Improving Your Drug’s Value Proposition throughout the Product Lifecycle: How Optimized Clinical Outcomes Assessment (COA) Strategies Can Drive Commercialization Success

Posted on April 11, 2013 by ertglobal

Typically, pharmaceutical and biotech companies have focused their Clinical Outcome Assessment (COA) development efforts solely on the requirements necessary for regulatory approval.  While we recognize that is extremely important, today we are going to discuss how pharmaceutical companies may reap benefits from a longer term approach.  An approach that addresses long-term market access hurdles can lead to continued product differentiation in the face of ongoing competition and subsequent long-term payer acceptance.  Drug development strategies that optimize COA data – including patient, clinician, and observer reported outcomes (PRO, ClinRO, and ObsRO) – can be used strategically to support regulatory approval and, increasingly, post-marketing success.

The development of COA endpoints, wherever you are in the product lifecycle, should always answer three clear questions (in order):

1. What messages are you trying to test and convey?

  • Create the messages you want to deliver at the end of your work
  • Identify the concepts, or what you want to measure, that will support your messages
  • What you want to measure depends upon:
    • Who is in your target patient population
    • Who you want to influence with your results – regulators, payers, clinicians, and/or patients themselves

2. How are you going to measure the concepts behind the messages?

  • Select instruments, based on your own research, that measure exactly what you want to measure
  • Only select instruments after deciding on what to measure

3. How are you going to implement the study that gives you the data?

  • Implement the instruments in study designs that give you the optimal endpoints to evaluate what you want to measure

This takes you beyond the very limited thinking regarding regulators and the narrow concepts of what you measure, to the broader focus on what the impact of this product is on the patient’s Health Related Quality of Life (HRQOL).  It should also get you thinking about how you are going to convey that information in the most compelling way.  For example, if you are dealing with a debilitated population, maybe it’s mobility information you want to convey.  If it is a very healthy population, maybe it’s strong physical exertion.  This is why really understanding the message and patient population and then focusing on the concept is important.  Once this is established, you need to determine how you are going to measure and implement that concept, and finally, you need to select which instrument you will use.  We suggest following this process for all stakeholders – not just for regulators.

With that foundation in place, we can now move to where we think the market is heading and how pharmaceutical companies can prepare for those changes. We believe that several combined elements – such as payer interest, big data and manufacturer needs – suggest that there will be an increased demand for and use of phase 4 economic reviews. Ultimately, payers and reviewers are going to evaluate your drug and make the decision whether to cover it (or not) and at what price.

Payer Interest:
As always, payers are interested in cost control and soon they will be able to measure costs very well.  Also, there is the diffusion of use of more formal Health Technology Assessment (HTA) methods, which uses only generic utility measures – unless other credible measures are provided by you.  Finally, there is always the pressure to drive therapeutic substitution.

Big Data:
With the ability to slice and dice data from populations into subgroups, it is much easier to measure hard outcomes.  There is relentless pressure to measure outcomes, so a manufacturer will need to prove a drug’s benefits.

Manufacturer Needs:
Product differentiation is increasingly important, yet there is a need to control development costs.  You’ll want to be able to defend long-term product value without needing to run another huge trial or contract discount.

Based on these factors, if you anticipate additional reviews, you’ll want to start thinking about the type of data payers will want to examine.  If you talk to payers directly, some may lead to you believe that they only care about budget impact and not much else.  However, there are good reasons for investing in the collection of COA data.  It is true, payers are looking to treat their patients and to do so at a good price. However, once the product characteristics are known, it is in the payers’ interests to say they care less about patient benefit. The fact that they say it doesn’t matter doesn’t make it true.  So never stop selling benefit to stakeholders!  This is where COAs can help, because you can come in with credible measures rather than some qualitative statements. Payers need to gather product information, design the rules for the selection, and conduct a selection.  All of these are affected by the medical community, particularly inside the payer and also patients. So the implication is that tangible benefits data will be helpful to a manufacturer during a negotiation, and in the “game” before the negotiation.

You may be thinking, “What will payers likely ask/want at these frequent, ad-hoc reviews?” Here is a list we’ve put together to help you get started:

  • Why is your drug better than your competitor’s?
  • Show us something new in our patient population – we’ve already seen your registrational data.
  • Your competitor went generic. We want a discount.
  • Please respond to your competitor’s observational studies in our patients showing that its life-cycle costs are lower than yours.
  • We just read an AHRQ/NICE/PCORI study that shows that all the drugs in this class have only tiny differences. Give us a reason not to implement the obvious implications of that finding – which is to engage in competitive contracting.

You’ll need to get started early on answering these questions because the lead time to respond is usually very short (weeks or a few months).  How long might it take to produce credible data in publications, which could then be taken to review bodies that control access? We estimate the total time from brainstorming to publication is approximately 5 years.

  • Planning COA strategy: 1 year
  • Beta testing COA instruments: 1 year
  • Full scale trial in the field: 2 years
  • Write up and publications: 1 year

Clinical Outcomes Assessments and Economic Reviews

Post-marketing COA could be a valuable addition in a difficult market.  ERT is readily available to support you – whatever the size, complexity and therapeutic area of your clinical program.  Contact us to speak with an expert consultant on how to optimize your COA strategy.  This is an opportunity to speak with a Senior Scientist and discuss what reasonable steps you can take to reduce risks and ensure the success of your clinical development program.

If you enjoyed this blog and would like to learn more, please visit www.ert.com/webinars to view a full 1-hour presentation on this topic.

Thank you for being a part of the global ERT Community.

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Metrics Champion Consortium – Cardiopulmonary Performance Metrics Initiative

Posted on December 21, 2012 by ertglobal

ERT Blog with guest, Linda Sullivan – Vice President Operations, MCC

The Metrics Champion Consortium (MCC) is a non-profit organization comprised of approximately 90 biotechnology, pharmaceutical, medical device and service provider organizations.  Their mission is to help sponsor and service providers improve their overall clinical trial development processes through the utilization of standardized clinical trial performance metrics such as time, cost & quality.  The MCC has been in operation since 2006, when the first set of metrics were defined and released.  ERT has been involved with the MCC’s working groups and initiatives since its inception.

