To TQT or Not TQT? Recent Regulatory Discussions on The Future of The Thorough QT Study

Is The Thorough QT Study Still Required?
Recent proposals are in play which may have an impact on the future of the Thorough QT (TQT) study and on the evaluation of cardiac safety for new drugs.  ERT is involved in the conversation with regulators and with the evaluation of these new proposals, and we can guide your team through this evolving regulatory landscape.  Here, we aim to provide answers to some of the questions we often receive on the current status and future of this cardiac safety requirement.

What is driving the effort to replace the TQT study?
Since 2005, ICH E14 has been successful in that no drug developed under its guidance has been withdrawn for QT prolongation or Torsade de Pointes (TdP).  However, the unintended consequence of E14 is that too many drugs, some of which may be safe and effective, are dropped early in development due to minor QT concerns or equivocal preclinical signals.  In response, over the past few years the FDA, other regulatory bodies, and pharma have been exploring options to replace TQTs with preclinical testing or with data collected during standard Phase I trials.

What are the current FDA proposals to replace TQT studies?
There are two proposals at different stages of development.  The first is to use increased preclinical testing – the CiPA Proposal (Comprehensive in Vitro Proarrhythmia Assay) – to replace the TQT.  We anticipate that it will be at least several years before we know if this will be an effective replacement for assessing cardiac safety during drug development.  The second proposal would substitute intense ECG collection in SAD/MAD Phase I for the TQT – the CSRC/IQ Consortium proposal.  Since the cohort sizes in typical Phase I trials are small, the typical analysis of QTc changes by time point will not be very useful.  Instead, this strategy would use concentration effect modeling (CEM), or PK-PD assessments, to detect drug induced increases in QTc. A CSRC/IQ Consortium trial recently tested whether ECG and PK-PD data collected in Phase I could generate data equivalent to a TQT.  The trial design was similar to a typical SAD study, and the FDA contributed to the trial and selected six drugs to be tested: five known QT prolongers as well as one non-QT prolonger.  In December 2014, the CSRC/IQ Consortium announced the successful results of the trial.  PK-PD modeling was able to successfully generate data for these 6 drugs which were very similar to the results of TQT studies.  These findings raise the possibility that, depending on the regulatory response, Phase I ECG and PK-PD data may be permitted to replace a TQT study in the future.

Has ICH E14 changed to allow TQT waivers based on intense ECG PK-PD data from Phase I trials?
Regulatory authorities have not yet approved a change to ICH E14, but the ICH E14 Working Group has already begun to review the recent trial and proposal.  If approved, this is a very exciting potential opportunity for our industry.  Data could be collected in standard Phase I trials with minimal change to current practices, and in many cases could eliminate the need for a dedicated TQT study.  Adding Holter ECG collection to a Phase I study is inexpensive, and this change could reduce individual study costs dramatically.  Cardiac safety could potentially be determined much earlier in drug development, allowing sponsors to prioritize development efforts and make faster decisions on investments.  Most importantly, we will develop more life-saving and life-enhancing medical products for the patients who need them.

Are there any issues with replacing the TQT with intense ECG PK-PD data from Phase I trials? Will this apply to all drugs?
There are many open issues to navigate with this potential regulatory change, and the Phase I strategy may not work for every compound.  False positive and false negative rates are as yet unknown, and there is also potential regulatory concern about the lack of positive controls.  Larger cohorts and trial design changes in Phase I might potentially be needed.  There are also questions about whether this design will be effective for drugs with active metabolites (PK-PD assessment of the parent compound will not necessarily detect QTc effects of metabolites) or unusual pharmacokinetics (which often will not be understood at the time of Phase I studies).  There are number of other specific dimensions to consider, and ERT would like to review the whole range of issues and options with your team to fully optimize your next cardiac safety trial.

Can ERT implement the proposed new approach?
Yes, ERT can support this immediately.  Our cardiology experts with decades of trial design and regulatory experience will work with you to develop the most cost-effective and secure strategy for your next trial.  We have successfully conducted over 1,000 Phase I cardiac safety studies, and our precise, validated semi-auto analysis with industry leading SD of 5 to 8 ms delivers the highest data quality.  ERT has performed intense ECG collection as well as PK-PD analysis for many Phase I trials since 2000, and our expertise, innovation, and integration in cardiac safety centralization are unparalleled.

