FDA Requests for Cardiac Safety Data after Drug Approval: A Case Study from 15 Years in the Future

All new pharmaceutical products must go through comprehensive testing to assess their effect on the cardiac system of patients before being approved for release to the market. As cardiac safety concerns are the number one reason that drugs are refused regulatory approval, delayed, or are withdrawn from the market, the need for reliable, accurate collection, interpretation, and distribution of ECG and blood pressure data during the clinical trial process is paramount.

Centralizing the collection of cardiac safety data during trials in any phase reduces burden and risks while lowering overall costs for stakeholders and investigation sites.  ERT’s centralized Cardiac Safety solution ensures:

  • The highest quality data with consistent devices, algorithms, training, and analysis across sites
  • Rigorous QA/QC and multiple eyes on the data with cardiologists’ and electrophysiologists’ analysis
  • Real-time digital access
  • Global site support and proactive project management
  • Clean, formatted data for correct regulatory submission and archiving

In the following case study, you’ll see how centralization better protects not only patients but also compounds and sponsors themselves – if and when regulatory questions arise…

Case Study
Regulations and best practices have led to increasing industry centralization of cardiac safety studies, but an estimated 50% of clinical trials still follow a decentralized, paper-based approach, leaving sponsors with no digital ECG database. Using a paper-based, decentralized approach to cardiac safety data collection may introduce regulatory risks, even after a compound is approved.

One pharmaceutical sponsor who worked with ERT on a centralized cardiac safety study 15 years ago recently recognized the enduring benefits of a centralized approach to ECG data collection:

  • A global pharmaceutical sponsor worked with ERT to conduct a cardiac safety in 1999, collecting 5,400 ECGs centrally from 200 patients at different sites. ERT archived the data on tapes and put them into secure storage.
  • Unexpectedly in 2014 – well after the compound was approved – the FDA requested to review the study’s ECG data.  ERT quickly found the raw data in storage and analyzed it on legacy software. It was soon discovered that the old data had inconsistent wave lengths incompatible with current FDA XML submission standards.
  • ERT’s technology team transformed the raw data into the correct format and delivered proper ECG XML files to the sponsor in time to comply with the FDA’s request.
  • The sponsor submitted the data to FDA, which was accepted in the new format and is currently under review.

Had the sponsor not planned ahead to centralize with a reliable partner like ERT, they may not have been able to fulfill this regulatory request, placing their compound in regulatory jeopardy.

ERT has invested in systems and processes that deliver this type of solution, even over a decade after a study has been completed.   By working closely with our sponsor and CRO partners, and by offering innovative and reliable tools to provide a proven centralized cardiac safety solution, ERT offers the most effective strategy for reducing regulatory risk and for helping sponsors solve challenges if and when they arise.

 

 

 

 

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One Program, Four Stakeholders: An Overview of the Utilization of Patient-Reported Outcomes in Intervention Development to Meet the Needs of Regulators, Payers, Healthcare Professionals and Patients

In a competitive market where interventions often demonstrate similar effects on primary endpoints, patient-centric endpoint data can be valuable drivers of differentiation.  Many of these patient-centric endpoints are best measured with patient-reported outcomes (PROs).

A PRO is a measure of any aspect of a patient’s health status that comes directly from the patient, and is based on the patient’s perception of a disease and its treatments.  PRO instruments can measure a range of concepts, including signs and symptoms of a condition, side effects of medication, physical and psychosocial impact of treatment on daily life, treatment satisfaction, adherence to treatment, health-related quality of life (HRQOL), or a combination of these factors.

In clinical trials evaluating the efficacy of treatments, PRO instruments are used as a primary outcome in some therapeutic areas, and as a secondary or exploratory outcome in many other areas.  However, there is a lack of clarity about the most appropriate way to incorporate PRO instruments in the clinical development of pharmaceutical interventions in a way that will resonate with the four key stakeholder groups – regulators, payers, HCPs and patients.

The focus on patient experiences differs between regulatory, payer, healthcare professional and patient stakeholders.  The regulator is primarily interested in ‘first-order impacts’ and their direct effects, the payer is increasingly interested in HRQOL and healthcare professionals and patients are interested in a broader set of endpoints that may be used to aid clinical decision making.

In the recently published “One Programme, Four Stakeholders:  an Overview of the Utilization of Patient-Reported Outcomes in Intervention Development to Meet the Needs of Regulators, Payers, Healthcare Professionals and Patients” (Reaney, et al; Pharmaceutical Medicine; March 2014), the authors discuss how a robust, comprehensive and systematic endpoint strategy can be developed to meet the needs of all stakeholders, if considered early in clinical development.