In 2011, the MCC changed the name of the ECG working group from the ECG Performance Metric Steering Committee to the MCC Cardiopulmonary Performance Metrics Initiative.  The new name reflects the broadened scope of metrics that the initiative are discussing and developing at this time. The specific areas covered by this initiative include implementation support of the MCC ECG Performance Metrics version 2.0 and developing/implementing other MCC performance metrics in the areas of Ambulatory Blood Pressure Monitoring (ABPM), Spirometry and Echocardiography.  These performance metrics share a similar set of “core” metrics and contain their own area-specific metrics as well.

On June 27, 2011, the MCC launched version 2.0 of the MCC ECG Performance Metrics.  Version 1.0 of these metrics were initially introduced to the industry in 2007.  This set of standardized performance metrics, selected and defined by MCC members (sponsors and ECG core labs), were implemented in the hope that they would facilitate discussions for process improvements and a better understanding of the processes within each organization that affect the management of centralized ECGs.  MCC Members felt that this has been accomplished (AstraZeneca Case Study) and believe that more improvements can be realized using the newest version of the MCC ECG Performance Metrics.  Version 2.0 contains 15 core metrics and 2 ECG specific metrics.  The types of performance metrics include cycle time, timeliness, quality, efficiency/cost and tracking.  Additional and more specific information regarding Version 2.0 of the MCC ECG Performance Metrics can be found here. 

On December 21, 2012, as a part of the Cardiopulmonary Performance Metrics Initiative, the MCC released version 1.0 of the Spirometry Performance Metrics.  For background information purposes, forced spirometry is when a patient takes a deep breath in and exhales as rapidly and forcefully as possible, then the amount of air exhaled at different time points is measured.  The keys to centralized spirometry are that forced expiratory volume in 1 second (FEV1) is a primary endpoint in Respiratory clinical trials, a secondary endpoint for inhaled medications and it is also an effort dependent test.  According to the ATS/ERS 2005 Guidelines, best practices for forced spirometry include three acceptable efforts, two of which are repeatable.  Acceptability entails a good start of the test, no artifact (i.e. coughing) during the first second of expiration and a satisfactory end of test.  Repeatability requires that subjects with a forced vital capacity (FVC) < 1 liter, the best and second best acceptable efforts must be within 100 mls of one another for both FEV1 and FVC, and for those subjects with a FVC ≥ 1 liter, the best and second best acceptable efforts must be within 150 mls of one another for both FEV1 and FVC.

Amy Furlong, Chief Operations Officer at ERT, and Jim Sowash, Director of Respiratory OverRead at ERT, have been instrumental in helping to lead group discussions regarding the development and implementation of the Spirometry Performance Metrics.  The spirometry metrics include the same 15 core metrics as the aforementioned ECG Performance Metrics as well as 3 additional metrics specific to spirometry.  The three additional metrics are designed to evaluate the overall quality of the data from proficiency training of personnel through the quality of the data received by the central reader.  Unlike the collection for ECG data, the spirometry data requires significant interaction between the site staff and the subject to obtain quality data. Proper training of site personnel on how to coach subjects to complete a successful maneuver is critical. As noted above, there are strict guidelines on the definition of an acceptable test.  The central overread plays an important role in assuring only the best data in compliance with these standards are selected by the site.  The “deselection” of data is a metric used to track the ability of the site to recognize and submit good data.   As with the ECG Performance metrics, the goal here is to facilitate process improvements and open up the dialogue between sponsors and service providers to change the way we look at performance and ultimately change performance itself when necessary.  Additional and more specific information regarding Version 1.0 of the MCC  Spirometry Metrics can be found here.

While the MCC has been initiating moves to develop and implement standardized performance metrics in other areas of clinical research, another major initiative involves closing the loop with the sites themselves.  This will help drive quality improvements at the site level with their own set of metrics.  What people sometimes don’t understand about the MCC is that half of these metrics are measuring the performance of the sites and are not always in the vendor’s control.  They are sometimes more about the quality and timeliness of the interactions with the sites.  Sites are essentially the be all and end all of where clinical data is coming from and even though they are consistently being measured on their performance, often times, they are not given this feedback.  The sites would like to compare performance against themselves in order to make better business decisions. They want to know if they are they the only one having “this” problem, how they can do a better job, how they can become more efficient, and what they need to know to select better partners on projects and studies as sponsors do.  The MCC Site Initiative group is working diligently to make this happen as a next step for the organization.  Linda Sullivan has said it best in that, “All parts have to work together.  The industry has to sink or swim together.  We all share a common goal, and that is to keep people safe and get products in the market place that will help them.”

To learn more about the MCC, please visit http://www.metricschampionconsortium.org or contact Linda Sullivan, Vice President Operations, MCC, for membership inquiries.

For more information on ERT’s Centralized Spirometry services, please visit http://www.ert.com/respiratory
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The Importance of Inspiratory Capacity in COPD Clinical Trials

Posted on October 22, 2012 by ertglobal

Written by: Dawn Patterson, Supervisor Respiratory OverRead

On average, it costs $539 per person annually to treat an asthmatic and $4,150 to treat COPD.  These costs reveal a need for improved symptom management and reduction in exacerbations that would reduce the need for escalated care and in return reduce overall costs.  In addition, it would increase the quality of life for patients by avoiding or preventing an exacerbation event.

This post will address these three basic questions:

  • Can spirometry be used to measure hyperinflation?
  • Is inspiratory capacity a dependable parameter to measure hyperinflation?
  • What impact does centralization have on inspiratory capacity?

Before we get started, let’s step back to basics for a minute: what is hyperinflation and why do we measure it?

Hyperinflation is the volume of air that is trapped in a patient’s lungs at the end of exhalation.  The ability to fully exhale depends on the degree of airflow limitation and the time available for exhalation, which is why greater hyperinflation occurs during exacerbations or exercise.   Because COPD is an irreversible disease characterized by a reduced expiratory airflow, COPD patients already start at a higher lung volume than that of a healthy individual.  With increased activity, anxiety or if the patient becomes hypoxic, their respiratory rate increases, decreasing expiration time and ultimately creating dyspnea.  As the disease progresses so does the hyperinflation, producing significant detrimental effects on a patient’s breathing.

