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REGULATORY : Document Management Practices  CARDIAC SAFETY : Safety Testing Has Evolved  Also in this issue : PDUFA Legislation Expansion, EU Pharmacovigilance, Aggregate Data, Sunshine Act

Applied Clinical Trials Digital Edition - October 2011

As pharmaceutical, biotechnology, and medical device manufacturers of every kind are discovering in the wake of March 2010's Patient Protection and Affordable Care Act (PPACA), big legislation can mean big change in the world of drug development and clinical trials. 

As the healthcare industry initially mobilized to comply with dozens of immediately enforceable changes, even those able to wade through the 2,000-page act may have initially deferred preparation for less urgent provisions—those to be made compulsory eventually, but "not for a few years."   

But time moves quickly, and just a few months from now a tiny little statute comprising about 1 percent of the PPACA's text and receiving even less attention from policy analysts will become increasingly prominent in the clinical trials community.  

As 22 short pages tucked neatly into the mammoth PPACA, the Physician Payments Sunshine Provision—The Sunshine Act—mandates that drug, biological supply, and medical device manufacturers track all payments of over $10 made to investigators and research sites on an annual basis, beginning on January 1, 2012. This payment information will be reported beginning on March 31, 2013, with records becoming publicly available on September 30, 2013.  

Facing penalties of up to $10,000 per payment omission means that pharmaceutical, biotechnology, and medical device companies need robust methods to track and report physician, vendor, and site payments, now more than ever. 

Sponsors may deliver payments to research sites directly or, as is increasingly the norm, outsource their payment management to CROs for service charges of between $100 and $200 per payment. Given the scale of modern clinical trials, delivering, tracking, and reporting thousands of these transactions can turn into a substantial administrative burden and drive significant costs. In light of the Sunshine Act, payment management is also emerging as a regulatory liability. 

Whether opting for an in-house or outsourced payment management strategy, the process of delivering, recording, tracking, and reporting site, vendor, and investigator payments has traditionally been undertaken manually, with limited use of automated, web-based resources. But just as technology has emerged to enhance so many other aspects of the clinical trials environment (think CTMS, EDC, IVRS, IWRS, ePRO, etc.), clinical technology developers have recently shifted their focus towards streamlining payment delivery and management processes. By centralizing all payment activity through a web-based system, technology enables detailed tracking and reporting across multiple CROs, vendors, sites, and investigators, where manual processes would be prohibitively costly and alarmingly unreliable.  

Efficiently and accurately tracking and reporting site, investigator, and vendor payments is no longer the purview of only internal accounting and finance departments; soon, conformity with Sunshine Act provisions will demand the attention of compliance, regulatory, and top management for pharmaceutical corporations of all sizes and types.  

In advance of the Sunshine Act's upcoming commencement, forward-thinking executives should recall the technological innovations now shaping the modern clinical environment and capitalize on the emergence of technology-based solutions for clinical payments.

A Closing Thought

Drug, biological supply, and medical device manufacturers must track all payments of over $10.

Here Comes the Sun(shine Act)

Less than 15 years ago the CPMP released a points-to-consider memorandum describing steps to be taken to study the ventricular repolarization liability on the 12-lead ECG. Since that time, many steps have been undertaken by regulatory bodies and the industry (ICH S7A, S7B, and ICHE14 Guidance) as a whole to ensure that drugs that make it to market are safe and without ventricular repolarization liabilities as seen on the surface ECG, as evidenced by a prolongation of the QT interval. Despite these key steps on assessment of the risk of cardiac arrhythmias, drugs such as Vioxx and Avandia have shown a propensity for cardiac toxicity outside the risk of torsades de pointes. 

It is now realized that cardiac safety involves more than just measuring the QT interval on the surface ECG. This article reviews, briefly, the current state of affairs in the area of cardiac safety in the world of drug development.  

The ICH has released three guidelines that are important to cardiac safety; S7A, S7B, and E14. The S7A deals with a variety of preclinical issues while the S7B and E14 address the need for dedicated experiments and clinical trials for assessing the QT interval. Since that time these guidelines have been useful for the sponsor to determine what is needed to prove to regulatory agencies that the compound has no overt cardiac safety liability. 

The ICH S7A (July 2001) was constructed to help describe a rational approach for conducting preclinical safety pharmacology studies. Among other evaluations, the S7A recommends certain tests to be conducted for cardiovascular safety. This "core battery" of tests includes primary and follow-up assessments for the central nervous system, respiratory system, and the cardiovascular system.  

The cardiovascular system tests can include investigations for heart rate, blood pressure, and electrocardiograms (to include an assessment for ventricular repolarization). Additional tests may include assessments for cardiac output, ventricular contractility, vascular resistance, and effects for endogenous and/or exogenous substances. These preclinical studies, in combination with short-term and long-term toxicology studies will help the sponsor determine the direction of cardiovascular testing as the compound advances through different phases of clinical testing. 

The ICH S7B (October 2005) specifically addresses the non-clinical evaluation of delayed ventricular repolarization in human pharmaceuticals. It is an extension of the ICH S7A and the non-clinical correlate to the ICH E14. The S7B calls for an integrated risk assessment using both in-vivo and in-vitro testing. 

Section 2.3.1 of the S7B mentions the hERG (human ether-go-go related gene). The so-called "hERG-assay" gives a relatively reliable indication as to whether or not the compound has the ability to prolong the QT-interval in human subjects via a block of the potassium outward current ("loss of function"). Caution is required, as the correlation from the hERG assay to the QT-interval on the ECG is not perfect. In addition, the hERG testing could also evidence a potential for a drug-induced QT shortening when the drug is associated with a gain of function of the repolarizing potassium currents.  

Other testing methodology is addressed including measuring of ionic currents in isolated myocytes, measurement of ECGs in animals, action potential duration, and proarrhythmic effects. 

The ICH E14 calls for a dedicated trial in humans to establish the propensity of a non-antiarrhythmic compound to prolong the QT interval. Anti-arrhythmic compounds are exempt from this requirement as their mechanism of action sometimes prolongs the QT interval. 