The CSRC/IQ Consortium trial utilized “high-precision QT analysis”. Is this the preferred or only accepted ECG methodology for Phase I intense ECGs? No, the trial employed a methodology utilized by only a single ECG core lab, and other methodologies are just as effective, if not more so, for intense ECG PK-PD collection and analysis in Phase I.  The CSRC stated in a clarification letter published to members and industry in January 2015 that they do not endorse any specific technology or ECG methodology. Regulatory bodies like the FDA, EMA, Health Canada, and PMDA similarly do not endorse any vendor’s technology or methodology.

Is ERT’s approach as precise as “high-precision QT analysis”?
Yes.  “High-precision QT analysis” is based on the COMPAS system, a proprietary algorithm developed in 1990s/early 2000s.  It calls for 10 ECGs to be collected per time point and for automated measurements.  3 ECGs per time point is the industry standard, and published data suggests that beyond 3-5 replicates, there is little additional reduction in variability, but, of course, higher cost.  ERT recommends that measurements be performed with a semi-automated analysis methodology that leverages an algorithm for initial caliper placements and then human adjudication of all measurements.  Semi-automated measurements are currently the industry standard.  ERT recommends human review and adjudication of all ECGs, and ERT’s precise semi-auto analysis with industry leading SD of 5 to 8 ms in Phase I cardiac safety studies was used to support 20% of all new drug approvals in 2014 alone.

Where can I learn more?
You can view a recently recorded webinar on the future of the TQT – or schedule an information session with an ERT cardiologist to review the whole range of issues and options to optimize your next cardiac safety trial.

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The Increasing Use of PROs in Oncology Trials: Addressing the How, Why, and Who

The use of Patient Reported Outcome (PRO) endpoints in new drug development in oncology are relatively low compared to other disease areas such as respiratory, neurology, gastroenterology and rheumatology.  However, with newer cancer drug therapies delivering better survival rates, quality of life is becoming as important as survival in cancer patients.  Today, there are many ways in which the voice of the patient is influencing clinical decision making in oncology, which is increasing the need for new drug developers to measure clinical trial outcomes that are relevant to patients.

The most common way to capture the voice of the patient is through PROs.  There are significant benefits of collecting PRO data in clinical trials, including:

  • PRO Measures (PROMs) are the most relevant/sole endpoints in symptomatic cancers, especially in patients with longer survival
  • Patient reports help understand the value of changes in their disease, from the patient’s point of view
    • Patients’ views are sometimes different from clinician and laboratory/radiology assessments
  • PROMs estimate the impact on both efficacy and tolerability
  • PROMs help identify the segments of patients who may benefit the most from treatment
  • PROMs help demonstrate the burden of the disease on patients
  • PROMs predict longer-term outcomes

The past decade has seen a significant increase in the number of new oncology treatments that incorporated PRO measures during clinical development.  This may be in part, due to the inherent nature of PROs to address the many different needs of key stakeholders – regulators, payers, physicians, and patients.

In a January 2015 webinar, Vasudha Bal of Novartis Pharmaceuticals reviewed the current move toward more patient-centric care in oncology, demonstrated how it is becoming increasingly important to all key stakeholders, and provided examples of how trial sponsors are implementing effective PRO strategies in their clinical development programs while minimizing burden on patients and sites.

Click here for complimentary access to the recorded webinar, “Patient Centric Focus in Oncology Trials:  Changing Paradigms”.

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eCOA in Diabetes Trials: Capturing Key Patient Data for All Stakeholders’ Needs

The diabetes marketplace is saturated. Actually, with 13 classes of therapies licensed & available to treat hyperglycemia in Type 2 Diabetes Mellitus (T2DM), each containing multiple safe and effective medications, some might say it is over-saturated. However, many T2DM patients who are prescribed these medications are still not achieving their glucose targets – largely due to poor medication adherence. In fact, 30% of new diabetes prescriptions are never even filled at the pharmacy.

At the same time, diabetes is one of the western world’s most common chronic conditions, with global prevalence increasing rapidly. T2DM constitutes 85-95% of diabetes and is accompanied by significant clinical and economic burden.

Biopharmaceutical developers are realizing the great opportunity that exists for developing new, safe and effective diabetes treatments. However, in order to be clinically and commercially successful, new entries to the diabetes market need to go beyond simply demonstrating efficacy and safety; they need to improve upon existing patient adherence levels of available treatments.