There are several ways to confirm Hyperinflation including a physical exam, X-ray or CT scan.  Another and more accurate way to confirm hyperinflated lungs is to measure lung volumes and capacities.  Measurement of lung volumes provides a tool for understanding normal function of the lungs as well as disease states.  The amount of air in the lungs is subdivided in two groups, lung volumes (VT, IRV, ERV and RV) and lung capacities (TLC, VC, IC, FRC).  Measuring lung volumes in COPD patients can give us a better understanding of hyperinflation and how treatments work to improve their daily activity.

So, how do we measure IC?  One way is by using body plethysmograph, also known as body box.  Body Box is the GOLD standard for measuring lung volume.  What is nice about the body box is that it not only measures spirometry, but also thoracic lung volumes and resistance.  Most importantly it can be performed quickly and will give absolute values. However, it does have a few draw backs. Some COPD patients are claustrophobic and may not want to be placed in an airtight closed system.   It’s also rather large and takes up a lot of room.  In addition, severe COPD patients may require Oxygen and have other devices which may not be able to go into the body box. The most significant disadvantage, especially within clinical research, is having non-standardized equipment at each site. With sites using their own equipment, there is a possibility of equipment variability, poor equipment feedback (inconsistent assessment) and inconsistent site training – this will likely result in poor quality data, thus having inconclusive results.  Having the same body box at each site will provide you with a greater percentage of acceptable data but unfortunately, it can be quite costly.

An alternative to the body box is spirometry.  Spirometry (forced or slow) is used to confirm airway obstruction and physicians are in a position to detect COPD in its early stages.  Spirometry is a relatively simple and noninvasive test which only takes a few minutes of the patient’s and technician’s time.   There are many different devices to choose from which are smaller in size, and much lighter than the body box.  More importantly, it’s affordable.  According to the GOLD standard, FEV1 is the parameter of choice for diagnosis and monitoring progression of airway obstruction.  It also provides a starting point for determining a patients initial treatment plan, however it does have its limitations.  The changes in FEV1 value does not necessarily reflect changes in dyspnea and is limited to exercise performance.  It is also limited in clinically assessing patients.  For example, patients with mild and severe COPD may have similar FEV1s but they can be at complete opposite ends of the spectrum when it comes to quality of life.

Forced spirometry consists of a patient taking a deep breath in and forcefully expiring until the patient cannot exhale out any more, then the patient is asked to take another deep breath in. It is essential that the patient performing the test be clearly instructed in the procedure prior to the start of each test.  A very enthusiastic demonstration by the technician is crucial so that the patient makes a maximum effort when carrying out the forced expiratory test.  With this test, the forced expiration may cause airways to prematurely close and trap air, resulting in an inaccurate measurement.

The primary difference with slow spirometry is that the expiration into the spirometer is done slowly.  Patients who have trouble with the force maneuver, due to an inability to complete a full exhalation, may do better with this test.   Patients should be relaxed and asked to breathe regularly for several breaths until the end expiratory lung volume is stable (this usually requires at least 5 tidal breaths).  They are then encouraged to take a deep breath to TLC with no hesitation, followed by an expiration.  It is important, as with all the other tests, to make sure that it is done properly.  If the inspiratory breath is too slow due to poor effort or hesitation, or if there is premature closure of the glottis, the IC may be underestimated.  As with force, it is important for the patient’s cooperation and understanding of the test.  The technician should be enthusiastic about the test but not as demanding.

In a study of 93 patients in a primary care setting, it was shown that in addition to measuring dyspnea and quality of life, IC is also an established reliable parameter in measuring hyperinflation.  It has also been noted that Spirometry is highly reproducible and gives a clear indication of the extent of hyperinflation.  After gathering all of the data, it is important to make sure that the data collected in clinical trials is of the best possible quality.  The best way to eliminate any transcriptional errors and reduce variability is by having the data centralized.

Respiratory clinical trials can be challenging and centralizing IC data plays an important role in clinical research.  Patients entering these trials already have breathing that is compromised, raising variability from the beginning.  However, performance by the patient is extremely important to producing accurate results.  Just as relying on the technician to be an enthusiastic motivator for the patient undergoing a test, it is important that the site is delivering data that is acceptable. A centralized approach to spirometry helps you increase data quality, by providing the ability to better see treatment effects. Centralization 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.   For example, before centralization, there were 45,497 measurements with 6,094 (or 14%) that were unusable data.  After having a team of expert reviewers assess the measurement and data quality based on the current ATS/ERS standards that percentage of unusable data dropped down to 9%.

As previously stated, improper training and poor patient effort will result in poor quality data and it is crucial to educate and monitor the technicians to improve the accuracy of data reporting.  With centralizing, 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.  As noted in the chart below, the most frequent error is repeatability. The 2005 ERS/ATS guideline on spirometry has established a repeatability criterion (highest to 2nd highest value) of 150 mL for Vital Capacity (VC), while for the Inspiratory Capacity (IC) there are no set established criteria.  More studies need to be evaluated to estimate an achievable repeatability for IC.  Some of the other errors are unstable baseline, cough, unstable breathing, breathing frequency, and improper procedure.

*Source:  ERT Respiratory Solutions
 

In summary, although body plethysmography gives absolute values, it is an expensive way to monitor hyperinflation.  IC together with spirometry on the other hand has been shown to be a dependable, inexpensive and simpler parameter that can indicate the presence and management of lung hyperinflation.  The aim of centralization, standardized equipment and training, is to increase the percentage of acceptable data and provide the best quality data – resulting in greater patient retention, and increasing statistical power at a reduced price.

For more information on ERT’s Respiratory Solutions, please visit: http://www.ert.com/respiratory 
Posted in Clinical Trials, COPD, Inspiratory Capacity | Leave a comment

CLEAR Study Update: A look inside the collaboration between ERT and UCLA

Posted on October 1, 2012 by ertglobal

Written by: Michael Taylor – Senior Director, Healthcare Solutions

As some of you may remember, back in February 2012, ERT collaborated with the University of California, Los Angeles (UCLA) to launch the CLEAR study, an innovative research study aimed at helping patients suffering from Chronic Obstructive Pulmonary Disease (COPD). You can read the press release, here.