The endpoint of an E14 trial will be to exclude a QTcF prolongation of 10 msecs as measured by the upper-bound of the one-sided 95% confidence interval. This does not mean, however, that a 9.9 millisecond change will be deemed safe. The overall profile of the drug will be taken into account when looking at approvability. 

The design of an E14 trial will usually be either a parallel or crossover trial. The study is generally four arms: placebo, therapeutic, supratherapeutic, and positive control. Some sponsors have chosen to reduce the trial size by eliminating the therapeutic arm. This design should be discussed with the regulatory bodies before starting the study. 

 In 1981, approval was granted to market Seldane (terfenadine), a non-sedating anti-histamine for the treatment of allergic rhinitis. Reportedly, the number of prescriptions for terfenadine products reached 16 million in 1991. 

Among the mounting evidence of terfenadine-related cardiac-toxicity, in a 1993 article Honig showed terfenadine had a modest effect on the Bazett's corrected QTc interval (QTcB) of the surface ECG. The effect, a modest prolongation of the QTcB of approximately 8 msecs only was increased to approximately 82 msecs with the administration of ketoconazole, an anti-fungal agent that blocked the CYP450 enzyme, the same pathway that cleared terfenadine from the body. 

In 1998, the US FDA requested the withdrawal of terfenadine from the market. This helped spur the regulators to demand increased scrutiny when reading ECGs. Regulations came in two forms: technical and study requirements. 

The deaths "caused" by the interaction of terfenadine and ketoconazole were due to a rare, sometimes-fatal, polymorphic ventricular tachycardia called "torsade de pointes." The name was coined in 1961 by François Dessertenne, who described this as "twisting of the pointes." On surface ECGs, because this is a rare finding, never detected during Phase I to Phase III trials that include a limited number of subjects and patients, prolongation of the QT interval still acts as a surrogate for the possibility of TdP, despite its well-known limitations. As said above, anti-arrhythmics that are developed to control cardiac arrhythmias and that have been proved to be "neutral" regarding total mortality rates in large multicenter clinical trials are QT prolongers (amiodarone, dronedarone, dofetilide). 

Since the ICH E14 was released, changes in the industry standard have occurred. It is well known that other "channelopathies" (impairment of cardiac ion channels function) can occur with pharmaceutical products. To help study these effects, the initial thorough QT evaluation has been expanded to the so-called "TECG" trial. The TECG trial looks at the PR-interval and QRS duration in addition to the QT interval.  

It is also well recognized using S7B core battery tests that some compounds affect more than a single ion channel in the heart, namely the potassium, the sodium, and the calcium cardiac currents. These are known as "multiple ion-channel blockers." One such compound is Ranexa (ranolazine). When being developed by CV Therapeutics, the FDA was very interested in the safety of such a drug. CV Therapeutics had to demonstrate the drug was safe given the multiple ion channel blocking properties. Extensive work was undertaken to prove cardiac safety. In 2006, CV Therapeutics was granted permission to market the compound. The label includes a warning about prolongation of the QTc. 

Another multiple ion-channel blocker was recently removed from the market in November, 2010. Propoxyphene was deemed unsafe by the FDA and the NDA holder (Xanodyne) was asked to voluntarily remove the compound from the market. The rationale given by the FDA: "The results of the new study showed that when propoxyphene was taken at therapeutic doses, there were significant changes to the electrical activity of the heart: prolonged PR interval, widened QRS complex, and prolonged QT interval. These changes, which can be seen on an electrocardiogram (EKG), can increase the risk for serious abnormal heart rhythms." 

 Before the ICH E14, "acceptable" ECG collection included using a standard print-out of the ECG wave form on thermal paper. Measurements were made by hand using either an ECG ruler or calipers on raw beats. Representative beats (median waveforms) were generally not available. 

Concurrent with the development of the E14 was the development of an HL7 standard for ECG waveforms. This calls for digital collection and measurement of the ECG waveform. 

The HL7 standard is the first industry-wide requirement for a common storage format for ECGs. Prior to this effort, ECGs stored using one manufacturers' format were not readable on a common platform as ECG stored in another manufacturers' format. Therefore, the US FDA could not easily compare trial data between trials. ECG core laboratories can now submit data in this format and the data is readable in widely available "viewers." This is commonly referred to and the "XML format." 

The "ECG warehouse" accepts these data for review by the agency. It is hoped that the wealth of data can help the FDA and scientific community determine whether or not the surface ECG has information that can help determine whether or not a drug has a potential to cause TdP. 

The C-QT plots the dependent variable, baseline, and placebo subtracted QT-interval against the plasma concentration of the study drug or metabolite. This type of analysis has become mandatory for TQT trials and can be used in early phase development to give the drug developer an early indication as to whether or not any repolarization liability exists. 

Generally, a linear mixed-effects model is used for this analysis. The slope of the regression line can give an indication of the amount of change in the QT-interval per unit of concentration. Other variables, such as the PR-interval or QRS duration can also be used in this model. This data is not only useful for non-cardiovascular compounds, but they can yield valuable information for all compounds that have a QT-reporting requirement, including oncology compounds. 

In some cases, and as recognized in the E14, a TQT trial is not feasible due to ethical or practicality reasons. For example, many neoplastic agents cannot be given to normal healthy volunteers due to toxicities. Nor can a supratherapeutic dose be given for the same reason. Many sponsors and primary investigators believe that a positive control and placebo cannot be given because it would be unethical. What is left is a single arm QT trial. This is the so-called "Intensive QT Trial." 

In addition to the QT-interval, other cardiac toxicities are important in these compounds. Some of these drugs can cause cardiac muscle damage or reduce the left ventricular ejection fraction. One of the tests used to find cardiac muscle damage is a troponin assay. Other techniques, such as echocardiography and imaging can be used to look at left ventricular ejection fraction (LVEF) as a surrogate for cardiac toxicity. 

Especially in clinical trials with anti-neoplastic agents, cardiac troponins are monitored as a measure of cardiac damage. There are three main varieties of cardiac troponins: C, I, and T. Each of these measures a different damage process in the heart. In cardiac safety trials, Troponin I (TnI) and Troponin T (TnT) are the most widely used. 

The LVEF can be assessed using a multi-gated acquisition (MUGA) or echocardiography. This is usually done both pre-treatment and the end of every other cycle of treatment for cancer patients. 