Diabetes is a self-management condition in which we expect patients to engage. It is the extent of patients’ engagement with lifestyle changes and medication that will determine clinical outcomes, not merely the presence of effective medication in the body. During a webinar on Nov. 17, 2014, ERT Scientific and Regulatory Consultant, Matthew Reaney reviewed how, in clinical practice, healthcare professionals and patients must work together to address the clinical, economic and humanistic (psychosocial) aspects of diabetes in order to improve patient adherence and treatment effectiveness.

Matthew demonstrated how the path to improved treatment adherence can be reached by examining the patient perspective during clinical development. Biopharmaceutical companies can use Clinical Outcome Assessments (COAs) to better understand the impact of diabetes treatments on psychosocial functioning, explore the relevance of non-glycemic parameters (including mode and method of administration), and help predict whether patients are likely to engage with therapy in routine clinical practice. COAs can be used to help developers understand how new medical products differ from existing therapies in terms of side-effect profiles (including hypoglycaemia, weight, nausea), safety concerns, and rapidity of achieving outcomes. Because few differences exist among available therapies in terms of glycemic control, quantitative data on these patient (or care-giver) experiences may make a big difference on not only patient adherence, but could lead to favorable outcomes with other keys stakeholders, including regulators, payers, and healthcare providers.

For complimentary access to the recorded webinar, please visit

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Benefits of Standardized, Centralized DLCO in Respiratory Clinical Trials

The largest source of subject variability within a respiratory clinical trial is the improper performance of a test. Such “noise” in spirometry and other pulmonary function testing (PFT), coupled with device calibration and technician training inconsistencies, can restrict the ability to find important clinical signals relating to treatment effects.

For your trial, this means a heightened risk of inaccurate and unusable data that can only be prevented by utilizing standardized and centralized respiratory services. Standardization involves the use of consistent devices and calibration across sites, as well as identical training regimes for technicians to ensure consistent patient performance. Centralization delivers digital collection of test results and helps increase data quality by providing the ability to better see treatment effects through accurate analysis. Centralization also institutes quality control measures in each step of the clinical trial process so the study has the advantage of cleaner data, which in turn minimizes the negative impact to your data and your budget.

These benefits apply to the carbon monoxide diffusing capacity test (DLCO), a commonly used pulmonary function test that measures the gas exchange ability of the lungs. While spirometry measures lung mechanics and lung volume PFTs ascertain size, DLCO tests indicate how well the lungs and heart are able to oxygenate blood. DLCO measurements specifically test the integrity of the alveolar/capillary interface in the lungs. Repeated measures of DLCO aid in determining disease progression or therapy efficacy and enable clinicians to identify diagnostic details that are not visible by spirometry or other PFT approaches.

Unfortunately, many DLCO measurements are subject to variability as a result of patient, equipment, or technician errors. To obtain consistent, credible data, DLCO equipment must be properly maintained and regularly calibrated. In addition, diffusion testing requires a specially trained technician who can validate the data by understanding the measurements and also their plausibility in relationship to the subject’s condition.

According to a study published in Respiratory Care, DLCO measurements of the same patient in different labs vary as much as 50%. In an effort to reduce these differences, the American Thoracic Society (ATS) and European Respiratory Society (ERS) published the standardized testing procedures and equipment recommendations for DLCO in 2005, which can be found here:

Since improper training and poor patient effort will lead to poor quality data, it is crucial to educate and monitor the technicians to improve the accuracy of the data being reported. It is equally important to ensure the equipment and measurement procedures meet performance criteria so that end assessments have the greatest, most consistent data – significantly reducing variability.

Using standard equipment across all investigator sites is also vital to producing consistent, quality data. Standardized devices significantly reduce variability often caused between instruments, meeting ATS/ERS standards for accuracy.

With centralization, data is transmitted to a central database and is graded according to a combination of the ATS/ERS standards and pharmaceutical company specifications.  The overread of data quality is reviewed proactively, so sites with a large amount of poor quality data can be targeted during the trial for retraining.

