How can eClinical deliver on the vision?

Although EDC has taken a tighter grip over the last 5 years, replacing Paper as the primary medium for capturing clinical trial data, often, the value of EDC is not being realized.

I have certain theories as to the root cause - some of which I have witnessed first hand. The question is, what can be done to tackle these barriers to progress?

PROCESSES

Such a simple issue on the surface, but so often being the primary reason for failure to achieve ROI. Here are my 6 reasons why poor Processes impact efficient clinical trials

1. Processes are not re-written to take advantage of the end-to-end impact of EDC.
   
2. Processes are left as generic, therefore failing to leverage the capabilities of specific EDC systems over others.
3. Process Silos - rather than having a set of processes that work efficiently across Clinical Research, processes are developed within the different departments - Protocol Authoring, Study Build, Data Management and Programming / BioStats. This means that potentially work carried out in Study Build is detrimental to what occurs in Data Management and in BioStats.
4. Process Bloat - Processes are developed to such as level of detail, that they become a hindrance to getting the job done. Processes should not instruct the reader on the use of a System User Interface. Processes should guide, but not replace the skills and common sense of trained staff.
5. Process Training - Writing the processes is the easy part - communicating these processes in a way that staff understand and follow is where it becomes tough. eLearning, wiki's and other such tools can change the endless tedious reading into 'knowledge on demand'.
   
6. Processes are good for business first and foremost, and secondly to support a company comply with rules and regulations. Often processes are seen as a necessary evil in a regulated environment.
   

CONSERVATISM

Often when implementing EDC organizations work on the basis of :- better do what we did before, in addition to what we do with EDC.

So - it may be the case that EDC is programmed by Data Management to check virtually all the data, but, just in case multiple subsequent reviews are carried out before the datapoints and therefore database is locked. Studies have shown that a negligible amount of data is modified after it has been first entered. It is really efficient to check, re-check and further check data, if the results have such a minimal effect on the quality of the resulting data?

CRA Monitoring duties related to the clinical data reduces by around 75% in comparison to paper studies. No more logging of enrollment, patient visits, SDV or such things. This should all be automatically captured by the EDC system and communicated through reporting, or a status portal. Repeating this is simply a waste of effort.

STANDARDS

The use of standards is a popular topic. CDISC have made great leaps. However, the actual resulting savings in the application of standards have often yet to be seen. Poor tools should take some blame, but also poor work practices. If 50% of a study is equivalent to a previous study, then the Design, Development, Testing and Programming should reflect equivalent savings to the degree of re-use. In reality, 50% re-use often only creates a small % saving.

PROFIT/POSITION PROTECTION
This applies to sponsor companies where big departments have built up as well as to CRO companies that maintain the perception of the need for old (timely) work methods. Put simply, if it takes longer, or cost more to implement and execute a clinical trial using EDC, then something is wrong. I appreciate that exceptions exist - i.e. on very small studies. However, even in these circumstances, standards can creating savings, and improve quality.

Within Sponsor companies, departments can be keen to protect their existence, even if this is at the cost of the company and efficient R&D as a whole.


SOLUTIONS?
Increasingly, I feel that we will see value and risk based assessments. For example, if traditionally, the BioStats / Programming group have re-checked the data that is delivered from Data Management, then unless they are able to prove that the efforts they applied have had a sufficiently significant impact on the final data, then, they will not be performing that task in the future. Similar situations will occur across other areas.


I would be interested in hearing of other experiences in how eClinical systems fail to achieve either quality or cost savings.

Source to eSource with EDC

One of the areas that I have felt for some time as being a compromise to the effectiveness of EDC, is the subject of Source data, or rather, the fact that source data is often not entered directly into an EDC system.

I appreciate that we have situations where this is impractical for logistical reasons - location of computers, circumstances of source data capture etc.

However, often, it is mandated by the sponsor that source data is not logged in the EDC system, but is instead recorded elsewhere first.   Some advocates will indicate the need to comply with the regulations that state data must remain ‘at the site’.   Personally, I don’t concur with this assessment. The data is ‘at the site’. The cable connecting the screen to the computer might be very very long (the internet) but the data is constantly available at site. I probably shouldn’t be flippant on this point, but, the conservatism in conflict with progress strikes a nerve.

Transposing information from paper to an EDC screen introduces the potential for error.   In the old world days of paper CDM, we had Double Data Entry as a method to confirm transcription errors did not occur - 2 staff enter the same data from the paper CRF’, and the differences flagged/corrected.   With onsite EDC we don’t have Double Data Entry, but, we do have Source Data Verification. Instead of 2 staff sitting next to each other double keying data, we have a monitor fly in to perform the 2^nd check. Yes, I know, they carry out other duties, but still. This seems like an enormous effort to check for transcription issues. It also has a massive effect on slowing down time to database lock.

So – where are the solutions:-

1). Data at Site

We could put on our ‘common sense hats’ and make a statement that allows the entry of source data into the online EDC system. I know of a number of EDC companies that have simply placed this in their procedures. No audit findings / concerns have been raised as a result that I am aware of. Come on Regulators – why the delay in making a statement on this subject? The confusion caused is creating a measurable delay in bringing drugs to market!

2). Physical availability

This one is harder to tackle. When you have data to log, do you always have access to a system/device to log the data? Possibly not. Do you simply try to remember it, like an Italian waiter remembering a dinner order… I don’t think so. We either need to provide portable data entry devices, or, we accept paper transcription for these elements.

3). Differentiating Source from eSource

This does open up one area of concern. If we have some data as source, and some as eSource, how do we know which is which? When a Monitor goes looking for the source data, if they don’t find it, does that make it eSource – no.   There needs to be some very simple flagging, and visual indication system built into such a mixed source/esource system that supports this. I have seen this in one system, but, it is very rare. Come on EDC vendors – you’re turn here!

4). Other systems

Health Record systems amongst others will often be the first point of entry for data that may apply to an eCRF.   The current approach for organizations such as CDISC and HL7 is to create interfaces between systems. This will be a slow burner, I predict. There are so many hurdles in the way. It requires active cooperation from both sides – EDC providers may be fully onboard, but, I am not so sure about most EHR providers.  

We may see a company emerge (maybe this is what some former PhaseForward employees are up to – who knows!) develop an online Clinical Development Electronic Health Record System that is immediately EDC ready. Of course, with such a small deployment potential, I am not sure that we will see this appear at all sites in a global study, but for domestic application – say within a single country, inside research hospitals, it could work. I digress - back to the integration issue – yes, when we have standards, the feeds will start to happen, but not for many years.

5). Patient Recorded Information

ePro, Patient Diaries etc.   These are increasingly realistic, for the right sort of study for the accurate capture of patient data. If used appropriately, they can cut down the volume of data that needs to be transposed into EDC, and therefore source data verified.