Some compounds can cause structural changes in the heart. The product, fen-phen, combined fenflouramine and phentermine as an aid for weight loss. In 1995, the FDA asked American Home Products to remove the products from the market. It was recognized that fen-phen caused valvulopathies in a subgroup of patients. It was recommended that some patients using the drug have an echocardiogram to see if there was damage to the heart. 

Not wanting to see another problem such as occurred with fen-phen, Arena Pharmaceuticals was asked by the FDA to conduct echocardiograms in the clinical development program of APD356. The Behavioral modification in Overweight and Obesity Management (BLOOM) trial, Arena conducted echocardiograms in approximately 3,200 patients.  

Another use for echocardiography is to estimate the LVEF. The LVEF can be compromised in certain trial with cardiotoxic compounds. These include some antineoplastic agents that have inotropic effects on the myocardium. 

Some investigative sites do not have access to or expertise in echocardiography. Therefore, the LVEF can be calculated by using a MUGA scan. Since these are mainly safety endpoints and usually not an efficacy endpoint, the combination of echocardiography and MUGA for LVEF measurements is common, but not interchangable within the same patient.  

Cardiac safety is also a concern when developing treatments for diabetes, as evidenced by the issues seen with pioglitizone. In the warning label of this drug, there is a mention of causing or worsening heart failure. 

Long-term trials in diabetes patient populations have demonstrated beneficial effects of glycemic control and lowering of HbA1c on both "macrovascular" outcomes and "microvascular" complications. Therefore, HbA1c remains an acceptable primary efficacy endpoint for approval of diabetes compounds. 

Diabetes mellitus being associated with an elevated risk of cardiovascular disease, the FDA Endocrinologic and Metabolic Drugs Advisory Committee has recommended in 2008 that the cardiovascular risk should be now thoroughly addressed during drug development. In particular, "To establish the safety of a new antidiabetic therapy to treat type 2 diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk" (Guidance for Industry, "Diabetes Mellitus," December 2008). 

The new responsibilities regarding cardiovascular safety for drug developers include:  

Safety committees to prospectively adjudicate cardiovascular events during all Phase II and Phase III trials. The mandatory cardiovascular events in the guidance are: cardiovascular mortality, myocardial infarction, stroke, hospitalization for acute coronary syndrome, urgent revascularization procedures.

Ensure that clinical trials (both Phase II and Phase III) designs will allow conduct of meta-analysis and provide a detailed description of the statistical methodology for meta-analysis.

Enroll patients at high risk of cardiovascular events (advanced disease, elderly patients, and patients with renal impairment.)

While the ECG is still the most important and easiest test used to assess cardiac safety in clinical trials, changes in regulations and technology have changed the way the ECG is both acquired and measured in clinical trials. Other cardiac safety tests are also important and have become part of an overall assessment of cardiac safety. 

Feature Article

Testing cardiac safety has developed into more than measuring a simple ECG test.

Cardiac Safety in Clinical Trials

 to lead ERT's Health Outcomes Research initiatives. 

 as President of inVentiv Health Patient Outcomes.  

With more than 20 years experience in the laboratory manufacturing and distribution services, construction, and public accounting industries, 

 (London, UK) as the company's Chief Financial Officer. Marken has also appointed 

as the Interim President of the Clinical Trials Distribution Business Unit.

 as its Chief Financial Officer, where she will oversee the finance, human resources, and information technology departments. 

 (Andernach , Germany) has been joined by two recent arrivals. 

, PhD, became CRS's new Director of Bioanalytics this Spring and 

, MD, joined as Director, Corporate Development. 

Thomas Jefferson University's School of Population 

(Philadelphia, PA) have entered into an alliance to provide pharmaceutical and biotechnology clients with a broad range of outcomes research services including comparative effectiveness, burden of illness, and quality of life studies. 

(Lausanne, Switzerland) announced a strategic partnership where Debiopharm will entrust INC Research with the management of a clinical study linked to an important project in Debiopharm's pipeline. 

(New York, NY) announced that specialty contract research organization 

 (Stirling, UK) has selected Medidata CTMS, including its investigator site payment module, to manage the operations of all their clinical studies. 

 (Glasgow, UK) attended a reception at Buckingham Palace to celebrate winning the Queens Award for Enterprise. 

, PhD, President of Research and Development with 

 (Wilmington, DE), has been awarded an honorary Doctor of Science from the University of Brighton in recognition of his "significant achievements in the pharmaceutical industry over the past 30 years."

(Ravensburg, Germany) received certification for its integrated management system for environmental, health, and safety. The company earned ISO 14001 certification for its environmental management system and BS OHSAS 18001 certification for its occupational health and safety management system. 

(Chicago, IL) announced that results of a new survey of life sciences professionals charged with forecasting and budgeting clinical studies at small, mid-sized, and top 20 biopharmaceutical and medical device companies show that the life sciences industry continues to experience difficulty accurately predicting spending for clinical development. The survey is available for download at 

http://info.cleartrial.com/budgeting-survey.html

(San Francisco, CA) announced the release of StudyOptimizer 4.3, the latest version of the company's flagship solution for patient enrollment planning, tracking, and forecasting. 

(Raleigh, NC) has created a legal entity in Bulgaria and opened a new office in Bucharest, Romania to further strengthen coverage of the Balkan region's burgeoning markets. The Bucharest office will also support projects in the neighboring Republic of Moldova.

(San Diego, CA) has completed the consolidation of its Molecular Genetic Services business at its newly expanded facilities in Manchester. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update October 2011

To help ensure that the most beneficial and safest therapies reach patients and that limited healthcare resources are invested wisely, manufacturers should be forced to show how their drugs compare to existing treatments before a new approval is issued, according to a group of UK researchers.  

"Numerous promising medicines have been developed," noted researchers at the London School of Economics and the European Observatory on Health Systems and Policies. "With this success comes an equally important additional need—to develop a systematic approach to evaluate the risks and benefits of these new therapies in the context of existing alternatives. An important initial step is to support a formal role for comparative efficacy evidence in drug licensing." 

