White Paper | Why is Cardiac Safety Testing

Required for Non-Cardiac Drugs?

Robert Kleiman, M.D.

Vice President, Cardiology and Chief Medical Officer, ERT

August 2014

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Why is Cardiac Safety Testing Required for Non-Cardiac Drugs?

Introduction – The Requirement for Cardiac Safety Data Collection Many drugs are intended for non-cardiac indications and have no obvious link to cardiac side

effects. However, FDA and international regulators require that all new chemical entities (NCEs)

undergo a variety of safety tests, including cardiac safety assessments. It is common to hear

members of drug development teams question why it is necessary to collect cardiac safety data on

their new noncardiac drug, which has no known preclinical or early clinical cardiac toxicities.

In order to understand the current regulatory requirements, one needs to understand the common

scenario in which drug safety concerns unfold (Table 1). Initially, there is a “golden era” during which

a class of drugs is thought to be generally safe and effective. This is also when clinical development

focuses on assessments of efficacy as well as general safety and tolerability. Then, at some point, an

index case is identified which raises the specter of a drug related side effect. As this is reported,

additional cases are identified, ultimately raising public concerns in the media. The media coverage

raises attention to the possible link between the drug and the adverse event, and researchers and

patient advocacy groups may become involved. Ultimately, there is a regulatory response,

sometimes limited to a single drug, but often affect an entire class of drugs. New regulatory

requirements then become the standard during drug development.

Table 1 Common Pathway for Unfolding of a New Safety Concern

1. The Golden Era – no specific safety concerns; development focuses on assessment of efficacy

(often through effects on biomarkers rather than clinical outcomes)

2. Index case – first report of a new adverse event not previously associated with the drug

3. Amplification – additional cases of the same event are linked to the drug

4. Media response – reports in newspapers, internet, and/or TV linking drug to new side effect

raise public concern about the safety of the drug

5. Regulatory response – regulators reevaluate data from the drug development program and

post marketing data; the label may be revised or the approval withdrawn

6. Generalization – in some cases, the adverse event may be linked to the entire class of drugs,

leading to new regulatory guidance

Several different classes of medication have demonstrated cardiac side effects and have prompted

regulatory agencies to issue new requirements for drug developers. One of the first was the

detection of anthracycline related cardiotoxicity. Daunorubicin, introduced in the 1960s, was a very

potent chemotherapeutic agent for a wide variety of cancers. In 1967, it was first reported that

patients treated with daunorubicin had an increased risk of developing congestive heart failure. A

number of trials confirmed that daunorubicin produces dose related myocardial damage and

congestive heart failure. This has been found to be true for all members of the anthracycline class of

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medications, although some agents have a greater or lesser propensity to produce direct myocardial

damage. Clinical oncologists have learned how to monitor the cumulative dosage of anthracyclines,

as well as the cardiac function in order to limit myocardial damage during therapy.

During the 1970s and 1980s, a very different cardiac safety issue was uncovered. A number of

approved medications, including prenylamine, lidoflavin, and terodiline were withdrawn from the

market after an unexpected number of patients receiving these drugs suffered sudden cardiac

death. In the late 1980s reports of sudden deaths began to appear in patients receiving terfenadine.

This drug was the first long acting, non-sedating antihistamine commonly prescribed for the treatment

of hayfever and allergic symptoms. Many of these deaths occurred in young and otherwise healthy

individuals. It was ultimately discovered that many of these individuals developed a particular type

of ventricular tachycardia, known as Torsade de Pointes (TdP), which can generate into ventricular

fibrillation and cardiac arrest. Terfenadine can block IKr, one of the ionic channels which allow the

movement of potassium into and out of cardiac myocytes. This process this can produce the milieu

in which lethal ventricular arrhythmias develop. Under normal circumstances, terfenadine is a very

weak blocker of IKr – but in certain susceptible individuals, and particularly in the presence of other

medications which prevent the metabolism and clearance of terfenadine, very high levels of the

drug may be seen. The likelihood of lethal arrhythmias becomes quite high under such conditions

and as such, terfenadine was ultimately removed from the market.