On a side note, I am sure we will see a downloadable iPhone app that will make the current hardware/software dependent or basic PDA browser based systems seem old and tired.

The advantage of diary based systems is that instead of an investigator quizzing a patient, writing down the responses, transposing the responses etc. The information is captured ‘at source’ often considerably closer to the time of event.

Expanding from my previous post, I expect to see systems like PatientsLikeMe expand onto portable devices and act as an entry point for both patient identification and data entry. Internet enabled device pervasiveness will simply make this happen.

Conclusion

A lack of eSource has direct impact on the time it takes to lock data. With adaptive clinical trials executed by forward thinking sponsor companies, the point at which an adaption can occur corresponds directly with how long it takes for the sample size end-point significant datapoints to achieve a locked status. To simplify - the less eSource you have, the longer your studies will take. Forget a few days - we are talking wasted months.

Applying XForms to CDISC

In a previous posting, I made reference to a technology called XForms.  I mentioned that it might prove of some value in addressing the challenges that eClinical systems face in meeting business demands.

XForms is an interesting technology in a number of ways.  To understand what it brings, it should be understood what the traditional method of browser data presentation lacks.  HTML remains the standard means of presenting form information on a screen.  It fundamentally dates back to 1995 in its present state when the Internet really took off. As far as broad standards for forms based data capture, things have not really moved forward greatly since then. 

HTML forms are built in 100's of different ways by software residing on the server.  Typically, the developers will take lots of strings containing things like <Head>, <TR> or <BR> etc and glue them together to make up the necessary codes required to present a form on a browser. Admittedly, there are lots of 'helper' technologies to make things easier such as Extensible Style Sheets (XSLT), Dynamic HTML etc, but, ultimately, there is no one way to effectively create and deploy forms to a browser. In particular, there is no way to easily separate what a Form Does from how a form Looks

The W3c group recognized this challenge and create the XForms standard released October 2003.

'So, yet another standard that will disappear into obscurity!'  I hear you say.  Well, maybe, but, even if it does, it has some attributes that are worth understanding, when considering how things should work in the ideal world.

Benefits of xForms

1. User Interfaces built on XForms require fewer round-trips from client to server - they are more self contained than pure HTML implementations.  This leads to a better, faster user experience
2. Mobile device capabilities vary significantly.  Creating a form interface that works on a iPhone as well as on a 1400x1200 resolution desktop is very difficult. XForms provides the separation to allow this to occur with common code.
3. Javascript is the tool many developers use, on the client browser side, to workaround the limitations of HTML.  However, Javascript is implemented differently by different browsers, and, can even be disabled for security reasons.  XForms provides a means to avoid this limitation.

More about xForms

All sounds cool.... so, lets find out more about xForms...

XForms implements the concept of Model/View/Controller.   Sounds like mumbo jumbo, yes, so lets translate that into some meaningful.

When you capture information from forms, you can define 3 distinct layers to efficiently achieve a design.  

Presentation - 'the View'

Starting at the user side, you have the Presentation side.  On a regular desktop browser, you will maybe have a form presented in a free form layout with 20 questions, nice shaded graphics etc etc.  On a PDA, you want something simply, that scrolls well - so you would have a smaller set of questions, presenting with no fancy graphics, and in a simple list layout.  The Data you are after is the same.  The Logical rules you want to apply to the data are the same - it is only the presentation medium that is changing.

Logic - 'the Controller'

Next, we have the brain.  The part where all the rules exist.   This is not 'eClinical' specific, but, to use an EDC requirement, this is where all the edit check rules exist.  The logic is attached here, and separated from the Presentation Layer in order to ensure that regardless of the layout of the form, or, the device used, the same rules can be applied (and most importantly) re-used.    This controller can be split into two areas - handling requests form the presentation for dynamic activities - as well as processing the results in a common way.

Data - 'the Model'

Finally, the 'what' in the structure. The data resides in the Model - or rather the definition of what data. Aligning with the eClinical analogy, SDTM would be an appropriate specification for the definition of what might exist here.

xForms and CDISC - applying the Model

So, how might XForms be applied to the CDISC in general?   

To some degree, CDASH defines a set of fields that will be captured without consideration of the device that might capture them.  You could have a situation where a PDA might capture 4 questions at a time whereas a desktop browser would capture 20.  The definition of the form itself will differ due to the medium.  So - CDASH in this perspective doesn't fully fit.  However, as a means to standardize the 90% rule - most forms are completed on a full size browser - it is fine. CDASH provides a recommendation of what would be captured together in the presentation layer for one type of device.

So, where would CDASH fit in the XForms Model / View / Controller paradigm?  

Lets look at a possible model for metadata that could be implemented with xForms:-

Starting from the left - the obvious model for the Data (Model) is SDTM.  This would include a list of all of the standards Domains. It could be extended as required, and include sponsor specific extensions structured as per the SDTM standards specification

Next in the middle, we have the Logic (Controller). CDASH could potentially work in this middle tier although you would need to add the logic elements.  A Module could equal a CDASH Domain with all of the potential (required and optional) fields included. 

Finally, at the Presentation (View) the Form. This would be a representation of the CDASH domain with specific controls (drop downs, radio's etc) added and fields not required for a specific instance removed. Multiple instances of the form might exist with the same rules and relationship to the Data Model carried forward.

 

Conclusion

xForms in the context of CDISC and eClinical is not so much a means of capturing the data. Rather, it is a means for modelling the metadata to better support the separation of the data that is needed from the logic that must be applied, and the presentation of how this is achieved.

With a model applied similar to the above SDTM data sets could be quickly achieved while at the same time offering flexibility in the medium used to capture the data together with a consistency in the rules enforced.

I have purposely left out references to ODM in the above article.  It may have a place here, but I will expand on this in a future posting.

eClinical in 2009?

So what will the eClinical landscape be like in 2009?   Here is a projection on what I believe will transpire in the eClinical business area over the course of the next year.  As ever, these are purely my opinions, and do not reflect the opinion of the company I work for...

We have seen significant changes over the preceding 2 years.  The number of vendors have shrunk with Medidata and PhaseForward apparently swallowing up the vast majority of new business.   

Oracle have been suggesting the availability of a new, improved product.  If they want to stand a chance against the big 2, then they are going to have to get the EDC portion right this time. Previous attempts were so far from the mark with regards basic EDC functionality and ease of use that they bombed in the market.

Medidata's announcement of Developer Central is potentially more significant.  ClinPage describes this as an API. However, I think that is a simplification that underplays the significance of the release. Back in September, I wrote a blog on Web Services, and how they might impact eClinical.

A number of EDC/CDM vendors have claimed to offer API's - FW-IMPACT and Oracle for example, but many were simply an exposure of a set of Stored Procedures. Techie's developing eClinical systems have talked about a full web service solution for many years. Medidata appear to have take their experiences with CDISC and actually delivered a fully operational solution - a full CDISC compliant Web Service for eClinical data Importing and Exporting.  