This position is supported increasingly by the European Medicines Agency (EMA) and European Commission, they wrote in an online article published by the 

on September 6. The EMA has recommended randomized active-control trials (RaCTs) when a new drug might be associated with safety or inferiority concerns, but the authors of the 

article propose that non-inferiority be recommended for all conditions where alternative treatment options exist. This would help to address the current variability in availability of such evidence across therapeutic areas. 

"It is clear that comparative efficacy assessment is not necessarily a panacea," they stated. "No particular study design alone is ideal for assessing comparative efficacy and there is the inherent challenge of ensuring studies adequately address the most relevant clinical and policy questions to support safe and effective use of new therapies." 

Currently, direct comparisons with existing therapies are only required when use of a placebo is deemed unethical. This does not allow patients, clinicians, and other healthcare decision makers to determine whether a new drug is superior, equivalent, or inferior to its existing alternatives, and can result in the widespread use of potentially less efficacious and unsafe drugs, they warned. 

The EMA has advocated that, when possible, pre-market studies should be undertaken to establish comparative efficacy and risk, but has yet to set comparative assessments as the standard for market approval. Requirements for comparative studies are made on a case-by-case basis, they pointed out. 

The researchers estimate that comparative efficacy data are available for 50%  to 70% of new molecular entities at the time of approval, but often only a fraction of evidence is accessible at the time of market authorization. A further challenge is that no particular type of study is ideal for assessing comparative efficacy. 

"An important first step is to achieve open dialogue and agreement between the EMA, manufacturers, payers, and governments on the outstanding methodological questions and hurdles associated with comparative efficacy studies. An independent EMA advisory board could be established to lead such discussions and ultimately provide guidance on: what type of study design(s) can be accepted as fit for purpose for generating comparative efficacy evidence; standards for comparator selection and assessed endpoints; dosing schemes; sample size requirements to demonstrate the margin of superiority, equivalence or non-inferiority; and options to make the conduct of comparative studies more efficient," they stated. 

A limitation of present regulatory systems, however, is the "suboptimal" publication of, and public access to, comparative information on the efficacy, effectiveness, and safety of new drugs. A lack of early comparative efficacy evidence can result in the widespread use of potentially less efficacious and unsafe drugs, as highlighted by the recent case of the diabetes drug rosiglitazone, according to the authors. The relative effect of rosiglitazone against pioglitazone emerged after years of widespread use, where rosiglitazone was shown to increase the risk of myocardial infarction and cardiovascular death, they explained. 

Regulators must insist on submission of full data, including trial protocols and raw datasets, and adopt and enforce a policy to publicly share available data, they argued. Better data exchange may involve including protocols and datasets within trial registries, enhancing the quality and transparency of the European Public Assessment Reports, reporting comparative evidence in product labels and marketing materials, and by journals adopting similar data submission requirements. These efforts would help ensure that researchers have access to detailed enough data to allow independent re-analysis of trials and potentially contribute to improving post-market comparative effectiveness assessment, they wrote. 

 article is Corinna Sorenson, a research fellow at the LSE.

Global News

UK officials stress importance of evaluating benefits of new therapies before approval.

Debate Grows Over Comparative Efficacy Trials

During a long getaway to northern Italy this summer, I was reminded again of modern life in this age of ubiquitous computing-staying connected didn't even merit an afterthought. Driving between mountaintop villages where cell phone coverage was often spotty, the satellite beacon GPS was always pulsing to guide our path through circuitous, pitched slaloms of narrow country roads. Wi-Fi access greeted my tablet at every hotel-including the remote agriturismo that housed us in an Arcadian vineyard-and almost every bar, restaurant, and café. While much of the old country seemed to be virtually unchanged from its likely appearance a century or more ago, these public meeting places previously reserved for social encounters or clandestine trysts now were filled with solitary intercourse between human and laptop, coffee and wine.

	The only things I couldn't keep up with were those related to data stored on my left behind laptop-a pretty convincing argument for me to move further into the cloud. Just give me that remote data access plus a tablet with browser and I should get by pretty well.

	Of course my data was in the form of business documents. Had I had a need to query clinical trials data, I would have quickly exceeded the capabilities of my tablet. But the analysis of the results of a clinical study is not something to be done on vacation anyway-as if the analyst would have been allowed to escape in the first place. Instead, the study team waits with bated breath to see what the data confesses once the blind has been broken. These results are reported, studied, debated, inserted into the common technical document and then on to the next study. Too often in research, the lifecycle of the knowledge gained by the study mostly ends there.

	What a waste. While the industry today is investing many resources toward exploiting secondary uses of observational healthcare data, the knowledge we gain through the blood, sweat, and tears of clinical trials seems to remain mostly single purpose-to support a regulatory submission rather than to be a persistent knowledge asset combined with previous experience used for multiple analytical and exploratory purposes by a larger research community. Combining the data into a pooled resource to support extended exploratory analysis certainly sounds like a good idea, but it's simply too hard.

	Not that the concept of aggregating data from a pool of clinical trials is entirely alien, since sponsors have long had to prepare an Integrated Summary of Safety (ISS) database as part of their submissions. An ISS includes a subset of the safety information included for multiple controlled clinical trials (including demographics, adverse events, laboratory results, and other relevant safety domains) using a common schema and coding dictionaries. This is typically created by the statistics organization, but might not be made available for other purposes to other researchers within a drug sponsor, much less those who are external.

	Then what about the FDA, which receives a copy of these same databases? They still lack a common repository to provide easy access for reviewing such data, which thus generally limits the scope of their review to the submission at hand. The Janus data warehouse initiative of the past decade offered a taste of what might be done, but the project was handicapped because most incoming data still does not conform consistently to the CDISC SDTM standard, and seldom includes standard terminologies other than MedDRA. So it was quite difficult to get data into this repository, much less pull it out, and so Janus has never gone into production use. FDA is now working on designing a new Clinical Trials Repository which will pick up where the Janus project left off, and they have indicated their intentions to publish the data model they're developing.