Centralized, standardized DLCO measurement benefits the development of new compounds for the treatment of asthma, chronic obstructive pulmonary disease (COPD), and other indications by reducing variability inherent to effort-dependent pulmonary tests.  ERT provides standardized devices and training as well as central data collection, and we will evaluate both digital and site-generated paper DLCO measurements for quality and performance. 100% data overread is provided by a highly qualified team with over 20 years of clinical experience guided by multiple levels of quality control and assurance. Standardizing and centralizing with ERT significantly increases the percentage of acceptable data and provides the best quality data – resulting in greater patient retention, increased statistical power at a reduced price, and ultimate determination of efficacy to support your new drug application’s regulatory approval.

Visit the ERT Resource Center at for more information on centralizing and standardizing DLCO and other measures in respiratory trials. There you can register to view the recently recorded webinar, “Current Pharmacotherapeutic Treatment and DLCO Monitoring Strategies for the Management of Asthma and COPD.”

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ERT Summary and Commentary on the ICH E14 Q&A(R2)

Written by: Dr. Robert Kleiman, Chief Medical Officer & Vice President, Global Cardiology

The ICH E14 Implementation Working Group (IWG) released a third set of Q&A responses on March 21, 2014.  The latest document discusses concentration response modelling of QTc data as well as three “special cases”.  Overall this Q&A adds valuable commentary and guidance regarding some of the questions about Thorough QT Studies (TQTs) – though a variety of additional topics would still benefit from further clarification.

The first topic addressed by the new Q&A document concerns the use of concentration response relationship (CRR) modelling of TQT data.  At the time that the ICH E14 guidance was drafted, CRR assessment was still considered an area of “active investigation”, but it has since become a very important and well respected part of the assessment for the proarrhythmic potential of new drugs.  The new Q&A document explains that the CRR can be a useful part of a drug’s evaluation, and goes on to explain the importance of prospectively describing the pharmacokinetic-pharmacodynamic (PK-PD) models which will be used.  This is to avoid post hoc attempts to utilize as many PK-PD models as possible until one finds the “best” PK-PD model which yields the most desirable results.  The IWG also acknowledges that there are situations in which a QT effect is delayed or persistent when compared to plasma concentrations, resulting in an exposure response relationship that shows hysteresis.  This may occur when a long acting metabolite has QT effects, when there is myocardial accumulation of a drug or metabolite, or when there are delayed effects on ion channel trafficking.  The IWG briefly discusses the use of PK-PD models which incorporate hysteresis, and then discusses the situations in which analysis of CRR may be useful. This includes the estimation of the QT effect of doses of a drug which have not been formally tested, clarifying ambiguous QTc results from a TQT or early phase study, or helping to predict the QTc effect of factors which may alter a drug’s PK.

The IWG then proceeds to discuss 3 “special cases”.  First, when a single dose crossover design TQT is not feasible, the IWG mentions that alternative designs using a parallel arm design, using patients with the targeted disease rather than healthy volunteers, or using other alternative designs may still be possible.  When a placebo controlled arm is not appropriate (as is the case for many new oncologic agents), the IWG recommends that study designs should incorporate as many of the usual TQT features as possible.  In particular, intense ECG and PK collection during early phase ascending dose studies, or even in a late stage trial, may be able to provide sufficient data to assess a drug’s proarrhythmic risk.

The IWG then briefly discusses QT assessment for combination drug products.  If the component drugs in a new product have all undergone TQTs which show no relevant QT effects, then a TQT or intense late stage ECG monitoring will probably not be necessary.  However, if one or more of the component drugs has never had a thorough QT/QTc assessment, the IWG states that they may be evaluated in combination or independently.

Finally, the IWG states that large targeted proteins and monoclonal antibodies have a low likelihood of direct interactions with ion channels, and therefore a TQT would usually not be required unless there are unusual circumstances suggesting the potential for proarrhythmia.

While this latest Q&A document does clarify some of the important issues which remain regarding the QT/QTc assessment of new drugs; further clarity would still be helpful regarding several other issues, including:

  • Use of PK-PD models which better account for the effects of active metabolites
  • The need for use of a positive control when a drug can only be studied in patients
  • How best to assess combination products: the IWG statement about performing QTc evaluation of “independently or in combination” does not clearly help us understand the design elements which would best meet regulatory approval
  • The best strategy for assessing the QT/QTc effects of large proteins and macromolecules.  Although a TQT may not be required, it is well known that many proteins do have QTc and other cardiovascular effects, and regulators do still expect submission of some ECG data for large molecules.  A further clarification concerning what type of ECG data is expected would be helpful.