The article also provides an overview of the similarities, differences and the manner with which the various stake-holders seek, use and interpret data about the patient’s experience.  Furthermore, it seeks to provide guidance on how to efficiently incorporate PRO instruments into a clinical development program in order to maximize the validity and acceptability of the data generated, thereby ensuring adequate evidence relative to the perspective of the patient is provided to all stakeholder groups.

To access this article, please visit www.ert.com/clinical/resources/white-papers.

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European Medicines Agency (EMA) Approves First PRO Label Claim in New Diabetes Treatment

Trulicity® (dulaglutide), approved by the EMA in November 2014 for the treatment of type 2 diabetes in adults, is the first diabetes drug to have a Patient Reported Outcome (PRO) (other than self-monitored blood glucose profiles) included in it’s summary of product characteristics (“label”). The following text has been included under the clinical efficacy and safety section: “Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily.”

This claim is important for multiple reasons.  Not only does it exemplify EMA’s stance on the use of PROs in new medical product development, but also because the developer – Eli Lily –has garnered important insight into patients’ perspectives of dulaglutide. Demonstrating improvements from baseline in treatment satisfaction with dulaglutide, and showing that this improvement was greater with dulaglutide when compared to exenatide twice daily allows Eli Lilly to summarize with one metric both the relative balance (from the users’ perspective) between positive clinical outcomes and negative side-effects of dulaglutide, and the patient perceived benefit of improved clinical efficacy and reduced injection frequency versus an efficacious comparator. It also loosely allows them to hypothesize patients’ adherence to dulaglutide in clinical practice. As indicated in a press release by Eli Lilly when the data was published in 2013, “These results, coupled with dulaglutide’s positive clinical data, suggest that.. (dulaglutide) may be an attractive treatment option for patients with type 2 diabetes.”

The data is derived from a Phase 3 trial comparing dulaglutide to exenatide twice daily (open-label) and placebo (double-blind) when added to maximally tolerated doses of metformin and pioglitazone1. Matthew Reaney, a Practitioner Health Psychologist in the UK and Senior Scientist at ERT, was the primary author on the treatment satisfaction data when presented at the American Diabetes Association meeting in 2013.2.

Matthew is delighted that the EMA has included the treatment satisfaction data in the dulaglutide label: “Type 2 diabetes is a chronic self-management condition. We ask our patients to engage with many aspects of self care, including the routine taking of medication to control their blood glucose. Adherence rates for medication in type 2 diabetes is poor, despite patients’ acknowledgement about the importance of their medication (and the clinical and economic detriments of non-adherent behaviour).”

Matthew continues, “A patient who is satisfied with their treatment is more likely to engage and will therefore derive the maximal therapeutic benefit that medication can offer. Treatment satisfaction is therefore a relevant endpoint for clinical research in type 2 diabetes, and perhaps more importantly, a key point for discussion between provider and patient in evidence-based prescribing. The inclusion of treatment satisfaction data in the label for dulaglutide shows that the EMA is acknowledging the relevance of the patient perspective as it pertains to the saturated market of type 2 diabetes treatment.”

Matthew Reaney recently published three editorials/commentaries related to this topic; on selecting PRO measures in diabetes research3, on interpreting diabetes PRO data4, and on the importance of understanding patient preferences in diabetes research5. Further, he recently conducted a Webinar “eCOA in Diabetes Trials:  Capturing Key Patient Data for All Stakeholders’ Needs” as part of ERT’s monthly webinar series which further reviews the importance of the patient perspective in driving diabetes medication adherence.  For complimentary access to the recorded webinar, please visit https://www.ert.com/clinical/resources/webinars.

References:

  1. http://www.ncbi.nlm.nih.gov/pubmed/24879836
  2. http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3217&sKey=e68ac573-fe45-4c2f-9485-6270854fc10b&cKey=9164e616-5bf1-4f0c-83bf-d82c6601db84&mKey=89918d6d-3018-4ea9-9d4f-711f98a7ae5d
  3. http://spectrum.diabetesjournals.org/content/27/4/229.short
  4. http://www.hoajonline.com/jdrcm/2050-0866/3/7
  5. http://onlinelibrary.wiley.com/doi/10.1111/1753-0407.12187/epdf
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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 https://www.ert.com/clinical/resources/webinars.

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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:  http://www.thoracic.org/statements/resources/pfet/pft4.pdf.

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 https://www.ert.com/clinical/resources 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 www.diacastaway.com and follow all the social media buzz on www.tagboard.com/diacastaway.

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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