	So defining a consistent repository for these data is one important step. But populating it with data ready for scientifically sound analysis is quite another. The inherent complexity of clinical data combined with the one study at a time attitude means that the data just can't align easily for pooling-even the data for one sponsor's drug program much less many others. For example, a critical clinical endpoint such as "bleeding" may vary in its description, attributes, and thresholds from study to study (not to mention drug to drug) while using the same label. The nuances of these definitions are generally buried within the protocol document, rather than metadata. While the CDISC SDTM provides a structural model for representing data, it does not really ensure consistency of meaning, especially when most users currently map data retrospectively to SDTM, which is rather like sorting your recycling for pickup into paper and plastic. That may be better than dumping it all into a single bin, but just barely, since we're just deferring the more difficult sorting by type, color, etc. farther downstream (and hopefully not just to a landfill). A particularly striking example of a semantic web approach to removing ambiguity from language can be found at tiny.cc/semanticweb.

	So it's not enough just to address the structure. To handle this most challenging of problems, we have to have a much more comprehensive way to fully describe and represent data using rich metadata, complex datatypes, patterns, and models. One approach offered by Thomas Beale as part of the openEHR Foundation, is to represent scientific observations as a triplet (there's that semantic web concept again) of data, state, and protocol. The data contain the value of a precisely defined measurement itself- say systolic blood pressure value. The state indicates the patient condition at the time-was this at rest or after exertion? Was the patient standing, sitting, or supine? The protocol describes the method: what size of cuff, which arm was measured, what type of measuring device, did it occur after some other set of mandated procedures (such as a blood draw, which may have created anxiety in the patient?).

	Ideally all of these aspects of a clinical observation would be specified in a machine-readable protocol which uses information objects fully characterized in a metadata repository, and carried through data collection and analysis as metadata, so that advanced clinical query tools in an aggregate data repository would be smart enough to recognize which particular measurements were scientifically consistent-and which do not line up sufficiently to allow them to be aggregated for a meaningful pooled analysis.

	And even that does not get us all the way there-we have to be certain we understand the clinical subject population as well. Clinical trials are extremely choosy about their subjects, who must meet what can often be a very complex set of eligibility criteria. These criteria are adjusted from study to study, so joining records from one study to those of another can create an unbalanced mixture of separate homogeneous populations, which bears little resemblance to the real world. Here again, it should be possible for new aggregate data analysis tools to understand the eligibility criteria so they could identify studies where the populations are sufficiently similar to allow meaningful pooling of data once the characteristics of the study population are well described.

	A further degree of complexity is introduced by the design of the protocols themselves, such as the scheduling of events, order and types of procedures, and definition of treatment groups (especially those that involve changes in treatment during the course of the study, such as crossover designs). Then there are the many assumptions that may have been made by the biostatisticians when analyzing the data, and the additional data elements they derive to facilitate analysis. It's nearly impossible for a human being to be able to absorb and retain sufficient information to make it possible to keep track of all of these variations especially when delving into an ocean of possibilities. These have to be represented within the data repository directly before they can be interpreted by query tools.

	Making this transition requires adoption of a uniform information model, consistent data types, and common semantics by all studies in the repository-a level of harmonization which we haven't come close to achieving yet. Even those who are trying to solve this problem often break into separate competing camps with different approaches and perspectives-not unlike our political environment in the United States. But at least the range of variation is slowly receding, and the different camps are beginning to huddle more around the same campfires to continue the conversation in forums such as the Clinical Information Modeling Activity being led by Stan Huff of Intermountain Healthcare. So while we are still a great distance from achieving a lingua franca for medical research, we may have gotten to the stage where those who speak different languages are at least able to communicate basic concepts in rudimentary ways. This situation will only improve over time, as long as we provide a learning environment to capture the knowledge as it accumulates, and the proper infrastructure to share it at its fundamental atomic/elemental/molecular levels to all researchers to not just inform but to drive the design of new studies so that the data uncovered by that research can persist for many other secondary purposes across the extent of foreseeable future time.

	So to use aggregated data with scientific prudence, we'll need much more metadata than we have today to supply the relevant context and parameters, systems that can keep track of all that, and tools that are smart enough to process it all with sufficient understanding to guide us toward making meaningful and defensible analyses.

	Again, conducting analysis of research data is not exactly something to be done on the road, on an iPad, when one should really be on vacation, rather than crunching against a database. Unless, of course, crunching numbers in a database is your idea of a vacation. Maybe someday it will all be so easy, it will seem like one.

is Senior Director, Life Sciences Product Strategy at Oracle Health Sciences. He can be reached at 

Technology Viewpoint

Public to private switch gives CROs better chance to "fix" and transform themselves.

The Power and Pitfalls of Aggregate Data

It's been said that a new drug application is 100,000 pages (or more) in support of a label. While this might be a simplified view, it does provide some idea of the scope and challenges involved in preparing the enormous body of documentation that is needed to convince a regulatory authority that a product is safe and effective. 

In taking a closer look at the required documentation, it's easy to see that a number of challenges await those responsible for assembling the submission: 

Administrative and prescribing information. 

Agencies require a variety of forms, which may be locked down PDF fillable forms, XML forms, or scanned paper. Correspondence and certifications are required that may originate from a variety of different sources. Labeling required in a submission may take several forms ranging from MS Word documents showing tracked changes for draft labeling to XML (e.g., FDA's Structured Product Information). 

 Because the documents depend on being able to analyze and reference final documents in other parts of the submission, the ability to finalize them depends on the other documents being available and stable. 

 In this area, the submission publisher must locate the correct content taking into account document versions and specific authority requirements. For example, different stability documents and compendial excipients may apply in different parts of the world, despite the harmonization goals of the International Council on Harmonization. Other challenges include the need to include scanned content such as batch records as well as manufacturing documents that may be subject to late modifications during manufacturing scale-up. 

Because the nonclinical program is so lengthy for most products, reports may be needed that were created five years ago or even earlier. The reports were often created by contract research organizations (CROs) or by scientists no longer working on the drug project. These factors often contribute to difficulties in locating reports and in issues related to the fact that they were not created to current standards. 

 Clinical reports represent the largest portion of submission content, averaging around two-thirds of an application. In this area, the publisher must work with study reports that may not have been formatted in accordance with agency requirements, or that many exist in many small pieces. In the United States, a large volume of case report forms and SAS datasets must be assembled in accordance with their own specifications. 