In summary, the latest Q&A document further refines our understanding of the regulatory pathways for evaluating the proarrhythmic potential of new drugs.  As always, there are always further issues which may still require additional clarification, and we await future releases from the E14 IWG.

For more information on TQT studies, contact ERT here.

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ERT Goes to the 50th Annual DIA in San Diego

This year at the DIA, the industry’s largest annual conference, ERT had lots of exciting news to share. With several product launches happening at the booth, ERT continues to improve clinical technology and innovate better health for patients.

We had the Senior Director of Global Cardiac Safety Solutions on hand to discuss the new QT Guard Plus Analysis System and an upcoming SITEpro/ELI-PC integration. The QT Guard is the latest novel technology provided by our EXPERT® platform as part of ERT’s centralized cardiac safety solutions. Using the standard 12-lead ECG, biopharmaceutical companies can perform quantitative analysis of drug induced changes in T-wave morphology. This technology is set to improve cardiac safety while preserving sponsors’ drug development pipelines. ELI-PC and SITEpro provides ECG integration with eCOA studies to drive value to clients for integrated service delivery. The goal is to utilize ELI-PC hardware and software (or API) to collect ECG and eCOA data during the clinical trial patient visit, and to use SITEpro to seamlessly transfer the data to ERT.

eCOA Product Managers were also at the booth to demonstrate ERT’s new eCOA app which enables a Bring Your Own Device (BYOD) approach for collecting patient data in clinical trials. Since this Apple® (iOS) and Android™ app use patients’ smartphone devices, sponsors eliminate the need to purchase and manage hardware, which means reduced cost and logistics burden. Patients benefit from a familiar user interface that fits into their daily lives. Unlike other mobile applications that run within web browsers and require a live internet connection, this BYOD solution allows fully-offline operation for when data must be entered during strict time windows, regardless of internet connectivity.

Respiratory Product Managers provided demos of the new MasterScope v2.0. This system delivers an improved and fully integrated solution for Spirometry, ECG, home monitoring, and collection of exhaled nitric oxide (NIOX Mino). While at DIA, ERT also received 510(k) clearance from the U.S. Food and Drug Administration to market our AM3® GSM devices in respiratory clinical trials.  The AM3 GSM device provides a robust and reliable wireless option for clinical trial patients to communicate key spirometry data during the clinical development of new respiratory treatments. Now with the availability of AM3 GSM, important respiratory data can be simply and cost-effectively transferred from a patient’s home which allows near real-time access to patient data for investigators and sponsors, enabling better patient monitoring and, ultimately, better care.

MasterScope Respitatory Platform

In addition to all of this hard work and launch planning, we also made sure to have a little fun. We participated in a Medical Heroes 5k first thing Monday morning. Together 300 professionals, patients, and community members celebrated the people who give the gift of participation in clinical research. At the ERT booth, we were streaming the World Cup games live, held several contests, gave away things like ice cream, beer and wine, healthy snacks, hacky sacks, flash drives, and gift cards. We also had two stations for customers to come by and “refresh and recharge” – allowing some time to stop and talk with us while they added some juice to their mobile devices. One of the most memorable events was the Monday night DIA Castaway party. ERT, in conjunction with TransPerfect, put together the biggest event of the year at the Port Pavilion in San Diego. So many of our customers and colleagues (1,500 to be exact!) came out to join us for food, drinks, and music. The venue was amazing, the castaway/beach themed décor couldn’t have been better, and seriously, who doesn’t love a rockin’ 80’s cover band?

Medical Heroes 5k  World Cup at DIA    ca3


You can view more photos at and follow all the social media buzz on

See you next year!


Posted in Clinical Research, Clinical Trials, DIA, DIA Annual Meeting, Drug Information Association, Pharmaceutical | Leave a comment

ERT Clinical Applications Not Susceptible to Heartbleed OpenSSL Exploit

Message to our customers regarding Heartbleed security bug – ERT clinical applications were not impacted: 

As widely publicized, there was a recently discovered vulnerability detected within a very popular encryption software known as OpenSSL. This vulnerability, known as Heartbleed, allows internet traffic, thought to be secured via SSL encryption, to be exposed to persons who have created methods of exploiting this vulnerability.