Google were the first company to really generate buzz around the principle of an API over the Internet with the release of the Google Toolkit.  With this, any developer with an Internet connection could send a program request - using web service calls - to Google, and receive search responses that they could use for their own purposes.    If the Web Service eClinical API that Medidata has announced is all its potentially cracked up to be, then we should see a long queue of  eClinical providers - eDiary, CTMS etc all lining up to be in a position to offer Medidata Rave real-time connectivity out of the box.

On a technical note, it will be interesting to see if the use of the CDASH standards will be utilized as a means to standardize the metadata used to capture the data.  If this does occur, we could see a simple handshake occurring at the start-point between the two inter-connected systems to confirm 100% compliance with CDASH. If this is the case, then no manual metadata synchronization need occur. In reality, I suspect ALL CDASH based implementations will be customized, but, its a good start.

Back to 2009 forecasting...

The financial crisis will clearly impact the industry.  The smaller companies - BioTech's specifically - will struggle to find cash.  If the development programs they are running rely on a constant cash flow, then they could go under.  This might provide rich pickings for the big companies looking to pick up a bargain, but, potentially at the cost of new innovations.  For the lower end of the eClinical marketplace, things will be tough.    eClinical vendors that can demonstrate lowering costs - especially over paper - will see increasing business.

eDiary vendors will continue to see business grow provided they can show interoperability, and, can manage to keep infrastructure costs down.   We may see an increase in the prevalence of eDiary solutions based around Off the Shelf or pre-existing hardware - the iPhone for example appears to have the ease of use, connectivity  and synchronization capabilities to make it more widely usable then any other OTS product today.

CTMS vendors will increasingly struggle.  The value of such solutions is increasingly marginalized with the enhancements offered by leading EDC system providers.  Similar to the eDiary space, if they can 'play nicely' with the other systems, they stand a chance.  Otherwise, they will be considered unnecessary in the overall eClinical Life Cycle.

Overall, I think we will see the more marginal areas of the eClinical vendor solution business impacted the most.  When finances are tight, the argument for these types of systems will be difficult.  Life Science companies will focus on cost saving and direct efficiency gain solutions.  This will be no time for long term technology prospecting.

 

For those following these blogs, I wish you well for the holiday period, and Best Wishes for 2009.

Return of the 4GL for eClinical - Part 2

In the first part of the series, I described how in the Technology business, Fourth Generation Languages provided a platform for the effective development of database driven application software.   With this instalment, I would like to examine how the principles of a 4GL might be applied in the design of an eClinical Application Development Tool. 

This part of the series of articles will focus on the requirements - in particular for handling rules, and briefly how these requirements might be met with a syntax.  It should be noted that many of the principles apply directly to EDC systems, however, the target application area is not EDC specifically, but rather a full eClinical platform.

Here are the bullet requirement items;

• Triggers - Capable of defining rules that can be applied based on the occurrence of an event
• Powerful - capable of describing all required rules that might arise in capturing and cleaning eClinical Data
• Human readable syntax - it must act as a specification to a user as well as machine readable instructions when executed
• Referencing - must provide a simple unambiguous mechanism to reference data
• Repeatable - must be re-executable
• Multi-Action - Queries - yes, but what about other actions
• Testable - through a black box paradigm, built in self testing
• Speed - must execute very quickly. <10ms per rule on a typical environment.
• Business aware - must provide features that automate certain common business elements typical of eClinical

Triggers

Firing mechanism

Not Winnie the Pooh's buddy, but a logical method of controlling the execution of rules in an EDC system, is to base the triggering mechanism on the change of an input value.  For example, to check if a subject is between the ages of 18 and 65 simply set an input value of the field containing the 'Age'.  When the age changes, the rule executes.

In practice, this works for the majority of requirements, but not for all.  Sometimes, triggers are required based on the change of other study elements or attributes.  For example, it might be required that when a query is raised for a subject, that a rule is triggered.  In this example, this is subject level triggering rather than response value triggering.

To achieve this, the syntax should support the attachment of rules to study objects.  For example a possible syntax for triggering might be;

on change of [subject|visit|repeat|field].[Object Id].[attribute]:

Each object would have a default attribute - this would be applied if not specified.   A sample reference might be;

on change of field.Age:

or

on change of subject.Status:

The default attribute of a field object might be the value. 

Also, the 'on change' syntax would be assumed based on the reference values.  If you referenced the 'age' in a rule, then that would automatically become the trigger point in addition to any 'on change' attributes defined.

Should a rule trigger based on all values being in existence, or, just some of the values?   With EDC application in particular,  a positive response is required - a page that is left blank cannot be assumed to represent no data - it could simply mean the data hasn't yet been entered.  Special consideration is required here.  Readers familiar with eCRF implementations will recognize the common Header question such as 'Have any Adverse Events occurred?' This is often used to interpret missing subsequent values from entries left blank on purpose. From a triggering perspective, rather than looking at value that may not have been entered - such as AE Description - the code would need to first check the AnyAE flag.

Prerequisites

This is a more advanced concept, but important from the perspective of keeping the resulting tool simple.  Looking at the example above.  More thought is required when developed rules when conditional questions are involved.   So - with a dynamic eCRF, how can we simplify things.

A feature I will refer to a 'pre-requisites' that are aware to the rules engine would potentially solve this problem.  It is necessary to relate, at the metadata level the required need for a particular value. In our example, if AnyAE = No, then we would not expect a AEDescription. However, if a rule looked at AEDescription in isolation, it may not work. In reality, the rule would need to check AEDescription AND AnyAE.  Infact, this would be the case on any check that cross referenced the AE eCRF.

Now, lets image we could place a Pre-Requisite rule against the AEDescription field; AnyAE='Yes'.  That rule could meet two purposes.  1). it could control the availability of the field on the page and 2). it could act as a additional criteria for any rule that referenced the field.  With a Pre-requisite principle, the rule would simple check AEDescription.  The AND condition would be automatically added (behind the scenes) based on the attached pre-requisite rule.

The end result to the study developer would be that they wouldn't need to worry about whether or not a value should exist based on other criteria - this would be catered for by the pre-requisites.  The resulting syntax for rules would be easier.

Powerful

This requirement is at odds with some of the other requirements.  How do you create a syntax that can cater for each and every rules situation, while at the same time be human readable, and re-executable.    The answer is that you will never ever create the perfect syntax that does everything.   What you do need, is a syntax that delivers on at least 99% of requirements.  The enhancements to the syntax from that of handling regular expressions need to be business aware.  Constructs for things that are common to eClinical system must be available as standard.  By providing support for these, the need to go outside of the 4GL bounds should be reduced to a negligible degree.