Initial Regulatory Guidance

In the 1990s, after many approved medications were removed from the market due to increased risk

of sudden cardiac death (Table 2), researchers, drug developers, and regulators struggled to find a

way to prevent such drugs from reaching the market in the first place. The major problem was that

these cases of sudden arrhythmic death were rare (estimated at 1 in 50,000 for terfenadine). The

types of clinical trials performed during the development of a new drug typically involve hundreds, or

sometimes thousands of patients – hardly enough to detect a side effect this uncommon. To put the

dangers into perspective, however, millions of patients took terfenadine while it was marketed –

resulting in hundreds or even thousands of deaths. As a result, it became clear that a surrogate

marker which would more readily identify drugs with a high risk of producing TdP was needed.

Researchers evaluated a number of preclinical and clinical tests, and the regulatory authorities

ultimately identified a single clinical biomarker for detecting drugs with an increased risk of producing

lethal arrhythmias. This surrogate marker involves the collection of serial electrocardiograms (ECGs)

prior to and after administration of a new drug, as well as very precise measurement of the QT

interval on the ECG. It was recognized that all drugs which produce lethal arrhythmias increase the

QT interval, and that this could be detected in clinical trials of reasonable size.

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Table 2 Approved Drugs Withdrawn from the Market due to Proarrhythmia Concerns

Prenylamine (Segontin) – Ca Channel Blocker

Terfenadine (Seldane) - antihistamine

Terodiline – antimuscarinic agent for bladder spasm

Sertindole (Serlect) – atypical antipsychotic

Astemizole (Hismanal) - antihistamine

Grapafloxicin (Razar) - antibiotic

Cisapride (Propulsid) – serotonin agonist, GI

Bepedril (Vascor) - antianginal

Droperidol –sedative, antiemetic, antipsychotic

Levomethadyl (Orlaam) – treatment of opioid addiction

Propoxyphene (Darvon) – narcotic analgesic

The International Conference on Harmonisation (ICH), an international organization dedicated to

harmonizing the pharmaceutical regulations in different nations and regions, organized groups to

evaluate preclinical and clinical strategies to detect drugs with increased risk of producing lethal

arrhythmias. This resulted in the release of guidances for the pharmaceutical industry that delineate

the preclinical (ICH S7B) and clinical (ICH E14) strategies for drug developers to follow as they bring

NCEs through the development process.

The ICH E14 document is currently the ultimate word for planning how to assess the proarrhythmic risk

of a NCE. ICH E14 describes a new type of clinical trial, often referred to as a Thorough QT Trial (TQT)

or Thorough ECG Trial (TET), designed to assess the risk that a NCE will produce TdP. The document

states that this requirement holds for all new drugs with systemic bioavailability, regardless of

therapeutic area, and regardless of preclinical profile. Furthermore, the same principles apply to

approved products brought back for a new dose, new indication, new population, or new route of

administration (particularly if the expected systemic exposures are higher than for the current

formulation and use).

The ICH E14 guidance describes the design features for a TET; more specifically that it should be

performed in healthy volunteers in order to eliminate as many confounding variables as possible, and

that it should also involve at least three arms. These arms include a placebo arm, a positive

comparator arm, and a supratherapeutic dosage arm. The positive control is required to

demonstrate that the trial design and conduct are adequate to detect the very small QT effects of

concern. The supratherapeutic dosage of the drug is intended to demonstrate what might happen in

the worst case scenario – a patient receiving too high a dose, or receiving a concomitant metabolic

inhibitor, or with renal or hepatic insufficiency. (Most pharmaceutical firms also add a 4th arm, and

test a therapeutic dosage of the drug as well). The guidance goes on to state that the trial needs to

be able to detect a 5 ms effect (the positive control) with a one sided 95% CI that excludes a 10 ms

effect (for the active drug) using time matched methods.

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Regulatory Updates and Explanations

While the basic format has remained unchanged since 2005, there have been a number Q&A

releases by the E14 working group which further clarify the design requirements of a TET. A TET may

use a parallel or crossover design, depending on the pharmacokinetics of the NME and its

metabolites, but the threshold of regulatory concern, an effect with a one sided 95% CI that exceed

10 ms, remains the standard. Any drug which produces systemic exposures must undergo evaluation

of its QT effects. There are a few exceptions – drugs which are too toxic to give to healthy volunteers

(often cytotoxic chemotherapeutic agents), or large macromolecules which are believed to be too

large to interact directly with cardiac ion channels (such as antibodies and other macromolecules).

In these cases, it is still expected that an evaluation of the effects on QT will be assessed – but not with

the type of TET described in the ICH E14 document.