For the first time in the industry, UCLA and ERT worked together to design a study that would enable home-based spirometry. If the trial is successful, it will represent a major step forward for the treatment management and continued care of COPD. It is hoped that if the methods used within this study demonstrate better, more reproducible data that indicate more specificity or sensitivity to predict exacerbations, it could change the future of clinical trials. The on-going study has already made significant progress in the first six months, something which couldn’t have been achieved without the combined expertise, knowledge and support of ERT and the UCLA teams. The broad range of skills and experience within the partnership has ensured that the methodology for the study is completely focused on improving the lives of individuals living with COPD.

ERT’s wide understanding of how to efficiently record data in clinical trials was the basis on which the study was built. Prior to meeting with the UCLA team, ERT had already developed a series of hypotheses for the trial and prepared an initial protocol covering the objectives to be achieved, the type of equipment that would be used and the specific aims of the program. Dr. Christopher Cooper, MD, Professor of Medicine and Physiology at the David Geffen School of Medicine at UCLA, took ERT’s protocol and applied his many years of experience to expand the hypotheses, getting to the very core of ERT’s objectives. Together, the two parties went on to co-develop an extensive protocol comprising primary and secondary outcomes, the entire study design, baseline assessments and specifications about how the study would work based upon the patients that it would be monitoring (view press release for more information). Once the study protocol was finalized, ERT implemented methods and criteria within its instruments that were specifically adapted for the study and trained UCLA’s team on how to efficiently and effectively record optimized data. This involved ensuring they knew how to use the devices, how to train patients to effectively use electronic PRO devices, and how to analyze the data reported on the online portal. This helped to expand UCLA’s knowledge of how technology can improve the quality of patient data in studies, demonstrating the mutual benefits of collaboration between manufacturers and academia.

The first of the study’s 200 patients were recruited in February 2012 with trial results to be reported in late 2013. Upon enrollment, each patient was provided with a full physical examination and an exit consultation planned for when the study is concluded. To date, the study has been developed to address the needs of physicians with the aim of achieving better treatment for patients living with COPD. The data being collated in the study is wide-ranging, to ascertain exactly which treatments and therapies are most effective. Due to the large population used within the study, there has been a large volume of interest generated about the program across the industry.  Throughout the duration of the study, ERT and UCLA remain in constant contact to discuss what’s working, revisit the objectives, ensure progress is in line with their goals and ascertain if there are any improvements that could be implemented. Some of the main challenges associated with the study have been the high number of participants required for the ambitious project and, consequently, the high volume of data resulting from the program. As a result, additional time and effort has had to be contributed by both parties to ensure that all the data is collected and analyzed in the most efficient and effective way possible.

Built on a 12 year relationship, ERT and UCLA both demonstrate a clear understanding of and commitment to helping each other achieve their aims. A key difference between this trial and similar ones is the dedication of both parties to developing new methods that will provide information about what is really important to COPD patients. This patient-centric approach goes further than simply mimicking existing research; it has resulted in the development of a questionnaire tailored to the specific objectives of the study by collating information on multiple parameters including not only data on sufferers’ symptoms, but also information on physical activity and patients’ medications. ERT and UCLA have combined their technologies, knowledge and expertise, with the aim of changing the lives of patients living with a condition where the burden of illness is high and the need for quick intervention, vital. Without the involvement of either party, the volume of data and participant numbers would simply not be attainable by the organizations individually. Bringing their resources together means that the study will be able to successfully demonstrate the benefits of on-going symptom management, early intervention of exacerbations, and on-going patient assessments for medication; helping to progress the adoption of remote healthcare monitoring.

For more information on ERT’s Respiratory Solutions, please visit: http://www.ert.com/respiratory
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Brief Report – Changes to the FDA Draft Guidance Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials

Posted on September 13, 2012 by ertglobal

The original Draft Guidance was released September 8, 2010

  • Prospective assessment of  suicidality
    • Identify patients at risk
    • Collect complete, timely data
    • Perform in every phase, in every trial, at every visit
      • In all psychiatric indications
      • In all neurology compounds
      • For all other drugs pharmacologically similar to drugs about which there has been concern
  • The C-SSRS is an ‘acceptable’ prospective assessment 
  • Administration by ‘phone and computer’ are acceptable

Update: August 6, 2012

After two years of review, comment and redrafting, the FDA’s changes were centered around reinforcement and clarification of their original objectives – patient safety and quality data.  Overall, there were no fundamental policy shifts. These changes are instrumental to sponsors understanding and getting more specifics around assessing suicidal ideation and behavior in clinical trials.  The most important changes include:

  • Changes the term “Suicidality” to “Suicidal Ideation and Behavior”
    • This is a good change and makes the language much clearer
  • Expansion of the C-CASA categories
    • The Guidance shifts from four of the nine previous C-CASA classifications to 11. 10 of those 11 are exactly the ones that are in the Columbia Suicide Severity Rating Scale, five for ideation, five for behaviors and then added as the 11th is the non-suicidal self-injurious behaviors.
  • Slight revisions on particular trials and patients that need assessment and timing of assessments
    • The updated draft Guidance outlines any drug for a psychiatric condition, epilepsy, neurologic drugs with CNS activity, drugs that are pharmacologically similar to isotretinoin and other tretinoins, beta blockers (especially those entering the brain), reserpine, drugs for smoking cessation, and drugs for weight loss.
  • Addresses concerns about assessment time burden on people in the sites and on the patients – FDA saw the burden was very small and is not to be a reason not to do these assessments
    • We have learned from the first 35,000 assessments of the electronic Columbia Suicide Severity Rating Scale that the mean completion time was 3.8 minutes. It was 3.5 minutes for the 98.3% of negative assessments and only 7.7 minutes for the 1.7% of assessments that had a positive signal for suicidal ideation or behavior.  The completion rate was 99.89%, which is the confirmation that the time burden from the patient perspective, as well as from the site perspective, is not great.
  • Recognizes the value of the lifetime assessments in providing protection for patients at risk
    • Based on the study findings of 35,000 assessments (6,000 of which were performed at baseline and questioned lifetime ideation and behavior), we found quite strikingly that lifetime assessments did predict a substantial increase in the odds ratio of subsequent positive signals for suicidal ideation or behavior, between four and nine times, depending on which combination of ideation and behaviors were there.
  • Explicitly mentions the electronic Columbia Suicide Severity Rating Scale
    • “The eC-SSRS … is an alternative approach to obtaining data on suicidal ideation and behavior.”
    • C-SSRS & the eC-SSRS are the only two assessments specifically identified in the guidance