Human Readable Syntax

eClinicalOpinion raised the question of syntax on a comment on Part 1 of the series.  I see syntax applying to all language components.  What I mean by that is that all application components should be representable as a syntax that can be manipulated as free format text through a text editor OR from within an Application Development Environment. The maintenance of the syntax though will depend on the activity being performed.  For example, it might prove easier to create a data collection form (i.e. CRF) through a point and click UI.  The end result though would be a human and machine readable syntax.

So - if the metadata is all described in the form of a syntax, does that mean that the preparation of the syntax cannot be table driven - not at all - a syntax would consist of 3 things - basic language constructs, references to data/metadata and references to application objects. The preparation of the syntax would be through a table driven approach. Lists of metadata (fields, forms etc) would be stored in tables as would list of application objects such as what can be done to a subject or a visit event.

Should the syntax be XML - I don't think so.  XML might be one of the languages for representing the metadata - ala CDISC ODM - but the most effective syntax should be optimized for purpose. XML is not easily Human readable.

A number of other factors govern syntax.  Writing a compiler or an interpreter is not that easy to do well. Also, the execution of the resulting interpreted or compiled code needs to be fast. If the code that is produced needs to be processed many times before it reaches the executable machine code, then the length of time it takes to execute is longer. 4GL's are processed through 4 iterations. There are answers. For ECMAScript or JavaScript - SpiderMonkey is an opensource Javascript engine.  This can be embedded into an application and extended with high level application area constructs.  Other embedded scripting tools are available.

The combination of an open source script engine with an object model that is eClinical aware, it is possible to create a syntax that has all the power and flexibility required, while at the same time keeps the complexity of an underlying (potentially super normalized) database hidden.

Value Referencing

This is a key consideration in the definition of a rules syntax.  The inputs and outputs must be easy to reference (readable), non ambiguous and re-usable.  Control of the inputs and outputs is important in order to assure stability of the rules once deployed.   A form of 'black box' approach allows simplified and potentially even automated testing.

Repeatable

Version and Change Management

One of the critical factors in providing an application development solution for EDC is the need to support Version and Change Management - this is a key factor in defining the scripting language scope. Clinical Trials are unusual in that the structure and rules associated with the data may change during the deployment. More import still, the data that may have already been entered may need to be re-applied to the revised structure and rules.  This can prove to be considerably challenging.  If a Study Builder is given total control to add fields, CRF Pages and Visits to an existing study, it would be virtually impossibly to programmatically manage the mapping of data between an old version of a study definition to the new, and still guarantee data integrity.  What this means is that any environment must support metadata release management. In addition, to protect the integrity of regulatory compliance, once data is entered, it must be impossible to delete it even if a protocol change is applied.

Metadata Release Management

Two methods exist for the redeployment of a revised set of metadata against existing data.   You can either only process the changes, or, you can re-apply the existing data to the new definition.  Both methods are workable, but, the latter option can be slow, and requires an extensive and complete object based audit trail containing the former data and actions that can be re-executed against the new metadata.  The former option - to - process changes - requires that the metadata that has been released is managed.  Once data is entered into a system against a set of metadata - the metadata must go into a 'managed' state where all subsequent changes to the metadata can only be re-deployed when it is compatible with the data that has previously been entered.

So - how does this all impact the syntax?

Well, if the syntax is entirely open as far as the actions it performs, and the inputs that it receives, then it is very difficult to handle changes.  On the other hand, if the syntax is limited to operating in a 'blackbox' fashion - for example, comparing datapoints - and returning a boolean followed by the raising of a Query, then the management of a change, or, specifically, the re-execution of the rule against existing data, is predictable.

Lets imagine a large study. It has 1000 rules associated with data.  The study is up and running, and 1,000's of patients have been created.  During the 4th visit, it is discovered that one of the rules defined needs to be changed. The many thousands of other data points, and, rules executed are fine, but, the data points associated with this one rule needs to be changed. The change may effect the previous outcome.  With a combination of managed metadata - where the system is aware of the rule that has changed - and the object based audit trail, it is possible to limit the impact of the change to only the area of the study, and the associated data effected.  This is achieved by only re-executing the actions relative to the changes.

Some Metadata will arrive from an unmanaged source - for example, as an import from an external tool - in this instance, all unmanaged metadata will be assumed to be 'unclean'  and therefore changed.

Rule Actions

So, if a rule executes - by whatever mechanism - and the result of the execution demands an action, what should the action or actions be?   

Some EDC solutions are limited to raising Discrepancies or Queries. Even for the systems that support other actions, Queries, are by far the most common.  However, EDC systems are often differentiated by their ability to offer more advanced forms of actions.

Conditionally adding CRF Pages is one particular action that makes sense.  Changing the status of elements - such as a Subject status might also be useful.

However, one very specific consideration must be supported.  Any actions carried out here may potentially need to be rolled back, or, re-applied as the result of a Protocol update.  Each action that is offered must be fully compatible with the need for re-execution with no adverse results.

Testable

Many eClinical systems fall short when it comes to supporting the full requirements for implementations. In particular, support for testing.  In a strictly controlled, regulated environment, it is as important to prove that a configured eClinical system has been fully tested. The underlying product must be fully validated of course, but, over and above that, regulatory bodies are becoming increasingly aware of the need for configuration testing. 

Good test support in a eClinical 4GL must be built in from the start.  Adding this later is often impossible to achieve well.

To ensure a language is testable, the metadata objects - rules in many cases - need to be managed. The system must keep track of the elements that have been tested, and those that have not.

Speed

The underlying platform probably has a greater bearing on the performance of the 4GL, than simply the syntax.  Also, with web based systems, network latency is an issue.  A potential language needs to be capable of rapid execution. On a typical eCRF it should take less than 50ms to turn around the submission of a page - outside of network latency. Achieving this requires optimization at each step in the execution process.  Extracting data from a super-normalized database - 1 value from 1 record is an issue.  A means to address this is critical.  Avoiding slow interpretation of high level 4GL code is also key.   If the code that is manipulated by the user can be pre-compiled into a more CPU friendly form, then that will help.

Business Aware

Object Orientation

I must admit to being a person that has struggled to get my head around true - or pure - object orientation.  When people start talking about Polymorphism, modularity etc... it all becomes rather cryptic to me. For study developers this could all be too much.

However, I do think that Object Oriented Programming or OOP does lend itself well to specific business problem modelling.  With eClinical, you have certain rules that can be built into objects.  For example, lets imagine we have created an object called a 'Visit'.   A visit can have an attribute 'Name' with values of 'Screening, Visit 1 etc'.  It can also have another attribute 'Number' with values of  '1.0, 2.0 etc'.   Visits could belong to subjects.  Visits can have CRF Pages associated with them.  By defining these 'business objects' and 'object attributes' within the application tool, we can take away some of the complexity of handling relationships and actions from the study programmer.  Instead of having to create a SQL Select inner join between a Visit table and a CRF Form table, the relationship is pre-formed within the application business layer.

