CDASH, SDTM and the FDA

Hurrah!  The FDA have made an announcement on their preference towards SDTM!!  Well.   Sort of.   They met up with representatives from CDISC. The CDISC organization wrote down some notes on the discussion, and posted them to their Blog.

Ok – maybe I am being overly flippant. However, why does this message need to come out by proxy from CDISC?  Why can the FDA CDER / CBER not step off the fence and make a firm statement on what they want, and when they want it?

One point made was that applying CDASH is the key to attaining SDTM datasets.  Well.  Sort of.  It is a good start point. But, it is only a start point.

The CDASH forms are very closely modeled on the structure of SDTM domains.   Do I always want to capture one domain, on one eCRF form – not always.  Do I want to sometimes capture information that is logically grouped together according to source documents that belongs to multiple domains on the same eCRF – often I do.  We should not compromise the user friendliness and therefore compliance at the sites because of a need to capture data according to the structure of the data extracts.

CDASH was developed around the principle that the EDC or CDM system modeled eCRF’s to equal SDTM domains.   If your EDC or CDM system does not do that, then compliance with CDASH is not entirely valuable.

However – or rather HOWEVER – if you fail to apply equivalent naming conventions to CDASH/SDTM and fail to use matching Controlled Terminology, and, you expect to achieve SDTM – you will be severely disappointed. Achieving SDTM will not be hard – it will be virtually impossible.

With regards to the statement that applying CDASH can create 70-90% savings.  That is not the whole story.  Apply CDASH + standardizing all of the other elements such as rules, visits etc – and automating testing and documentation – yes, then you can achieve a 70-90% savings.

CDISC Rules!

Ok, so a play on words. CDISC may rule in the field of Clinical Data standards, but, it does not rule in the standardisation of rules associated with data.

Let me expand here for those not familiar with the issue.

CDISC ODM provides a syntax for the definition of metadata (and data) used in the interchange of information between (and sometimes within) systems. CDISC ODM does not scope the definition of edit check rules that are applied to the data when it is captured. I feel that is a significant omission as the rules element of the data a) take a considerable time to develop and b). provide a context to the data.

Question - So, why do we not already have rules built into the standards?

Answer - rules are often technology or vendor specific. There are almost as many methods of implementing rules, as there are EDC products.

Question - Why not define a standard mechanism for creating rules that vendors could either comply with, or, support as part of interfacing?

Answer - Well, it all depends on what you want the rules to do. In their simplest form, rules are boolean expressions that result in the production of a Query or Discrepancy. However, many systems go well beyond simply raising queries. The boolean element of the rule may be consistent, but the activity performed in the situation that the boolean returns true, is often very vendor specific.

Lowest Common Denominator

So - lets assume that we are looking at implementing a lowest common denominator of rules and actions that the majority of systems support, and require

What can we do to standardize a syntax. Three options I think;

1) Choose a syntax from one of the leading vendors,

2). Develop a new syntax building on existing ODM conventions

3). Bring in another standard syntax, potentially already in the Health or LifeScience field

Lets look at them in order.   

No. 1 - Choosing a Leading Vendor Syntax is probably great for the chosen leading vendor, but, bad for most other vendors. A benefit though would be that it would already be proven as a means to represent rules and actions in a clinical study. Some syntaxes are based around standard tools such as Visual Basic for Applications, JavaScript or even SQL. This approach may create almost insurmountable boundaries for other vendor systems that do not, or cannot implement the technology - for example, it is not easy to interpret VBA on a non Microsoft platform. So - option 1 has some potential, but, depending on the chosen vendor, may result in closing the door to the standard for others.

No. 2 - Creating a new Syntax would result in something most vendors would be happy with, but, would require considerable effort from the contributors in order to develop a complete specification for the standard, as well as a reference implementation. The advantage of such approach would of course be that it would be seen as a common standard open to all, and not specifically biased to any one vendor company. In practice, the technology approach chosen would favor some more than others.

No. 3 - Leverage an existing Syntax may well bring the benefits of No. 2 without all the costs of designing something from scratch.

Ok, so lets say we go ahead with option 3 - what are the candidate standards for rules in the Health and/or LifeSciences are?

As far as I can tell, not many. In fact, I was only able to find one candidate that had any level of success - a syntax called ARDEN.

ARDEN has existed since 1989 as a syntax for describing Medical Logic. Similar to typical Rules in EDC, they are defined in Modules - Medical Logic Modules - and called based on the triggering of an event.

[For an accurate definition of ARDEN and its roots, check Google Books - search for ARDEN Syntax and examine Clinical knowledge management: opportunities and challenges By Rajeev K. Bali, Pages 209 --> 211]

As a syntax, it is mostly general purpose. Here is a snip from an Arden Syntax module,

logic:

if

last_creat is null and last_BUN is null

then

alert_text := "No recent serum creatinine available. Consider patient's kidney function before ordering contrast studies.";

conclude true;

elseif

last_creat > 1.5 or last_BUN > 30

then

alert_text := "Consider impaired kidney function when ordering contrast studies for this patient.";

conclude true;

else

conclude false;

endif;

;;

In the example, you can see that the syntax uses standard if/then/elseif/endif constructs. Assignments use the := combination etc.