In the world of paper submissions, the assembly process was complicated, but largely free of technical compliance requirements. In other words, the publisher could take documents in many formats, assemble and print them, with the main concern being the appearance of the final paper product. If a problem was found, often a replacement page could be slipped in at the last moment. 

Now, electronic submissions standards place many technical requirements on the individual documents included in a submission, resulting in a new set of quality assurance responsibilities that sometimes fall on a documentation group, but more often end up with the regulatory publisher. 

Of course, a primary component of profitability for a drug, biologic, or medical device is its effective patent life. Delivering a submission to a regulatory agency and triggering a review clock directly affects the effective patent life. So why do so many companies wait until the last minute to address document quality issues that can jeopardize their carefully planned timelines? 

In general, the root causes trace back to not fully understanding the requirements and failing to put in place a system to ensure they are addressed throughout the entire process:  

Sponsors may have put off becoming compliant for years, believing that they did not have to worry about electronic submissions yet and not understanding that the documents they were creating would someday be included in electronic submissions in the not-so distant future.

Sponsors may not have studied the requirements thoroughly, or may have believed that they would be fully met through the use of commercially available document templates. They may also have relied too much on their CROs, suppliers, or partners to produce compliant documents.

Sponsors may have instituted a program for compliant documentation, but failed to monitor it and make corrections.

Whatever the reasons, dealing with documents that are not e-submission-ready at the last minute is costly and time consuming. If problems are found with approved documents in PDF format, fixing them may invalidate electronic or digital signatures, break hyperlinks and bookmarks, and result in the need for re-review and additional publishing activities. 

In the past, regulatory authorities were so eager to encourage electronic submissions that they would often accept significantly flawed applications. However, sponsor adoption of electronic submissions has increased significantly in recent years. For example, the FDA now receives over 50% of new drug applications (originals and supplements) in electronic common technical document (eCTD) format.

  As a result, agencies are beginning to demand greater compliance with the published specifications and standards. For example:  

The FDA began checking for dozens of errors related to PDFs and fillable forms in 2010.

  Currently, FDA is rejecting around 7% of eCTD applications due to errors.

Reportedly, the French health authority has revealed that it is rejecting half of all NeeS (non-eCTD electronic submissions) dossiers because they have been poorly formatted and do not meet basic validation standards.

The Belgian authority has required full compliance with published standards since 2007.

SwissMedic requires the sponsor to perform technical validation of an eCTD before submission, and to submit a form documenting all unresolved errors.

Each of the major authorities accepting eCTD has published validation specifications and established their authority to reject electronic submissions.

  The impact of a rejected submission is obvious—delay due to rework. What is less commonly understood is that a technically deficient submission may result in review problems and delays—

 leading to additional delays in approval, such as the issuance of a complete response letter in the United States. Understanding and complying with requirements, as documents are created, reviewed, and assembled, minimizes the risk of such costly delays due to technical and organizational issues. 

We've established some of the underlying causes of non-compliance, as well as the risks and consequences. The remainder of this article will discuss key document management practices supporting compliant e-submissions. The practical information and recommendations offered will help to identify gaps in current practices and understand how to address them. 

The key document management practices that will be discussed include:  

Establishing taxonomy and metadata that map to eCTD/NeeS definition of documents and granularity

Taxonomy and metadata are buzzwords for concepts, which most of us are already familiar. 

Taxonomy is the practice and science of classification. In the document management world, this means the classification scheme for the types of documents that you manage. For example, in the general sense, a document may be a "quality" or "CMC" document, then more specifically a "control of drug substance" document, and then a "specification." Taken together, the entire inventory of documents included in a submission (and sometimes others as well) are organized in an electronic document management system (EDMS) using a taxonomy. 

Metadata is loosely defined as data about data. In the document management world, this means information about your documents which may or may not be included within the documents themselves. Document metadata (also known as properties or attributes) is used to organize and retrieve documents. It may include title, author, approval date, study number, drug substance, or many other pieces of information. 

 In the paper world, it didn't make much difference how your documents were structured. You could create a single large document representing all of module 3, paginate it continuously, and break it up (or "volumate" it) for binding into physical volumes. For electronic submissions, however, files (documents) are expected to be provided at very specific levels, slotting into a submission table of contents (the eCTD backbone). Compliance with this requirement has a profound effect on authoring, review, and approval—and starts with the implementation of a compliant taxonomy in an EDMS. 

The ICH Electronic Common Technical Document Specification defines the standard sections (overall table of contents) of the CTD/eCTD. The guideline "Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use M4" adds the concept of granularity—the level at which distinct, standalone documents can exist. This reference provides a definition for the term document: 

A document is defined for a paper submission as a set of pages, numbered sequentially and divided from other documents by a tab. A document can be equated to a file for an electronic submission... In an electronic submission, a new file starts at the same point at which in a paper submission, a tab divides the documents.  

The guideline then defines the appropriate granularity to support the submission table of contents (Figure 1). 

 Figure 1. Yellow shading indicates that documents rolled up to this level are not considered appropriate, and the purple shading indicates that a single document can be submitted at this level. 

So how does this affect the EDMS? The answer is that that taxonomy in your EDMS should be optimized to support the organization and taxonomy of the CTD/eCTD (as well as any other submission types you might need to produce). For example:  

The system should not normally allow you to create a "module 2" document.

The system should allow you to create a single document representing all of 2.3 (the quality overall summary). However, it should also allow you to create a document representing the drug substance portion of the QOS (2.3.S) or even general information about the drug substance (2.3.S.1).

The taxonomy should be specific enough to map back to the submission sections. For example, if a user creating a document only identifies it as a "report" or "protocol," it could belong in many locations in the quality, nonclinical, or clinical section of a submission.

The taxonomy should ensure that there is a logical place for everything to be included in a submission, while minimizing the use of categories like "other."

Five key steps for e-submission ready documents to avoid pre-submission rework.

Document Management

Eighty-five to 90% of clinical trials have a stipend or travel reimbursement to compensate subjects for their participation. While reimbursement amounts may not be large from the perspective of industry professionals, the payments can still make a difference to a volunteer. Greenphire CEO Sam Whitaker says, "Many studies typically deliver reimbursements on a monthly or even quarterly basis. And it may only be $50, but even four to six weeks can be a long time for a patient to wait to receive his payment, especially when a real cost is incurred to participate, and for these patients $50 is important." 