So - object orientation - yes, but, only where the resulting user (study developer) experience when preparing studies could be described as 'simple'.

Conclusion

This is all very high level still, but, the above does contain some concepts that may have value in the definition of a potential eClinical 4GL.  In the next posting of the series, we will most likely look at how technologies such as xForms might be supportive in providing an interactive user interface over a web front end to an eClinical 4GL.

Comments welcome!

Should eClinical systems be 'EndPoint' aware

 

EDC Wizard made some interest points in response to the earlier posting 'EDC EndPoints'

The original posting was probably incorrectly titled. It should have maybe said - "Should eClinical systems be EndPoint aware?"

I tend to stay away from the term EDC when I can. I think this term does not really apply now to some of the leading 'EDC' vendors. I think they are still labelled as EDC as customers expect to purchase an EDC solution. However, today, they are more 'Clinical Trial Support Suites'.  Vendors are adding more and more upstream and downstream functionality.  In doing so, some are clueing up to the fact that the 'bit in the middle' - the data capture and cleaning part - may benefit from early involvement from other parties traditionally left out of the mix.

SDV'ing is an interesting point. EDC Wizard states that

Many sponsors are implementing reduced SDV plans that take a risk-based approach to comparing source data to EDC entries

The activity list for Monitors will increasingly be led by the eClinical system tools.  They track what has, and what has not been SDV'd. With a % being applied, a model needs to be applied by the eClinical tool that applies this % appropriately.  I am not aware of a tool that has successfully implemented this. Another challenge exists regarding the classification of data that is eSource and that which is not.

What has, and what has not been SDV'd should not be shown to the Investigator by the tool. I believe most tools support differing views based on user roles. This functionality should be applied.

EDC Wizard goes on to say;

I am not sure I would recommend that EDC systems be modified to flag data as primary, secondary, SDV, or non-SDV. It's hard enough to move from protocol to EDC database to study start without adding more complications to database builds.

A very valid point - tools are becoming increasingly complex. 'Keep it Simple' is certainly a solid principle to hold where possible. However - with the current model of blanket significance / locking --> data delivery, I think we are missing an opportunity for early decision making.  If the move towards define once, use many times continues to be applied with eClinical systems, then complexity may reduce rather than increase - define the endpoint criteria up-front in one place, and have this information take downstream into EDC and onto data delivery.

Web Services in eClinical

Web Services is one of these technical terms than many folk have heard of, some people understand, and a very few people can actually use.  The definition of a Web Service from a technical perspective - courtesy of Wikipedia -  is "a software system designed to support interoperable machine-to-machine interaction over a network.

From an eClinical perspective, Web Services allow disparate eClinical systems to communicate on a (near) real-time basis.

I believe that Web Services will help resolve many of the integration issues that eClinical systems suffer from today.  You can procedure 2 great systems, but if they don't speak properly together at lot of business value is lost.  Combining CDISC with Web Services may well be a solution to many problems encountered.

Web Services - the Basics

Technologies similar to web services have been around for many many years. For example, when you visit an autoteller, put your Visa card in the slot to withdrawn cash, a Web Service 'type' of communication goes on between the bank you communicate with and the Credit Card company actually releasing the funds.  What they actually say when such communications occur will of course differ depending on application, but, with Web Services, the way they say it is standardized.

Web Services have evolved into many different things, but,  the underlying principles remain the same.  Generally, they communicate using XML (Extensible Markup Language) based text over a Protocol called SOAP.

Many folk will be familiar with XML already - CDISC ODM is build around XML as a means to give meaning to clinical data that is transferred.  SOAP though may be new term.  SOAP, put simply provides a means to transfer - typically over the Internet, XML messages from system to system over firewall friendly channels (or Ports). 

When you open up a browser, and enter something like http://www.google.com/  what you are actually doing is asking to communicate with google on internet port '80'.  The http equates to Port 80.  You might also see https.  The 's' part signifies 'secure' and indicates the use of Port 443 (known as SSL).  Many corporate and site networks place restrictions on the ports that are open to the internet.  Ports 80 and 443 are some of the few ports almost always open, and therefore usable for communication.  SOAP can use both these ports.  Therefore, web services running on SOAP can speak between systems, avoiding firewall conflicts. This means that if you want System A to speak to System B via Web Services, all you need to do is ensure that an Internet link is available, and you're off and running.

CDISC & eClinical before Web Services

So, what about Web Services, CDISC and eClinical.  Why should I care?

Well, traditionally, eClinical systems have been relatively 'dumb' when it has come to communicating.  An IVR system would be used to capture the recruitment, or randomization of a subject.  The IVR would then send a Text file via old fashioned FTP file transfer to an EDC system, and the EDC system would - at some time in the future - process the text file - creating a new subject, or recording the randomization in the EDC system tables. Sounds ok... but.. what if things go wrong?

With this model, the EDC and IVR systems don't really speak to each other.  The IVR system sends something - yes, but if the EDC system doesn't like it - then oops! The IVR will keep sending things regardless.   That is one issue.   The second issue is that because the two systems don't actively communicate, they cannot cross check (or Handshake) with each other.  Imagine if the EDC system held information that the IVR did not.  Lets say for instance that the investigator recorded in the EDC system that the subject had dropped out. If the investigator later used the IVR to possibly then Randomize this same patient the IVR could check against the EDC system that the subject was valid and current. Maybe not a perfect example, but, the capability exists.

Web Services provides the mechanism for system A to speak with system B.  CDISC ODM provides the syntax with which to communicate.  When both systems make reference to a 'FORM', both systems know what is meant.

Web Services - eClinical  - so...

In traditional systems design, you had a decision to make when you developed new modules of software as part of a suite of applications.  Do I store database information in the same place - sharing a common database, or, do I store it in a separate database and communication / synchronize between the two systems.  If you stored everything in the same database - you simplified the table structure, and didn't need to worry about data replication, but, systems were tied together. If you separated the databases, then of course you had duplicate data between the databases, and you had to replicate.  This replication was complicated and problematic.

Ok, now lets imagine that the systems come from different vendors. Of course each vendor wants to sell their own system independently - a separate database is mandatory.  They hold common information.... no problem, we write interfaces. 

Complicated software is designed to examine information that is common between systems, and transfer this by batch transfer.  So, for example, we have a list of Sites in System A - we also have a list of Sites in System B.  We have a list of site personnel in system A, we also have a list of site personnel in system B - no problem I hear you say. Lets imagine that System A doesn't fully audit trail the information that has changed on the Site's tables.  How would System B know what to take....  we need to transfer all the sites, and compare the site information with the previous site information... getting tricky...and this is just a simple list of sites.

Now, lets imagine a more complicated situation, common in an eClinical system.  A Protocol amendment occurs, a new arm has been added to a study whereby subjects meeting particular criteria are branched into two separate dosing schemes.

