutional roles in the development of standards. Such initiatives are
beyond the capability of either the FDA or most private companies unless
they work together within a collaborative framework.
REFERENCES
FDA (Food and Drug Administration). 1997. International conference harmonization guidance
for industry: S preclinical safety evaluation of biotechnology-derived pharmaceuticals.
http://www.fda.gov/cder/guidance/1859fnl.pdf (accessed October 17, 2008).
FDA. 2001. International conference harmonization guidance for industry: SA safety pharma-
cology studies for human pharmaceuticals. http://www.fda.gov/Cber/gdlns/ichs7a071201.
pdf (accessed October 17, 2008).
FDA. 2002. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic
potential for non-antiarrhythmic drugs. Preliminary concept paper. http://www.fda.gov/
ohrms/dockets/ac/03/briefing/pubs%5Cprelim.pdf (accessed October 17, 2008).
FDA. 2005a. International conference harmonization guidance for industry: E clinical
evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-
antiarrhythmic drugs. http://www.fda.gov/cber/gdlns/iche14qtc.pdf (accessed October 17,
(accessed
2008).
FDA. 2005b. International conference harmonization guidance for industry: SB nonclinical
evaluation of the potential for delayed ventricular repolarization (QT interval pro-
longation) by human pharmaceuticals. http://www.fda.gov/cder/guidance/5533dft.htm
(accessed October 17, 2008).