A question often raised is “why does this apply to my drug?”. The reason is not immediately obvious,

but it is fairly simple. The common mechanism by which many chemically dissimilar drugs produce QT

prolongation and TdP involves their increasing the heterogeneity of repolarization in the heart –

primarily related to blockade of the IKr potassium channel. The cardiac IKr channel is encoded by

the hERG - “human ether-a go-go” gene, and the cardiac IKr channel (often referred to as the hERG

channel) is a very “promiscuous” channel. It is estimated that 25-30% of all small molecule drugs

interact to some extent with the hERG channel. Thus, drugs with entirely different chemical structures

may have similar effects on hERG, which affects the QT interval, and may be proarrhythmic.

If a block of the hERG channel is the common pathway by which drugs produce lethal arrhythmias,

why not just test the effects of a drug on the hERG channel? Again, this was considered early on by

the ICH E14 working group, but it was recognized that there are a number of problems with putting all

of our eggs in one basket. One of which is relying entirely on assessment of a new drug’s ability to

produce hERG channel block. First, hERG channel assays of a compound really assess only what is

tested – the NCE itself – and do not assess the effects of any metabolites. Furthermore, drug-drug

interactions are not assessed, and indirect effects of a drug or its metabolites are ignored. We have

learned that many drugs which do not directly block the hERG channel pore (and also some which

do) may interfere with the hERG channel function indirectly by altering channel trafficking. The hERG

channel is a large macromolecule which has a typical life cycle – DNA is transcribed at the ribosomes,

undergoes processing, must be transported from the cytosol to the cell membrane, and then

eventually undergoes degradation and recycling. Drugs may interfere with this lifecycle at any point

– and such effects will not be detected with a direct assessment of a drug’s effects on the ion

channel. Furthermore, it is uncommon to know the ultimate clinical dosage of a new drug until late

Phase II or Phase III, when the drug is administered to large numbers of patients. As a result, it may be

difficult or impossible to tell whether the hERG channel block detected during preclinical testing will

occur at clinically relevant systemic exposures. But perhaps the biggest problem with relying solely

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on assessments of hERG channel block to screen out drugs which are proarrhythmic is the issue of

false positives. There are drugs which can block the hERG channel to some extent, but which may

not prolong the QT interval, and which may not produce proarrhythmia. Reliance entirely upon hERG

channel block for screening would lead to the abandonment of many potentially valuable new

drugs.

The ICH E14 working group therefore chose to rely on a clinical test, the evaluation of a new drug’s

potential for producing QT prolongation, as the surrogate marker for ventricular proarrhythmia. This

strategy has been quite successful in that since the adoption of the ICH E14 guidance in 2005, no

drug which has gone through the E14 pathway has been removed from the market due to

ventricular proarrhythmia. There is concern, however, that this strategy has had a negative effect on

drug development, and that many potentially valuable new drugs have been shelved during

development because of concerns (sometimes not well founded) of possible QT effects. As a result

of these concerns, a variety of newer strategies to screen new drugs for proarrhythmic risk are being

considered, including increased use of Phase I QT data, increased use of preclinical ion channel

assays, and the use of quantitative T wave morphology assessments.

The Need for Complete Cardiac Safety Testing

It is quite important to remember that the mandate of the FDA is to ensure that new drugs are safe

and effective, not just to monitor the effect of new drugs on the QT interval. QT prolongation and

ventricular proarrhythmia are not the only cardiac safety issues that have led to the withdrawal of

approved drugs. Over the past few decades we have witnessed the withdrawal of fen-phen

(fenfluramine/phentermine) due to cardiac valve damage and pulmonary hypertension, Vioxx and

other Cox-2 inhibitors due to increased incidence of myocardial infarction and stroke, severe

restrictions on the use of Avandia (rosiglitazone) due to concerns about excess numbers of

myocardial infarction and stroke, and the termination of the development of torcetrapib due to

excess cardiovascular events and concerns about drug induced blood pressure. None of these

issues are related to QT prolongation, and none of these can be detected by hERG channel assays.

Instead, they require that we collect ECGs and other cardiac safety information (echocardiograms,

ambulatory blood pressure monitoring, and adjudication of cardiovascular adverse events)

throughout the development of a new drug in order to be able to detect off target cardiac adverse

events. The complexity of the human organism is so great that it is unlikely that we will ever be able

to completely understand a new drug’s effects simply by preclinical testing and a priori assumptions.

The collection of clinical cardiac safety data during drug development will remain our best

mechanism for detecting unanticipated and harmful cardiovascular side effects before a new drug

is widely prescribed to patients.