Transferring or Synchronizing this sort of information between 2 systems would be possible, but very very difficult.  System A may not have a good place to the put the information from System B.  The question is though - do both systems really need the same data?  If System B wants to know something, why doesn't it just ask System A at the time it needs the answer, instead of storing all the same data itself?

This is where Web Services can come in.

Lets imagine an IVR system wanted to check with an EDC system if a subject was current in a study (current meaning not dropped out, early terminated or a screen failure).  A Web Service could be offered by the EDC system to respond with a 'True' or 'False'  to a call 'IS_SUBJECT_CURRENT' ?  Of course hand-shaking would need to occur before it hand for security and so on, but following this, the IVR system would simply need to make the call, provide a unique Subject identifier, and the EDC system web service would respond with either 'True' or 'False.  With Web Services, this can potentially occur in less than a second.

Lets take this one step further.  The EDC system would like to record a subject randomization.  The site personnel enter all the key information into the EDC system.  The EDC system then makes a Web Service call to the IVR system - passing all of the necessary details.  The IVR takes these details, checks them, and if valid, returns the appropriate subject randomization no..  The EDC system presents the Randomization No. for the subject on the eCRF for the site personnel to use.  This all happens realtime, and via web service calls in systems located in completely different locations.

Web Services -  Metadata independence

Web Services are significant for a number of reasons.  Yes, they allow systems to communicate in a near real-time basis over the internet - that's quite cool in itself.  What's more significant though in terms of eClinical systems is that Systems A and B don't really need to understand how the other systems do what they do.

If System A had to read the database of System B, it would need to understand how System B actually used the data in the database.  The same applies to an interface.  If System A received data from System B, it needs to process that data with an understanding of how System B works before it could use it, or potentially update it.

Web Services - beyond CDISC?

CDISC ODM allows you to transfer data, and to some extent metadata from one system to another.   To ensure it works for all, the support is to some extent, the 'lowest common denominator' of metadata.  It is only really able to describe data that is common and understandable to every other system - (barring extensions - see eClinicalOpinion on these).

Imagine if we could create a common set of Web Service calls.  The common calls would take certain parameters, and, return a potential set of responses.  The Messaging might be based on CDISC ODM, but the actions would be new and common. 

• Add_Subject(Study, Site, SubjectId) returns ScreeningNo
• Add_DataValue(Study, Site, Subject, Visit....) returns Success, QueryResponse
• Read_DataValue(Study, Site, Subject, Visit....) returns DataValue,QueryResponse, DataStatus

With this sort of mechanism, the degree of processing of data and metadata between systems is limited.  The 'owning' system does all the work. The data and metadata that the systems need, stay with the original system. 

One remaining challenge exists - the common indexing of information - if a data value is targeted towards a particular site, subject, Visit, Page and Line, then they all must be known and specified.  That said, a bit of business logic (protocol knowledge) can be applied.  For example, if a DBP is captured for a subject, and the target study only has one reference to DBP for a subject in the whole CRF, should I really need to specify the Visit, Page and Instance? Sufficient uniqueness rules could apply.

If CDISC were to create a standard set of InBound and OutBound Web Service calls, you would see a great simplification in how normally disconnected systems inter-operate.  Not only could we send data from System A to System B, we could appreciate what happens when it gets there - 'Can I login', 'Did that Verbatim Code?' 'Can I have lab data for subject x'... etc etc.

Will Web Services technologies change the eClinical landscape?  No.  But, technology advances such as these all help to make the whole eClinical process somewhat less complicated.

Green EDC?

Besides working in Clinical Trial technologies, I also have an interest in tackling issues around global warming.  Electronic Data Capture in clinical trials has the advantage in that it inherently lends itself towards tackling many of the issues that contribute towards global warming.   I am interested in both the benefits that can be achieved during the implementation cycle, as well as the value during the execution phase.

Green EDC does make a lot of sense from many perspectives.  In almost all instances, working with an electronic medium is considerably faster than working with paper. This leads to a reduction in cycle times, and lower costs. You can basically 'do more with less'.

Using technology today

eLearning

Probably the most obvious one.

Large, expensive Investigator Meetings were common until only a few years ago.  Changes in rules and attitudes have ensured they have become more functional rather than an investigator incentive. As a result, unnecessary travel has been reduced.  However, are investigator meetings actually required?

From the EDC perspective, training is often provided during the course of the meeting.  This can take up as much as half the time spent.

eLearning solutions, available from many of the EDC vendors, should alleviate the need for Investigator meeting training.  At most, you might be looking at a short demonstration. If eLearning is implemented well, it has many advantages over traditional instructor led training.  It should be integrated into the product, it should be integrated into the workflow, and, it should adaptable to meet the changing training requirements from study to study.

Integration is important. The early eLearning solutions were often implemented as separate tools.  You would be provided a separate login to access the eLearning - you almost had to learn to operate the eLearning tool!   With fully integrated eLearning inside EDC, the EDC system login directs trainee through appropriate eLearning topics based on the role they have been assigned to, before they can participate in the study. Participation and test results are all logged ensuring an electronic record is maintained for process compliance.  Another advantage of eLearning is the ability to train new staff prior to Monitoring visits.  In the past, a new study nurse for example had to wait until potentially the Monitors next site visit.  With eLearning, they simply await a login, perform the eLearning and they are ready to participate.

Less Monitoring Visits

Besides the removal of the need for monitors to attend sites regularly for staff training, the overall number of Monitoring visits should be reduced with effective use of EDC systems themselves.  Monitors are increasingly taking the role of the Data Manager in carrying out the duties of data review over and above the cleaning functions of the study build itself.  Source Data Verification remains necessary, but the actual Q & A regarding the data itself can be carried out remotely.  Less Monitoring visits means typically less air-travel.

Less Paper

This seems obvious - we are talking about replacing paper with an electronic medium - however, we also have paper flows in other areas of the process.   The development of the EDC product itself together with the implementation phase of the system for a study often involves the preparation of many binders of paper materials designed to support a vendor (or regulatory) audit.  Despite the electronic nature of the solutions that EDC companies provide, very few companies effectively push a paper development and implementation process.  The use of electronic document management systems are beginning to change this, but, it does require the support of Quality Assurance and Regulatory groups who tend to be more comfortable with a large pile of paper binders and wet ink signatures than fully electronic systems.

Widely used standards for document signatures are currently a barrier.  The SAFE BioPharma Association have had some success in offering up a electronic document signing solution that could be used across the industry, but it still has some challenges related to Hardware and Technology dependency. We may see progress following SAFE's partnership with CDISC.

Paper itself is not that 'non-green', but the delivery of paper can be.  Organizations involved in clinical trials today are often global.  Fedex'ing a CRF, a specification or a submission in paper format is simply not necessary with technology available today.