To request more information or to speak with a PRO expert in regards to this guidance, please fill out this form or visit http://www.ert.com/ecssrs .  In the meantime, you can also review the following resources:

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Your 2012 DIA ePRO Community Survey Results

Posted on July 30, 2012 by ertglobal

During the 2012 DIA Annual Meeting, while folks flooded to the ERT booth to grab a cup of coffee, we asked those waiting in the queue to fill out a brief questionnaire regarding their perceptions of the Clinical Outcome Assessments/ePRO industry and likely trends they expect to see in the future. Below are your results from the nearly 200 people who responded to the ePRO Community survey.  Thanks again to all of those who stopped by the booth to learn more about ERT’s products and services!

About 30% of clinical studies currently collect some sort of Clinical Outcome Assessment. Do you think you will be collecting more PRO data in future trials?

Over 80% of respondents expect to see more PRO data in their future clinical trials.

Which of the following vendors do you associate with collecting ePRO/eDiary data?

The top five ePRO vendors recognized include: ERT, Oracle, PHT, invivodata (now ERT) and CRF Health.

How important is it for the vendor to have a scientific expert on staff to help consult and guide you in the way that the ePRO solution is commissioned?

A total of 77% of respondents indicated it was either important or very important to have a scientific expert on staff.

In terms of technology used by the patient (PDA, IVR, Web, Digital Pen), how important is the device in your decision-making process?

A total of 70% of respondents indicated device selection was either important or very important in their decision-making process.

What other factors are important to you when making a decision on what ePRO vendor to choose?

The top five other factors that are important when choosing an ePRO vendor include: Proven Track Record, Therapy Area Experience, Price, Integration with other Clinical Technologies (e.g. EDC), and Prior Experience of Collecting Data Using a Specific Gold Standard Instrument / Assessment.

In 5 years’ time what do you think will be the most widely used methods of collecting PRO data?

Not to anyone’s surprise, the combination of Tablet, Smartphone and Web responses accounted for over 75% of replies, while paper had a rating of merely 3%.  Collecting data on a Tablet or iPad had the highest percentage rating at 31%.

A special thank you to everyone who participated in this survey and also to those who visited us at the 2012 DIA Annual Meeting.  We certainly look forward to seeing you all again soon but in the meantime, you can stay connected with ERT through our Facebook, LinkedIn and/or Twitter pages!

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Partnerships Series Part II: What about CROs? Strategic Outsourcing Isn’t Just for Pharmaceutical Sponsors

Posted on June 5, 2012 by ertglobal

Written by: Tom Avery, Vice President, Strategic Business Development

Collaboration, transparency, executive oversight, mutual respect … these are all attributes we think of when we hear the words “strategic partnership.”  As mentioned in our previous blog Strategic vs. Tactical Outsourcing for Pharmaceutical Sponsors, there continues to be a huge shift from traditional, tactical outsourcing to a more strategic approach in the Pharmaceutical industry.  For Sponsors with mature partnership models in place, this means increased quality and R&D productivity as well as assurance in development timelines and ultimately costs.  For CROs, this means a greater need for innovation, an assumption of more risk and additional accountability for clinical output.  Just as sponsors are able to tap into additional resources in order to gain operational efficiencies and cost savings, CROs can do the same with specialized clinical service providers for cardiac safety, respiratory, imaging, ambulatory blood pressure, and other research related outcomes.

The increasing complexity of clinical trial activities has been driven by regulatory agencies’ growing demand for new endpoints.  Regulatory authorities are recommending new outcomes to be evaluated in both safety and efficacy trials, such as the need and expectation for quality of life outcomes in the development of oncologic drugs.  As the demand for these new outcomes increases, so will the CRO’s challenge for delivering reliable data and the need for specialty service providers whose core competencies are to deliver these outcomes efficiently.

For the CRO, a primary concern is the ability of the service provider to deliver high quality, reliable data in the context of the CRO’s service to the sponsor.  Successful collaboration between both parties is paramount since many new relationships between sponsor and CRO are built on risk and reward.  As the service provider becomes an extension of the CRO’s services, the success of a CRO’s relationship with a sponsor is directly impacted by the success of the relationship between the service provider and the CRO.  Therefore, if the service provider is unable to deliver the necessary quality outcomes data on a timely basis, then both organizations fail to deliver.

There are several considerations when laying the foundation for a successful strategic partnership.  For starters, it helps tremendously to have a basis of past collaboration and established success between the CRO and service provider.  Also, having a true understanding of the value the service provider brings to the CRO’s strategic focus and mission is imperative.  This strategic alignment, as well as mutual respect and trust must reach to the highest levels of both organizations.  Having executive buy-in may be the most important factor in building a successful collaboration.  A relationship that lacks a dedicated champion from each organization who is accountable and responsible for driving the relationship often leads to a communication breakdown.  Ensuring objectives are understood at the highest level will help prevent stakeholders from reverting back to the original, tactical touch points.  Also, establishing specific metrics and KPIs will facilitate relationship management and ensure that the standards of performance by the service provider are clearly understood.  If something does go wrong during service delivery, transparency is a must.  There cannot be an instance of finger pointing and looking to blame the other party.  Instead, there needs to be mutual responsibility and accountability.  Lessons learned meetings are a great way to measure, monitor and adjust the effectiveness of the relationship from a financial and operational perspective and to determine a strategic plan on how the relationship can be improved.  Failure to keep the executive management engaged would prove to be a huge hindrance to this process.