HL7 have a section dedicated to ARDEN here. The activity appears to be limited with no Postings or Documentation since 2004. On walking through some of the presentations, some of the consumer companies such as Eclipsys were proposing extensions to the syntax - for example to add object definition support. It would appear that the take-up of the standard has been limited to those organizations that had a problem to solve in the EHR area, and wanted to re-use a syntax, instead of inventing their own.

The fact that HL7 has lended support for ARDEN may be sufficient in itself. However, we would need to dig considerably deeper to understand how ARDEN syntax would fit with a syntax such as ODM. The first challenge is the conversion to an XML form. There are plenty of articles on ARDEN XML for further reading.

RuleML is another standard that may address the need to create Rules, as well as meeting the perceived need of being XML based.

More about ARDEN and RuleML in a later posting I think. This one is quite long enough for today.

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.

CDISC SDTM versus ODM?

I have read with great interest an article posted in ClinPage - The Future of ODM, SDTM and CDISC.   These discussions relate primarily to the proposed requirement from the FDA for data submissions to be made in XML format rather than SAS Transport file format.   I don't think we will see many arguments around this point - XML is now the accepted extensible method of describing the combined data and metadata.  What is more contentious is that it is requested that data be provided in the HL7 v3 Message format.  FDA Docket No. FDA-2008-N-0428 from August 2008 elaborates on where the FDA are in the process.

In addition to the move to an HL7 Message format rather than SAS XPT, commentary exists on a suggestion that a move to ODM rather than SDTM would be considered.   This point is also put forward by Jozef Aerts of xml4pharma.

I would like to comment on a comparison of SDTM versus ODM.

Operational Data Model

ODM was the first CDISC standard to successfully go through the authoring process.  It was aimed as a means to represent data in to context of data capture. Data was indexed to Visits and Forms. The syntax was designed to describe data not from an effective storage format, but from a source to destination format.  You could get data from System A by Visit and Form to System B by Visit and Form.   This is great where the presentation of the data has importance and meaning.

Submission Data Tabulation Model

SDTM, unlike ODM, focuses on groupings of data - not by CRF Form - but by the use of data.  All Demographics information appears on the same record for example.  The SDTM structure has now also become the basis for data delivery and storage within many organizations.  A number of large PharmaBio companies based internal cross company standards on SDTM.

Modelling from Data Captured

The format of data will differ depending on the medium used to capture the data.  Some form factors might have 30 questions on a form, others such as Patient Diaries, might only have 1 or 2 question per form. In addition, when designing a CRF for ease of use, it may not make sense to apply the content of each SDTM domain as the basis for deciding what does and does not go onto a single form. Whether the data appeared on one form, or across many forms is not important when it comes to the value of the data.  Many EDC vendors have gone down the route of designing the database for data capture according to EAV rules - Entity-Attribute-Value form - where each value captured on any form is dropped into a single table. Once captured, data is then re-modelling into a relation structure that may or may not model the layout of the page. (xForms is a generic technology touted as being a potential means of addressing this challenge - I will leave further discussion on this to a later article).

Based on the above, it would seem logical that SDTM is of greater value when used as the method of delivery of data for submission or analysis than ODM.

However, that is not the only reason why SDTM makes sense over ODM when developing and executing eClinical studies.  The primary reason related to metadata re-use.

ODM is not a suitable format for modelling studies because it does not lend itself to ensuring that similar studies are able to effectively re-use metadata.  Sure - I can take a study, copy the metadata, and I have another study... easy... but what about changes.   What if I remove a few fields, add a few fields, change the visit structure. That will of course change the data outputs format if ODM was the format- an issue - see above, but, more importantly it will greatly impact any rules that might exist on the forms.  Rules that use some form of wildcarding mechanism may, or may not work.   Anyway, this is not a posting on metadata architecture, so I will leave it at that.

Bringing together SDTM and HL7 v3

So back to SDTM and HL7.  Is this the right way to go?   I can understand the logic behind this.  Being able to bring EHR and Clinical Trial data together within a common standard could be very useful.  However, at what cost?  

I am not aware of any eClinical application that automatically creates SDTM compliant data sets - regardless of transport layer.  The mapping of proprietary metadata to SDTM is quiet involved with varying degrees of software development required from the various system vendors.  Typically, either SAS macro transformations are used, or, some form of ETL (Extract, Transform and Load) Tool.  This is all complicated enough. Creating a tool that creates SDTM datasets in HL7 v3 is considerably more complicated. Even for large companies it will be a major development under taking.  The complexity is such that smaller companies will simply fail to manage to effectively deliver the data in a cost effective way.

Tools providers may step in - they may offer a means to convert a basic SDTM ASCII file with additional information into a SDTM HL7 v3 file. XML4Pharma as based on recent critique of the approach do not appear to be wishing to jump into supporting this, but, if this becomes a mandate, some companies will.

Playing on the other side of the argument - one of the principles of XML is that the data is also human readable.  In reality, once you add all of the 'overhead', especially with a complicate syntax such as HL7 v3, you end up with something that is only readable by technical gurus.  But then, maybe it shouldn't be people that interpret these files, maybe the complexity has got to the point where it only makes sense that a computer application interprets the files and then presents the appropriate information to the user.  Modern eClinical systems offer views on data. Maybe the presentation of the Submission data is managed in the same way - through an application that presents a view based on purpose.