Thus the heart of Greenphire's ClinCard System, designed to execute clinical subject payment and subject messaging to improve the patient's—and the site's—experience. "Happy patients and happy sites equate to happy studies," says Whitaker. Implementing an automatic, electronic, patient-facing tool for a clinical trial is why Greenphire was chosen for subject payments in the first ever virtual and patient-facing REMOTE clinical trial currently being conducted by Pfizer.  

About four years ago, Whitaker and two other colleagues were working in product development at Citigroup to structure pre-paid debit card solutions in other industries. Whitaker, whose fiancée was working in clinical research, eventually left Citigroup and a couple months later started his own business with the ClinCard as its flagship product. He amassed a Board of Advisors, including Neil Rotherham, the founder of ClinPhone, and built Greenphire's original ClinCard solution, marrying subject payments with text messaging and other forms of electronic communication.  

"When the card is loaded, the system recognizes milestones and sends text, e-mail, or voice messages to patients. These messages, in conjunction with the convenience of real-time payments, reduce the number of patients lost-to-follow-up and help increase retention and participation, which drives protocol compliance," explained Whitaker. The system is neatly packaged and uses a web-based portal that is managed by site coordinators and study teams. It can use data feeds from the IVRS, EDC, or CTMS to execute milestone-based payments, or flag items where attention needs to be paid by payment approvers using the ClinCard System's portal.  

In the REMOTE trial, however, the ClinCard's functionality is limited to delivering subject payments, as the text messaging functions are handled by the eDiary cell phone-based solution provided for the trial by Exco InTouch (

Whitaker had noted that prior to the Pfizer study some clients wanted to break the messaging solution out of the original ClinCard System, so Greenphire also established a standalone Subject Messaging System. However, Whitaker believes the ClinCard System ideally incorporates both the payment and the communication features to eliminate unnecessary burdens on the site coordinator's daily routine. 

For Pfizer's REMOTE trial, discussions about using the Greenphire technology began as early as spring 2010. Other vendors in the virtual trial chain include the aforementioned Exco, as well as Mytrus, which serves as the single coordinating center for patients, recruitment, the principal investigator, sub-investigator, and the coordinators; and Perceptive Informatics, which provides IVRS. Greenphire works directly with Mytrus, and the ClinCard that is distributed to participants based on subject IDs is Mytrus-branded and funded by Mytrus. "We didn't realize the impact it would have," Whitaker said. "It creates a real-time way for patients to receive the stipends and reimbursements they deserve. The funds automatically get loaded as they leave the site, providing access to funds immediately and eliminating a lengthy delay. This is one of the ways we are improving the overall patient experience in the clinical environment." 

For a more visual take on how the patient ClinCard experience works, view the Mytrus video at 

Greenphire signed its 100th site client to the ClinCard System in mid-July, has contracts with nearly 40 sponsors and CROs, and has partnered with Mytrus to provide the ClinCard for a number of upcoming virtual studies. However, there are still challenges with the ClinCard. Whitaker said, "It is not easy to drive adoption of a new solution in our industry, which is generally slow to adopt new technology."  

But if happy patients who follow through to the end of a trial and beyond isn't enough, Greenphire is addressing another clinical trial "pain point" in its next generation solution—the delay for sponsors in delivering site and investigator payments. Greenphire's eClinicalGPS is a global clinical payment system that automates payment delivery from sponsors to sites, investigators, and vendors. 

Whitaker explains that traditionally CROs take on these payment tasks, a manual and expensive process. The CRO can charge anywhere from $100 to $200 per site payment. Greenphire strives to reduce these costs by 70% to 75% per payment. 

eClinicalGPS' also facilitates faster site payments and centralizes invoice payments for sponsors, enabling any Sunshine Act disclosure requirements. 

While both of Greenphire's existing technologies address real needs in the clinical trials industry, Whitaker believes technology will continue toward a more patient-centric model in the next five years. 

 CBI's Patient Centricity in Clinical Trials conference is January 2012. 

News

New ClinCard system helps deliver payments in a faster and more efficient manner.

Technology Helps Trim Reimbursement Times

The campaign has begun to enact new policies to "improve" the drug approval process through legislation to reauthorize the drug user fee program; that always carries multiple initiatives designed to spur biopharmaceutical innovation. After a year of consultation with all interest groups, regulators and manufacturers reached agreement last spring for renewing the Prescription Drug User Fee Act (PDUFA), on track to transmit the PDUFA V plan to Congress next January. The current user fee program expires September 30, 2012, and a new program has to be in place before then for the Food and Drug Administration (FDA) to be able to continue collecting industry payments. 

The debate will be shaped by growing pressure on the Obama administration and Congress to cut government spending, which promises to curb resources for the FDA and further squeeze drug reimbursement. Legislation adopted in August to extend the national debt ceiling established a new "super" deficit reduction committee to identify $1.5 trillion in spending cuts for the next 10 years. If the panel fails to reach agreement on a savings plan, the default is an 8% across-the-board reduction in government spending, a tough cut for agencies like FDA that are required by recent legislation to expand oversight programs.  

The situation makes it even more important for Congress to quickly approve user fees to offset anticipated curbs on appropriated funding. Even though user fees already support some 60% of FDA's expenditures on assessing new drugs and biologics, the demand for more resources will make policy makers less likely to complain that fees make FDA overly dependent on industry.  

The basic PDUFA V proposal, which FDA posted September 1, is not radically different from the current program and by itself should win congressional support fairly easily. FDA is looking to boost user fee revenue by about $40 million a year, a "modest" 6% annual increase that will bring in nearly $700 million in fiscal year 2013. The most notable change gives FDA an extra two months to review applications, here in the guise of a 60-day "administrative filing period" after submission of an application; this will permit agency reviewers to fully vet the filing before starting the official review clock.  

The larger fees will support more meetings between reviewers and sponsors, and a new cadre of FDA liaison officials will be assigned to enhance communications. The plan also calls for standardizing risk evaluation and mitigation strategies (REMS); expanding FDA's Sentinel system to improve post-market drug safety surveillance; and implementing an electronic submissions system for clinical data—something that has long been on the agenda for FDA and for the industry.  