Messaging and Video Conferencing

Is it not odd that a technology such as video conference has such limited use in business today, and yet teenagers all round the global use it regularly to chat with their friends over the internet? 

Some EDC systems make use of tools to provide interactive support, but they are often poor.

If I am using an Internet application - such as banking or the like, and I have a problem, I would like to chat - by keyboard or over the phone - immediately.  Messenger services either inside, or outside of the EDC application are available today.  I have yet to see a good implementation of interactive support within the tool.  [I am sure EDC vendors that already have such services built in will correct me here!]

By offering interactive support and communication tools within an EDC product, site personnel can achieve equivalent, or potentially better support than can be achieved through infrequent monitoring visits.

 

Tomorrows Technology?

So, what can we still do to improve our green credentials when carrying out clinical trials?

Standards

Applying standards, can improve overall efficiencies.

Since 2004, SDTM, the Submission Data Tabulation Model from CDISC is part of a move to a standard electronic medium for data submissions.  The electronic submission of course is not new, but the standardization of the format is new making it somewhat easier for regulatory bodies to process data received regardless of the source.  Standard outputs require standard inputs, so with the recent introduction of CDASH - Clinical Data Acquisition Standards Harmonization- a standardization of the input structures in clinical trials - the overall SDTM production process should become less onerous. 

Downstream from EDC, we have the eCTD - electronic Common Technical Document an interface for the pharmaceutical industry to agency transfer of regulatory information.  From 1/1/2008, this is a required format (barring a waiver) by the FDA and has/will result in a great reduction in the amount of paper delivered to regulatory authorities.

Trial Execution Efficiency

Both Adaptive Clinical trials as well as non adaptive studies where a Bayesian continual reassessment method (CRM) is taken, can help ensure that unnecessary trial execution work is avoided.  In the past, trials tended to be more serial in nature - complete study A before moving onto Study B.  With the ability to adjust the design, and, more commonly, the ability to examine data subsets early in the trial, either an early termination or a change of focus can be made saving time, money and of course our impact on the environment.

Source Data Verification

Going back to my eBanking analogy, if I want to record a payment transaction into my eBanking solution, I do not write it down on paper first, and then transcribe what I write down into the eBanking transaction form. There is no value in that.

In clinical trials, if an investigator is involved in a clinical trial where the subject responds to questions during data entry, it would make sense to in certain circumstances to enter these directly into the EDC system, and not on paper first  - as source date - this would avoid potential transcription errors. 

But no....The interpretation of guidelines regarding Source Data typically means that web based systems cannot be used to retain the 'Source Data'.  I personally have an issue with this interpretation, but I will not elaborate here.  It is indicated that the 'Source Data' must remain at the site. Web based systems do not hold data onsite, but instead hold the data on a central server.  [Dave Iberson-Hirst from CDISC provided a good description of the challenges of Source data in his article in Applied Clinical Trials focusing on electronic Patient Diaries - for the sake of brevity, I have summarized the points of argument.]

Workarounds have involved the use of an offline, or hybrid system where the data is stored on a local device at the site.  More commonly though, data is recorded on paper first, and then transcribed into the electronic CRF.  Admittedly, a lot of source data will come from Medical records, and other paper records, however, it seems rather regressive that due to the wording of a regulation, more data is captured on paper first for web based systems that the old fashion Remote Data Entry tools.  Hopefully improved guidance in the near future will avoid this.

Conclusion

I am a great believer that being 'Green' means being efficient in business. Reducing the inefficiencies in how we go about our work not only offers savings in time and money, it can also have a positive impact on our environment. Here's to an electronic clinical world!

Top 10 mistakes made when implementing EDC

(last update from admin @ eclinicalopinion)

Ok, I am calling for a challenge here.  I am making an attempt at identifying 10 top mistakes that I believe are made when companies attempt to implement EDC.  No science to this. Just a bit of fun.

I will make edits if anyone posts comments that I believe out do my own;

 

1. Pick the nastiest, most complex study to implement as a first study

Sponsors may be trying to check the EDC system and vendor as a confirmation of claims of functionality, services and support.  It may also be an internal organizations 'sell' when bringing in a new system. In reality, the risk factors are at their highest, and the chances of failure greater than at any subsequent time in an Enterprise EDC system rollout.  Instead of learning and improving with optimized processes and a well designed workflow model, a 'get it out the door quickly' approach is forced and pain is suffered from all parties!

2. Expecting the return on EDC to be immediate - admin @ eclinicalopinion

Many clients are very experienced with paper and have wrung the very last drop of efficiency out of their process. They start with EDC believing that they are entering a new golden era only to be disappointed with the gains (or losses!) on their first study.
As with any new process or technology, it takes time to refine. The potential gains are real but it will take a few trials before a company hits its stride with EDC.

3. Over emphasis on faster closeout- admin @ eclinicalopinion

Companies new to EDC getting excited about the faster closeout of EDC trials but ignoring the issue of longer start-up times with EDC. With paper you could print the CRF's and send them out before you have finalized (or even built) the database that will finally store the data.

4. Use all the functionality that was demonstrated

A common problem. When a sales person demo's the product, it looks cool. Almost every feature looks good, and could add value.... Well, in reality, not always.  Many EDC systems developed today offer features as a 'tick in the box', but when the feature is used and combined with other features, sometimes the value falls short.  For example, most systems offer some form of data flagging... Reviewed, SDV'd, Frozen, Locked etc etc. Do not use all flags on all fields.  That will be slower than paper.

5. Resource the same way

If you have the same resourcing for Data Management and Monitoring AND you are also resourcing separately for building and testing EDC studies - then you have done something wrong.

With a good EDC product, the rules that would typically be applied manually are applied automatically. The delta should be picked up by a smaller number of 'eyes'.  Many CRO's have played the 'better safe than sorry' card to charge for the same Monitoring and Data Management as paper as well as EDC license and deployment costs.  This demonstrates an inexperienced CRO.

6. Model the eCRF according to the paper CRF Layout

Trying to make an electronic CRF identical to an original paper CRF will result in tears.  The users will be frustrated with the workflow.  The 'e' nature of the medium will not be utilized and the study will be less effective.

Instead, consider appropriate workflow and dynamic eCRF's.  I will stress 'appropriate'. Overdoing the bells and whistles can cause frustration, but, no bells and whistles and many of the advantages of EDC are lost.

7. eCRF Design by committee

The surest way to blown budgets and timelines is to attempt to develop an eCRF based on a committee of individuals.  The sponsor should delegate a chosen few (ideally 1) to work with the EDC CRF Designer. The study should be built to a greater %, then following this period, a wider review should be carried out.

8. Wait until the end of the study to look at the Data

It is surprising how often this is still the case. EDC means cleaner data faster, but often sponsors, and their Statistical departments are geared towards working with final data-sets. Good EDC systems can deliver clean data on a continuous basis.  Whether the data is able to achieve a statistically significant sample size is another question, but, information is often available for companies that are willing to leverage it.