ERT maintains stringent security protocols during the development and production implementation of our applications and we apply multiple layers of protection for our client data. Following the identification of this vulnerability, we have conducted exhaustive tests to verify that our systems remain secure. Due to the fact that ERT’s clinical applications utilize the most current Java and Windows security stacks, we were not susceptible to this OpenSSL exploit – since OpenSSL is not used by our clinical applications.

As always, our security protocols as well as our package management process includes checks for current and older security exploits which we actively test for and correct when detected in accordance with ERT Standard Operating Procedures.

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Cardiovascular Outcomes Trials and COPD Drugs – The Latest Regulatory Point of View

Written by: Dr. Robert Kleiman, Chief Medical Officer & Vice President, Global Cardiology

It’s quite common for patients with chronic obstructive pulmonary disease (COPD) to have concomitant cardiovascular (CV) disease.   There’s no great mystery to this – COPD tends to occur in older patients, many of whom will also have common CV risk factors such as hypertension, diabetes and hyperlipidemia.  And of course, most cases of COPD are related to cigarette smoking, which itself is a strong risk factor for the development of CV disease.  Patients who participate in COPD trials often develop CV adverse events which are just related to their underlying CV disease.  As a result, during the development of new drugs to treat COPD, it becomes very difficult to tell whether CV adverse events are directly related to therapy or simply represent the natural history of the patient’s underlying CV disease.

There are similarities with the development of new drugs for the treatment of diabetes, as patients with diabetes often have CV disease, and have increased rates of CV events.  As part of the fallout from Rosiglitazone, regulators have raised CV concerns about all new anti-diabetic agents, and despite some controversy, have required large CV outcome safety trials (learn more on a previous ERT Blog). Are sponsors expected to go down the same path for COPD therapies?

Probably not.  During a recent Cardiac Safety Research Consortium (CSRC) Think Tank Meeting, several regulatory representatives commented that there was no clear evidence that current COPD treatment modalities (long acting beta agonists and long acting muscarinic antagonists) produce adverse CV outcomes.  In fact, the results of two large randomized clinical trials, TIOSPIR and UPLIFT, suggest that COPD therapies don’t result in an excess of CV events.  The regulators present at the recent CSRC meeting stated that they did not feel that dedicated CV outcomes trials would be routinely required for new COPD drugs. The CV safety of new COPD medications, however, does remain an area of regulatory concern, and a dedicated CV outcomes trial might be required on a case-by-case basis, depending on the data submitted. This is good news for the industry as a blanket requirement for CV outcomes studies could delay or even halt the development of new treatments for COPD due to the huge expense of these studies.

So how can sponsors prospectively avoid big, long, expensive outcomes trials? Here are a few recommendations based on comments from the FDA, EMA and PMDA:

  1. Include a representative sample of COPD patients – including sicker patients – in Phase III trials.  This may require reducing the exclusion criteria to allow at least a subset of patients with more severe COPD as well as baseline CV disease.
  2. Obtain better and more robust baseline assessments of CV risk factors and CV status during clinical trial enrollment.
  3. If a CV adverse event does occur, insure that the site asks the right questions and collects adequate clinical data for later analysis. The CSRC provides forms which can and should be used by sites here.  Formal event adjudication may not be required, but at least be prepared to help the regulators understand any CV adverse events which have occurred.
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A Global Crisis – The War on Suicide in Japan

Dr. Rene Duignan, not a professional film-maker but an Irish economist, was driven by a personal regret to create a film that would shed light on the crisis of suicide in Japan. Rene’s award winning documentary Saving 10,000 — Winning a War on Suicide in Japan explores the true causes of the high suicide rate in the region and suggests practical solutions for suicide prevention. The goal: to save 10,000 lives.

The suicide rate in Japan is twice that of America, with 30,000 lives lost each year. That’s 300,000 Japanese people in the last 10 years. While it is “taboo” to talk about suicide in Japan, there are manuals teaching you how to kill yourself that sell over a million copies. The culture sometimes portrays suicide as “beautiful” and is often “sensationalized” or used as a source of entertainment on Japanese television. Suicide is also a solution for many as a way to help their families from financial struggles. In Japan, life insurance companies pay out to the families of suicide victims.  Due to a deep sense of personal responsibility, some would rather take their own lives than continue to face economic hardship.