A strategic relationship between a CRO and an outsourced service provider can provide both organizations numerous benefits.  In the case of a traditional and contractual relationship between sponsor and CRO, you can expect an increase in operational efficiency which in turn will reduce site burden, direct costs and the probability of error in the final data delivery – leading to more usable outcomes data for the pharmaceutical sponsor.   With this success, the sponsor will understand the CRO and service provider as being aligned in terms of both quality and reliability, increasing the likelihood of moving toward a strategic relationship with that sponsor or at the very least, increasing the likelihood of repeat business. In the context of a strategic relationship, such as the Pfizer and ICON/PAREXEL partnership, where risk and reward are built into the contract, a CRO that is strategically in sync with its service providers will ultimately reduce risk of financial penalties and increase the chances of financial reward.  Finally, the expert consulting on how to conduct the sponsor’s clinical study in compliance with regulatory requirements offered by these specialized clinical service providers adds real value for the CRO and their clients.

Our advice is to be patient.  These types of relationships aren’t going to happen overnight.  Successful strategic partnerships take time, effort and other executive resources but the results are well worth the energy it takes.  Peter Gray, former CEO of ICON once said it best: “We believe the process of making these relationships work in a way that’s profitable takes time, but the whole premise behind these deals is that you align all your processes, and build and grow together, and the way you begin to interact soon enables CROs to be profitable and also allows the client to get good value for their money.”1

For more information on ERT’s Partnerships, please visit: http://www.ert.com/partners/

What do you think?  Vote on the poll below, leave your comments and as always, thank you for being a part of the global ERT community.

Posted in Clinical Research, Clinical Trial Outsourcing, Clinical Trials, Partnerships in Clinical Trials, Pharmaceutical | Leave a comment

Cardiac Safety in Obesity Drugs – FDA Advisory Committee

Posted on April 27, 2012 by ertglobal

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

Obesity is one of the nation’s largest health problems and has grown into a major epidemic.  Over the past 20 years, obesity rates in the US have continued to dramatically increase.  According to the Centers for Disease Control and Prevention, more than one-third of U.S. adults and approximately 17% (or 12.5 million) of children and adolescents aged 2—19 years are obese.1  Overweight and obese individuals are at increased risk for many diseases and chronic health conditions, including: hypertension, osteoarthritis, dyslipidemia, type 2 diabetes, heart disease, stroke, liver and gallbladder disease, sleep apnea and respiratory problems, and certain cancers (i.e. pancreas, kidney, prostate, endometrial, breast, and colon).2  A 2009 study by the Centers for Disease Control and Prevention, along with RTI International, demonstrated the economic burden of obesity and estimated that medical costs were as high as $147 billion annually, which accounted for approximately 10% of all medical spending.3

To date, there aren’t any satisfactorily safe and effective obesity drugs commercially available.   Many potential weight-loss drugs have either failed or been abandoned by drug development companies and there have been several obesity drugs withdrawn from the market due to safety concerns and adverse side effects.  There is a huge opportunity for pharmaceutical sponsors to make a significant impact on the lives of obese people with long-term drug therapy.  However, there have obviously been several challenges, mounting concerns and an increasing number of hurdles required to continue development programs and ultimately gain regulatory approval for any new weight-loss drugs.  In 1997, two popular anti-obesity drugs, Fen Phen and Redux, were pulled from the market by the FDA because of potentially life-threatening heart valve damage.  Also, in 2010, the obesity drug Meridia was recalled for causing an increased risk of stroke and heart attack in populations already prone to these dangerous cardiovascular events.       

Currently, there are three obesity drugs (QNEXA, Lorcaserin, and Contrave) which are again seeking regulatory approval after being previously rejected by US regulators over safety concerns.  To put the challenge here into perspective, the FDA has not approved a new prescription drug for long-term weight since Xenical (orlistat), over a decade ago in 1999. Xenical has demonstrated to be minimally effective and presents significant side effects which have inhibited its use over time.  In general, weight loss has been tied to positive effects on the heart, but the few trials conducted on the long-term heart safety of obesity drugs have shown to actually increase heart risks, or have little to no effect on heart health.  It is clear that the FDA will no longer approve a drug for the masses based on a small treatment benefit and without evidence of future improvement on patient health.  In clinical trials, Contrave raised pulse rates and blood pressure slightly, a warning sign that the drug might increase the risk of heart attacks, strokes or other cardiovascular problems. Consequently, the FDA told the drug maker that it must first do a cardiac safety study to prove Contrave does not increase the risk of adverse cardiovascular events in order to gain regulatory approval.

The FDA has clearly been grappling with cardiovascular risks in obesity drugs and on March 29th, 2012, the FDA Endocrinology and Metabolic Drugs Advisory Committee, after hearing from experts in obesity, diabetes, cardiology and statistics, recommended that drug companies be required to submit phase II or III data to prove absence of cardiovascular risk for new obesity drugs, even if clinical trials do not initially show evidence of precipitating cardiovascular events.  Obesity trials should randomize about 3000 subjects to the active drug and at least 1500 subjects to a placebo for one year of treatment. The FDA requires that patients in phase III obesity drug trials have a body-mass index (BMI) of at least 30 (or 27 plus comorbidities).  The drug should demonstrate either mean efficacy—a >5% difference in weight loss between treatment and placebo—or categorical efficacy—at least 35% of treated patients lose >5% of their baseline body weight, approximately double the proportion in the placebo group.4  In addition to these already established requirements to prove efficacy, almost all committee members agreed that the major adverse cardiac event (MACE) data should come from either cardiovascular-outcome trials or meta-analyses. While not an easy decision, torn between recommending the new safety requirements, which could dampen research efforts, or not extending the safety requirement, which could potentially expose millions of people who would be eligible to take these drugs to serious adverse events, 17 to 6 voted in favor of the new suggested requirements.  As you may recall, back in 2008, FDA advisors had a similar kind of discussion regarding the cardiovascular safety of diabetes drugs and the FDA later published its 2008 guidance for industry.  The new recommendations for obesity drugs to enrich phase II and III clinical trials by including older, sicker individuals with cardiovascular risk factors have mirrored those in the 2008 advisory.  Although not required, the FDA usually follows panel recommendations.  This news could and will likely affect the drug makers of QNEXA and Lorcaserin, which are also vying to get their obesity drug to market in the near future.

Do you think this will be a positive thing for the industry?  Vote below and leave your comments.