Along with PDUFA, FDA and manufacturers are working on a new user fee program for generic drugs, while also discussing a formula for fees for new biosimilar product applications. There's strong support for renewing pediatric drug development and research incentives, preferably on a permanent basis. The aim is to move away from the five-year sunset-and-reauthorization process linked to PDUFA for the Best Pharmaceutical for Children Act and the Pediatric Research Equity Act to encourage more pediatric product development.  

The Medical Device User Fee Act (MDUFA) also is up for renewal, and negotiations on that program have been much more contentious than for drugs. FDA is embroiled in evaluating proposals for overhauling its 510k regulatory process for low-risk devices, which threatens to expand clinical research requirements for certain products. A recent Institute of Medicine (IOM) report advises FDA to find a better way to assess the safety and efficacy of these products, but industry fears proposed changes will stymie medical device innovation and product development. 

The main obstacle to speedy approval of PDUFA V legislation is the tendency of members of Congress to hang multiple pet programs on the user-fee legislation "Christmas tree." There will be numerous proposals designed to generate savings for government health programs, such as bills to legitimize drug reimportation, to reduce exclusivity related to biosimilars, and to curb brand-generic patent settlements. The White House eyes hefty new revenues from a plan to impose rebates on generics drugs prescribed to Medicare beneficiaries who previously received drug benefits from state Medicaid programs, a policy that manufacturers vehemently oppose as a first step towards price controls. 

Instead, industry would like to see added incentives for developing new antibiotics and revisions in FDA's orphan drug program, along with efforts led by Rep. John Dingell (D-Mich) to strengthen oversight of imported drugs and active ingredients, which would enhance FDA authority to mandate recalls and import controls. There's bi-partisan support for REMS reform and for revisions in FDA financial conflict-of-interest policies that appear to exclude many qualified experts from seats on FDA advisory committees.  

A Biotechnology Industry Organization (BIO) wish list is less conventional, calling for FDA to become an independent agency and to de-politicize it by appointing the FDA commissioner to a fixed six-year term. BIO wants to require FDA to tell sponsors specifically why it's not approving an application and proposes a "progressive" drug approval procedure that permits therapies for diseases that lack effective treatment to come to market on a limited basis while the sponsor completes clinical studies.  

FDA laid out its goals for user-fee-renewal legislation at House and Senate committee hearings in July. Commissioner Margaret Hamburg outlined for the Senate Health, Education, Labor, and Pensions Committee how user fees support patient access to new drugs and medical products. Panel leaders expressed strong support for renewing user fees for drugs and devices, hopefully by next spring, although Sen. Richard Burr (R-NC) threatened to block PDUFA reauthorization if FDA doesn't fix the medical device approval process.  

There was similar high praise for the fee program at a hearing before the House Energy and Commerce Health Subcommittee. The main Republican concerns, as laid out by E&C chairman Fred Upton (R-Mich), are that REMS requirements thwart new drug development, and that "rigid and unrealistic" conflict-of-interest policies prevent advisory committees from vetting new drug candidates in a timely manner.  

Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER), provided the panel with a fairly positive report on FDA's drug approval process, describing how proposed PDUFA V enhancements will further address drug access and safety issues. Woodcock credited the 20-year-old user fee program for establishing a more efficient, predictable drug approval system that has sped up the review process for new drugs and biologics "without compromising the agency's high standards for demonstration of safety, efficacy, and quality of new drugs." FDA has provided patients with access to more than 1,500 new drugs over the past two decades, she commented, including important cancer therapies that often are available to US patients before reaching the market in Europe, according to a recent study.  

Woodcock was able to report that FDA is on track to approve more new medicines in 2011 than in recent years, with 20 new drugs already okayed at mid-year; the number rose to 21–the 2010 total—soon after when FDA added Astra-Zeneca's Brilinta to the list. Woodcock also noted that CDER's rate of first-cycle approvals for priority new molecular entities is going up, citing recent action on landmark treatments for hepatitis C and for late-stage melanoma. She credited the REMS program for facilitating access to high risk products, such as a new thyroid cancer treatment that FDA approved with a REMS to limit access to truly needy patients.  

The real problem, said Woodcock, is not slow approvals, but that too many experimental drugs continue to fail during development. PDUFA support for more FDA meetings with sponsors should help improve success rates, along with added resources to develop guidance and new methods for testing and evaluating experimental drugs.  

This fits with FDA plans to tap user fees to promote its Regulatory Science agenda, as spelled out in FDA's "Strategic Plan for Regulatory Science," published in August. The report outlines opportunities to enhance preclinical toxicology testing, improve drug manufacturing, assess new gene and cellular technologies, and improve the agency's data analysis capabilities. A key initiative is to refine clinical trial design, endpoints, and statistical analysis methods to support the development of personalized medicine and companion diagnostics. The report urges novel trial designs for orphan and pediatric studies, along with modeling and simulation methods to improve protocols. Collaborative research could advance meta-analysis methodologies, enhance the use of biomarkers and pharmacogenomics, and further develop patient reported outcomes and other endpoint assessment tools.  

Similarly, a July CDER report on scientific priorities cites the need to refine statistical methods for assessing missing data and multiple endpoints and to further assess the value of non-inferiority studies and methods for improving the selection of study endpoints. One idea is to evaluate failed trials to identify alternative designs appropriate for limited study populations. To ensure patient safety and clinical trial data quality, the agency looks to identify the most relevant parameters for assessing risk to guide research site inspections.

 is the Washington Editor of Applied Clinical Trials, (301) 656-4634 

View from Washington

Multiple regulatory and reimbursement proposals are slated to expand legislation to renew PDUFA.

Applied Clinical Trials-10-01-2011

Applied Clinical Trials Digital Edition - October 2011

Here Comes the Sun(shine Act)

Cardiac Safety in Clinical Trials

Business and News Update October 2011

Debate Grows Over Comparative Efficacy Trials

The Power and Pitfalls of Aggregate Data

Document Management

Technology Helps Trim Reimbursement Times

FDA, Sponsors Gear Up for User-Fee Action

Staying Vigilant on EU Pharmacovigilance

Sponsors Show a Preference for Large CROs

Oncology Drug Development