As in any country, suicidal ideation and behavior comes from an element of mental illness such as depression, and does not discriminate. It affects men, women, children, middle aged, elderly, rich, poor, famous or ordinary. It was noted in this documentary that 2/3 of all depression is triggered by a pressure of some sort – lack of sleep, being over worked, bullied, or abused, loneliness, failure, guilt, and the list goes on. There is a lack of mental health treatment and resources in Japan. The average clinic has upwards of 40-50 patients, which only leaves 3-4 minutes per individual. Therapy is too expensive for many people as it is not covered by health insurance.

For every suicide, there are 10 suicide attempts; that’s 300,000 attempts every year. This constitutes up to 20% of all patients in the most critical emergency medical centers. Of the 30,000 suicides completed annually, approximately 10,000 of those victims were already in the mental health system seeking active treatment, having consultations, taking medications or have been institutionalized. As healthcare providers, there is an opportunity to address this public health crisis. People who commit suicide see healthcare providers in the critical days before their death.

How can healthcare workers meet the increased demand for their time and address the challenge of rising suicides among patients? Standardized and efficient mental health screening and suicide risk assessment is a part of this answer.

In pharmaceutical product development, the Food and Drug Administration has mandated prospective monitoring of suicidal ideation and behavior for certain classes of drugs. Clinical researchers have used electronic, patient self-reported suicide risk assessment tools to ensure the safety of patients enrolled in clinical trials. AVERT™ is one such tool. AVERT utilizes the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to capture the full range of evidence-based suicidal ideation and behavior data. It has been used to conduct more than 160,000 assessments of over 35,000 patients across the globe – including Japan. Global healthcare providers can realize the same benefits clinical researchers continue to find in AVERT.

Electronic, self-reported systems enable patients to complete the assessment privately via the Web, an electronic tablet or their smartphones. People can complete them in just over three minutes, and the results are reported immediately to their healthcare provider. If the assessment finds the patient to be at risk for suicide, an alert will instantly be issued and the appropriate follow-up can be provided.

In addition to the solutions proposed by Dr. Rene Duignan, we believe that healthcare providers have an opportunity to provide community benefit through quick, efficient and effective suicide risk assessment. Systems like AVERT, which leverage good technology and good science, can help do that.

Please take a few moments to view: Saving 10,000 — Winning a War on Suicide in Japan below. For any questions regarding AVERT in clinical research or healthcare, you may contact us here.

Posted in Clinical Research, Clinical Trials, eC-SSRS, FDA, Suicidality Monitoring | Tagged , , | Leave a comment

Regulatory Trends in Reviewing Risk/Benefit Assessments: U.S. FDA Perspective

Today’s blog will discuss regulatory trends in reviewing benefit/harm assessments in medical interventions. The important question here is: how do we balance the two? When we use the term “benefits” we are referring to “the good” that actually happens to patients by prescribing medical interventions; more specifically, the ability of medical intervention to improve outcomes for patients in terms of decreasing symptoms, improving function, or improving survival. It could also mean fewer adverse effects compared to other interventions. Benefit is also termed “efficacy” or “effectiveness.”

Harms, on the other hand, are “the bad.” They are the adverse unwanted consequences reasonably associated with use of medical interventions. These can include things like signs, symptoms, lab values, vital signs, ECG, etc. Harms are often erroneously termed “safety.” However, no intervention is completely “safe” in terms of absence of all harms. Safety is really the balance of benefits vs. harms, not just harms alone. This concept was recognized early on in the history of FDA, even before the 1962 requirement for effectiveness.

Regulatory History:

Prior to 1938, there was no premarket review, only response to crises. However, based on the sulfanilamide tragedy that year, drugs had to be shown as “safe” prior to marketing and there was recognition that efficacy was important in this consideration. “If the drug that killed one person in ten thousand was of only minor use therapeutically, it might still be judged to be unsafe, whereas the drug that killed one in a thousand persons, if it had marked and undisputed therapeutic value it would still be a safe and valuable drug.” [J.J. Durett, Chief, Drug Division, FDA, December 1938] In other words, “safety” depends upon context of use – the magnitude of benefit, in what patient population, for what disease and at what dose/exposure.