Stay tuned for more news on any further recommendations or official guidances from the FDA regarding cardiac safety in obesity drugs.  If you have any questions for Dr. Kleiman, please visit our website at http://www.ert.com/contact-ert/ or write your questions/comments below. 

For more information on ERT’s Cardiac Safety Solutions, please visit: http://www.ert.com/cardiac-safety 

Thank you for being a part of the global ERT community.

Posted in Cardiac Safety, Clinical Research, Clinical Trials, FDA, Pharmaceutical | Leave a comment

FDA discussion: Evaluation of the Cardiac Safety for Serotonin Receptor Agonists as GI Therapies.

Posted on March 20, 2012 by ertglobal

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

A few months ago in November 2011, the FDA brought together a group of gastroenterologists and cardiologists to discuss the history of cardiac safety issues surrounding serotonin 5-HT4 agonists and the design of cardiac safety trials for new 5-HT4 agonists which are currently under development.

There is a great need for drugs to treat GI motility disorders, as there are currently few drugs approved for treatment of these diseases, and several of the drugs which did make it to market have since been withdrawn due to cardiac safety issues.  In particular, Cisapride was introduced in 1993 and withdrawn in 2000 due to QT prolongation and fatal ventricular arrhythmias, and Tegaserod (Zelnorm) was introduced in 2002 and withdrawn in 2007 due to excess ischemic cardiovascular events.

There are currently a number of new 5-HT4 agonists in various stages of development, and there is a great deal of effort to target receptors in the GI tract more specifically in order to try to avoid off target cardiac side effects.  Indications for which these drugs are targeted include chronic idiopathic constipation, irritable bowel syndrome, chronic irritable bowel syndrome with constipation, gastroparesis, and gastroesophageal reflux disease that does not respond to proton pump inhibitors.

As with all new compounds, new 5-HT4 agonists should be carefully assessed for QT prolongation and for drug-drug interactions.  In addition, assessments of risk of excess myocardial infarction, unstable angina and strokes should also be performed.  The ICH S7B and E14 guidances describe the preclinical and clinical assessments which should be performed for all new chemical entities to assess the risk of QT prolongation, including hERG assays and a formal Thorough QT (TQT) trial.

Assays of drug-drug interactions are also well established at this time.

Less clear is how the risk of cardiovascular events should be assessed during drug development.  Possible assessments discussed in this meeting included platelet aggregation assays, evaluation of smooth muscle contraction, as well as large, dedicated cardiovascular safety studies using “enriched” patient populations with pre-existing cardiovascular risk factors or disease.

You can access the Advisory Committees meeting materials on this discussion using the link below: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM286759.pdf

We will be sure to keep you updated on any further discussions regarding the evaluation of the cardiac safety for serotonin receptor agonists as GI therapies.  As always, if you have any questions for Dr. Kleiman or would like more information on how ERT can help support the Thorough QT trial or other centralized cardiac safety needs for your new 5-HT4 agonists in development please visit our website at http://www.ert.com/contact-ert/ or write your questions/comments below.

For more information on ERT’s Cardiac Safety Solutions, please visit: http://www.ert.com/cardiac-safety
Posted in Uncategorized | Leave a comment

Partnerships Series: Strategic vs. Tactical Outsourcing for Pharmaceutical Sponsors

Posted on February 29, 2012 by ertglobal

Outsourcing practices have become an increasing trend as the demand for capacity, speed, an expanded geographic footprint, and cost containment continue to grow in the pharmaceutical industry.  Other factors leading to project outsourcing are the increasing complexities of clinical trial activities and the rising number of smaller sponsors conducting their own clinical research.  The Tufts Center for the Study of Drug Development revealed that spending on new drug development is growing at a rate of 9.1% annually while global spending on contract clinical services is growing almost twice as fast at 13.4%[1]. Also, according to ERT’s own internal data, just five years ago in 2006, CROs accounted for 1% of total bookings.  To date, that number has grown to represent over 17% of ERT’s business.  This data exemplifies current trends and can clearly infer what other outsourcing firms are experiencing throughout the pharmaceutical industry.

As the industry moves forward and the current market pressures cause sponsors to change their relationships with vendors, outsourcing practices have begun to evolve and mature.  Pharmaceutical companies are challenged now, more than ever, to conduct their clinical research more efficiently in order to reduce costs while enhancing productivity.  More than 92% of sponsors and service providers surveyed, felt that the levels of outsourcing relationship efficiencies in 2009 would not adequately meet future needs[2].  Mature sponsors have begun to strategically look for high quality partnerships that will deliver the greatest results and the most satisfactory vendor relationships.  Others continue to outsource projects tactically to satisfy a short-term goal for the lowest possible price.  A company’s choice to outsource tactically through a transactional relationship, or strategically as business partners is uniquely driven by each company’s internal culture and business philosophies.  However, all sponsors, large and small, should be aware that the more mature the outsourcing practices, the higher the potential to yield greater outsourcing quality, value and overall vendor relationship satisfaction.

Key Attributes of Mature Outsourcing Partners

With the benefit of our experience, we have witnessed several customers maturing from the tactical, free-for-all competitive bidding processes, to creating short lists of qualified vendors, and finally to creating a strategic partnership with a trusted vendor.  This type of customer tends to see the bigger picture, in terms of a sensible business relationship, due to a more narrow focus on quality results and relationship satisfaction.  Often searching for a win-win situation, sponsors who outsource maturely are more concerned with the strategic aspect of their clinical study, not so much the ‘nickel and dime’ philosophy where much time can be wasted on relatively insignificant issues.  Since these Pharmaceutical companies recognize that it is in their best interest to understand, they proactively ask questions in an effort to identify their responsibilities and often share pertinent information concerning their company’s business goals, objectives and requirements in an open and transparent forum.  There is also an understanding that issues may arise, so with a constructive attitude and emotionless problem solving, they are able to work collaboratively to find a practical and innovative resolution.