9. Fail to use the built in communication tools provided

Many EDC systems offer the means for different parties involved in the execution to communicate.  These might be in the form of Post it Notes, Query Messages or internal email. Often these facilities are either not used, or not used effectively.  This means that the true status of study is a combination of information in the EDC tool, tasks in Outlook, actions in emails, scribbled notes on a Monitors pad etc etc.

10. Do lots of programming for a study

This covers many areas. It could be programming to handle complicated validation rules, or it could be programming to adapt data-sets to meet requirements. If you're EDC system requires lots of programming in order to define an EDC study, then I would suspect you have the wrong EDC system. Good EDC systems today are configured based on metadata stored in tables. Old systems relied on heavy customization of the core code for each deployment, or, relied on some form of programming in order to complete the study build. If you write code, then you need to test it. The testing is similar to software validation.  This takes time and money. 

Most EDC tools can be extended through 'programming'. If you need to do this, try to do the work outside of the critical path of a study.  Develop an interface, test and dry run it, and then, utilize it in a live study. In this way, you will have time to do it right with proper documentation, support and processes.

and relegated below the top 10...

11. Start by developing Library Standards from Day 1

This may sound like an odd one, but, let me explain.  Implementing EDC effectively with an EDC system, even with a highly experienced vendor, takes time.  All parties are learning, and, modern EDC systems take a while to adapt. Workflow, system settings and integrations all need to come up to speed and be optimized before standards can really be applied and add value. Start too early, and the library standards are just throw aways once the teams come up to speed. It is best to leverage the knowledge and skills of the CRO or Vendor first.

12. Develop your Data Extracts after First Patient In

Sometimes tempting due to tight timelines, but, if you have an EDC tool that requires either programming or mapping of data to reach the target format, then the less consideration you give to the outputs when you design the study, the harder it can be to meet the these requirements after FPI. This leads to higher costs, and, the potential for post deployment changes if you discover something is missing.

Conclusion

Many thanks to admin @ eclinicalopinion for the additional 2 mistakes made, now coming in at numbers 2 & 3!  More comments welcome...

CTMS in EDC?

One of the functional areas that I have been surprised at the lack of good support for is CTMS features built out of EDC products.

CTMS systems often perform a variety of tasks - Portfolio Management, Site Management, Trial Planning, Monitor Reporting, Study Progress Tracking, the list goes on for a while...

One of the difficulties with using separate EDC and CTMS systems was often the need to either synchronize or interchange the metadata relevant to both systems.  Both systems need to be aware of the visit structure, and, potential workflow associated with more complicated visit structures.  For example, it might be the case that a study has multiple arms, and, one or more trigger points that determine the branching.   In order to predict the CRF's to be completed from a trial planning perspective the CTMS either needs to recreate the structure - including an appreciation of the trigger points, or, it needs to import the structure from the CTMS.  This is all a bit messy.

So, why do EDC vendors not do a better job of leveraging the data and metadata in an EDC database in order to drive at least a % of the needs of a CTMS?

I am open to better ideas here, but to get this started :-

EDC systems try to generalize the definition of studies. Often things like Visit Dates, Visit Numbers, Branching points and subject statuses etc. are all purely data based - often simply fields on a CRF.  They have no special meaning that differentiates them from other CRF fields.  Vendors could tackle this by offering a form of user definable flags.  On the metadata, a spare attribute would be provided that in turn points to an internal metadata codelist. The codelist could be populated by trigger values such as 'Visit Date' or 'Visit Number' etc.  When interfacing, the CTMS system just need to be aware of the special nature of flags, and use them to pick up the one or more fields that are associated with the flags. So, even though 10 different fields are used to hold Visit Dates, provided the 'Visit Date' flag is attached, the CTMS knows the find them. Being data based, no special programming required from study to study.

A second issue is the lack of CTMS information defined on an eCRF. EDC systems are generally only geared to capture data through the eCRF medium. When a sponsor approaches either a CRO or Vendor, often, the contents of a CRF page is gospel. The thought of bolting on the capturing of additional fields is considered inappropriate - eek!  it could be mistaken for clinical data!  - for example - and I have seen it done - a standard could be developed that ensures that for every subject visit, an end of visit form is filled out.  The end of visit form would not capture clinical data. It would be used to capture (or derive) study progress information. Visit Date, End of Visit Subject Status and other such information could be captured a validated in one place. With this kind of information, it is somewhat less difficult to either report on status and progress using native EDC reporting tools, or, feed the standard information across to a CTMS.

The third reason I believe for EDC systems not effectively supporting CTMS needs is the whole lack of planning features - yes, when building a deploying a study it is possible to enter no. of expected subjects at a site level - all EDC systems include this, and, in my experience all EDC system rarely use it - but that doesn't give you the timeline planning - based on a specific recruitment interval, when will I reach my target subject recruitment.... when will the recruited subjects complete LPLV... etc.

So - could EDC systems better leverage the information they have to offer basic CTMS functionality - absolutely.  Should they do more - Yes.

The recent Clinpage article vendors offering multiple integrated solutions suggest that the existence of a fully integrated solution will prove to be a key decision influencer over and above the actual feature functionality of individual systems. There is something to be said for that, but (and this is a big but), the systems must be sufficiently well integrated, robust and flexible to actually work in real life.  I would venture that many of the purportedly fully integrated product suites are in fact separate products loosely coupled with single-sign-on and a similar UI.   I have known (and I will not mention any names) of products that were sold under the same branding, used the same UI, could be accessed through a portal using Single-Sign-on, but that did not share a single application table once utilized - data, and metadata went into entirely separate tables - seamless, yes - a chasm!

With a strong CTMS feature inside an EDC product - does a future exist for standalone CTMS tools - I personally think not.  Although more highly functional, their data entry requirements versus the EDC tools that leverage existing metadata and admin data offers a less convincing value proposition.   Then again, how many good EDC vendors know how to create a good CTMS? 

EDC Provider Shakedown

It was raised in a recent posting on the eClinical Opinion that we may be seeing the demise of some of the mid tier EDC solution providers.

The market is adjusting. In the past, many solution providers were able to get by through providing point solutions with products capable of scaling from the 1-10 study ranges. However, today the market has matured. Many sponsor companies are looking at systems that are capable of effectively supporting 100's of concurrent studies. The technical requirements differ.

Unless a software product is architected to work with large volumes of study building and execution perspectives, they will not work as scale up occurs.

Sledgehammer approaches have been used in the past - throwing hardware at the problem, switching to a chunkier database or web-enabling a legacy technologies. Often such solutions are just papering over the cracks. The problems lie deep in the design of the product.

Sponsor companies evaluating EDC technologies should drill into the systems to determine if architecturally they are capable of supporting the proposed volumes.