In 1962, the requirement to demonstrate efficacy (benefits) to justify any potential harms, prior to marketing, was established. The standard of efficacy is “substantial evidence” from “adequate and well-controlled studies.”  Efficacy is not based on p-values alone. You need to show clinically meaningful differences as well as statistical significance. [Warner-Lambert v Heckler 1986] This entails judgment of what is considered “clinically meaningful.” A better way to frame that judgment is to have actual evidence from patients about what is meaningful for them through the development and use of patient reported outcomes (PROs).

The standard for evaluating harms is not very clear in terms of law and regulations. In the Federal Food, Drug, Cosmetic Act, section 505 it states that “adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling.” “Adequate tests” are very contextual depending upon what kind of patients and medical interventions you are studying. During a recent court case [Matrixx vs. Siracusano, March 22, 2011], Justice Sotomayor stated statistical significance is not necessary to show harm – “Because adverse event reports can take many forms, assessing their materiality is a fact-specific inquiry…Something more than the mere existence of adverse event reports is needed to satisfy that standard, but that something more is not limited to statistical significance and can come from the source, content and context of the reports.” To address the need for improvement in the clarity and transparency of the FDA’s benefit-risk assessment in human drug review, the FDA has made recent efforts to move toward more structured assessments, entailing both quantitative and qualitative types of decision making.

Current FDA Thinking:

As part of Prescription Drug User Fee Act (PDUFA) V negotiations, the FDA was tasked to develop structured benefit-risk assessment to serve as a template in product reviews. In February 2013, a document entitled “Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision Making: Draft PDUFA V Implementation Plan” was published to lay out the thinking on the approach to the assessment of benefits and harms when reviewing medical interventions.

One of the things people have been pushing the FDA to do is to use a more “quantitative” approach to benefit-harm assessments. On page four of this document it states: “The term ‘quantitative benefit-risk assessment’ can have various meanings depending on who is asked. Some hold the view that a quantitative benefit-risk assessment encompasses approaches that seek to quantify benefits and risks, as well as the weight that is placed on each of the components such that the entire benefit-risk assessment is quantitative.” “This approach is typical of quantitative decision modeling. It usually requires assigning numerical weights to benefit and risk considerations in a process involving numerous judgments that are at best debatable and at worst arbitrary. The subjective judgments and assumptions that would inevitably be embodied in such quantitative decision modeling would be much less transparent, if not obscured, to those who wish to understand a regulator’s thinking.”  In other words, if you reduce this to only a number, the meaning behind that number will be lost. So, much like efficacy assessments, you cannot boil down assessments of harm to a “p value” which is independent of its clinical meaningfulness.

This document provides a very helpful way to think about doing benefit/harm assessments including the suggestion to divide up the considerations into two major areas: therapeutic and product specific. Therapeutic area considerations cover the disease and the types of patients being studied including an analysis of the condition as well as current treatment options. It lays out the problem but does not address whether the new intervention provides a solution to the problem. Product specific considerations cover the benefits of the particular intervention (what are they, the magnitude, and in whom) and the harms (risk), including how these harms can be mitigated (risk management).  In essence, you want to briefly frame the therapeutic area considerations and then spend your time on how your product actually addresses the problem.  Below is the provided matrix for FDA Benefit-Risk Framework.



“Uncertainty,” as presented in this matrix, refers to decisions based on assumptions that are not verifiable based on available information. The best way to de-risk development and decrease uncertainties regarding the nature and magnitude of benefits (to balance against harms) is through better measurement of benefits – using improved measurement tools, such as PROs. Oftentimes, sponsors are very hesitant to study additional potential benefits due to “regulatory uncertainty.” However, if we do not move beyond that thinking, FDA approval will become nothing more than a rubber stamp.

The FDA regulatory standard for most interventions, except for life threatening or contagious diseases, is that you only have to be better than nothing. However, patients, clinicians, and payers have no interest in whether your product is slightly better than placebo when there are other interventions out there for that particular disease. People will begin to look beyond FDA approval and compare how you have improved patients’ lives against other interventions in order to decide which they will pay for and ultimately use. Improved and additional information on benefits and harms through the use of PROs leads to more informed decision making. This will help you rely less on assumptions to address uncertainties and get you into more of a fact-based assessment that will actually help patients, clinicians, regulators, and payers understand which medical interventions are the better treatments options.

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