The Benefits of Strategic Outsourcing

Strategic outsourcing relationships and alliances often begin to take shape when the sponsor company realizes a particular contractor can provide value-added services and expertise that the company may not have the competency or resources to accomplish otherwise.  With true partnerships in place, relationships are based on trust and communication, allowing for greater transparency and service levels.  Also, having an established relationship with a short list of preferred providers who offer a broad range of services, global presence, financial stability, and best-in-class quality, can significantly increase the return on outsourced development efforts and dollars.  A Jeffries Survey of 60 Pharmaceutical and Biotech executives indicates that nearly 80% of respondents believe outsourcing provides efficiencies that reduce development times and in turn, costs[3].  An additional benefit, when working with a smaller number of best-in-class providers, is continual knowledge management.  Processes are able to become more aligned with experience, building long-term value and better integrating the operations of both companies to support business goals.  Finally, with the confidence that they are doing business with a trusted provider working in their best interest, Pharmaceutical executives are better able to focus on the strategic aspects of their roles instead of the operational day-to-day tasks.

The Drawbacks of Tactical Outsourcing

Tactical outsourcing is a fragmented approach where short-term goals and initial cost savings take priority and there appears to be less focus on quality.   Whether it is due to of a lack of financial resources, to relieve the burden of staffing in an absence of talent, or to eliminate the need for future investment, some pharmaceutical companies choose to outsource on a purely transactional basis.  This leads to the idea that every contract is done as a ‘one off’ or in a vacuum, where a high percentage of the deals have to be negotiated from a pricing perspective as individual projects, rather than as a part of a program of studies.  While sponsor’s immediate requirements (technology, price, capacity) and individual deals are satisfied, the sponsor’s future needs may be compromised.

In 2010, the Avoca Group conducted a survey in which they found that respondents, whose companies allocated 75% or more of their clinical outsourcing budgets to preferred providers, were less likely to be dissatisfied with the value received from their outsourcing relationships than those who allocated less or those without a preferred-provider relationship in place.  Only 5% of respondents whose companies outsource strategically were dissatisfied with the value obtained, as opposed to the 33% whose companies outsource in a more tactical manner[4] .   This type of adversarial, transaction based relationship may facilitate lower levels of trust and familiarity, disallowing both sides to fully benefit from the efficiencies that would otherwise be realized.  Finally, at an individual study level, much time is spent and wasted in pricing negotiations, and resources are not as well planned without visibility to the bigger client picture, access to key personnel and a well-developed outsourcing strategy where company synergies are formed.

The Future of Outsourcing

It appears change is already underway, in regards to the use of outsourced service providers within the pharmaceutical industry, as the assumptive percentage of total outsourcing market penetration is expected to rise from 40% to 46% in the next five years[5].  Despite growth and maturation of the market, the nature of these relationships continues to have dramatic room for improvement.  Due to the pressures of increasing efficiency, lowering costs and the focus on drug safety from regulatory agencies, there has been a growing concern over quality, causing a reevaluation of contracted third-party vendors.  Outsourcing relationships have begun to change considerably and will continue to push further in the direction of strategic partnerships.    In fact, a survey conducted by William Blair & Company, in conjunction with Life Sciences Strategy Group, indicated that over the past few years, roughly 60% of respondent’s companies have increased their outsourced R&D budget, and 69% of large pharmaceutical respondents expect that strategic partnership agreements will continue to increase the rate of outsourcing in the future[6] .

A recent example of this trend is the June 2011 announcement that Pfizer has selected two CROs, ICON and PAREXEL, as their strategic partners.  John Hubbard, Ph.D., senior VP and worldwide head of development operations for Pfizer, expressed that “the goal of this collaboration is to increase R&D productivity.” He also noted numerous other benefits from these relationships, including improved focus – moving from 17 functional service providers to two[7].  Based on the previously mentioned survey conducted by The Avoca Group, it appears that in the future Pharmaceutical companies will become much more selective in choosing their service providers based on their strong capabilities and the quality of their services.  When major sponsors were asked what specific changes they planned to make within the next five years regarding their outsourcing vendors, the majority responded by indicating they will be outsourcing work within preferred provider relationships, as well as begin to consolidate the number of vendors where possible.  At the time of the survey, 69% of the sponsor companies reported having preferred-provider relationships.  Sponsors also plan to modify the way they measure and manage the performance of their service providers and create stringent criteria for vendor selection.  Relationship management programs often consist of performance-metric assessments and reviews, lessons-learned meetings, issue handling procedures, and formal governance structures. Plans to change outsourcing models or to incorporate more risk-sharing clauses into their future contracts were also mentioned[8].

It is suggested that the rate of increased development effectiveness through a proper and mature R&D outsourcing strategy is approximately 15-20% in reference to improved time to market, and 10-40% in relation to efficient cost improvements[9]. As it appears, the industry is confident that the changes in outsourcing strategy toward long-term relationships, preferred-providers and relationship management programs will continue to enhance the level of efficiency and alignment between sponsor and vendor in clinical outsourcing.

For more information on ERT’s Partnerships, please visit: http://www.ert.com/partners/

References

[1] Estimates of Global Demand for Clinical Services Outsourcing.  Tufts Center for the Study of Drug Development. Outlook 2010. January 2010.

[2] The Future of Clinical Service Provider-Sponsor Relationships. http://pharmtech.findpharma.com/pharmtech/ article/articleDetail.jsp?id=707026

[3] Windley, Hilgenbrink, and Dodge, “Pharmaceutical Services: Growth Forecast in the High Singles, How Soon Will We Get There?,” Jeffries and Company, Inc., April 19, 2011

[4] The Future of Clinical Service Provider-Sponsor Relationships. http://pharmtech.findpharma.com/pharmtech/ article/articleDetail.jsp?id=707026

[5] Outsourcing Penetration Assumptions, by Phase, 2003-2015E.  Jeffries & Company

[6] “CRO Industry Update,” January 11, 2011, William Blair &Company L.L.C.

[7] Strategic Partnering For Innovation: Perspectives From The CRO Side Of The Table. Rob Wright

[8] The Future of Clinical Service Provider-Sponsor Relationships. http://pharmtech.findpharma.com/pharmtech/ article/articleDetail.jsp?id=707026

[9] Strategic review of R&D outsourcing — an essential step towards R&D transformation. http://www.atkearney. com/index.php/Our-expertise/strategic-review-of-rad-outsourcing.html

Posted in Clinical Trial Outsourcing, Partnerships in Clinical Trials, Pharmaceutical | Tagged | 1 Comment