Do We Need a Study Data Reviewer's Guide?

As part of a robust study data standardization program, the U.S. FDA publishes the Study Data Technical Conformance Guide. The purpose of this document is to provide "technical specifications for sponsors for the submission of animal and human study data and related information in a standardized electronic format" for investigational and marketing applications. Section 2.2 of the guide recommends the submission of a Study Data Reviewer's Guide to "describe any special considerations or directions or conformance issues that may facilitate and FDA reviewer's use of the submitted data and may help the reviewer understand the relationships between the study report and the data." Although FDA doesn't recommend the use of any specific SDRG template, it references a standard template developed by the Pharmaceutical Users Software exchange (PhUSE). 

Let's take a close look at this template. The Purpose of the document is to provide "context for tabulation datasets and terminology that benefit from additional explanation beyond the Data Definitions document (define.xml).  In addition, this document provides a summary of SDTM conformance findings." 

Here is some of the information suggested for inclusion in the SDRG

  1. Is the study ongoing? If so, describe the data cut or database status?
  2. Were SDTM used as sources for the analysis datasets?
  3. Do the submission datasets include screen failures?
  4. Were any domains planned but not submitted because no data were collected?
  5. A tabular listing of eligibility criteria that are not included in IE domain
Before we tackle the question posed at the top of this post, let's ponder a broader question: why do we need standardized data? This one is easy. Standardized data enable process efficiencies and automation. In the case of clinical trials data, reviewers are instantly familiar with the structure of the data, because it is the same across all SDTM-based study datasets. This immediate familiarity with the data structure certainly leads to review process efficiencies. But it only starts there. A common structure and common vocabularies lead to the development of standard analyses that can be automated and reused across studies.

If standardized data leads to increased familiarity with data structures then this should lead to a decrease in additional materials needed to explain the data. But we now have yet another document to explain the data that we didn't have before. The fact that a document like the SDRG is needed at all implies that there are additional data, or additional meaning behind the data, that are not captured in the datasets. 

If we had a truly semantically interoperable data exchange, there would be no need for an SDRG. The meaning behind the data would be with the data, not locked up somewhere else in a human-readable text document. In other words, the need for a Study Data Reviewers Guide represents a failure of the data standards and/or the implementation of the data standards in achieving an adequate degree of semantically interoperable data exchange.  

Sounds harsh? I believe this last statement is true. Let's look at some examples. The SDRG should describe if the study is ongoing. The data contain a study start date and study end date. If a study is ongoing, the study end date should be null. Because a null value for this variable could be due to other reasons, a separate variable (similar to the HL7 null flavor) can describe why the end date is null. Controlled vocabulary can describe the various possible reasons. This approach provides both a standard machine readable approach and human interpretable way of knowing if the study is ongoing. One could even add a 'ongoing study' flag in the trial summary (TS) domain if desired.

Here's another one: Were SDTM used as the source for analysis datasets? If one described each data point as a resource, each with a unique resource identifier (URI), then a system can easily determine where that resource came from. One could see that a data point in an analysis dataset is the same data point (i.e. resource) as what is in the SDTM. These URIs make traceability/data provenance analyses so much easier.

How about this one: Do the submission datasets include screen failures? Each subject should be linked to an administrative study activity called 'EligibilityTest" (or something similar) and the possible outcomes of which are TRUE or FALSE. A subject with EligibilityTest=TRUE means they passed screening and are eligible to continue in the study. EligibilityTest=FALSE means they failed screening. A quick scan of the data would determine if there are any subjects with EligibilityTest=FALSE indicates screen failures are present in the datasets. (Note that the rules for determining TRUE or FALSE are the eligibility criteria themselves, which have a bearing on the next example)

Another example is: the SDRG should contain a tabular listing of eligibility criteria not found in IE (inclusion/exclusion criteria dataset). All study activities should have well-described start rules. The study activity start rules for determining whether a study activity = Randomization can begin are themselves the eligibility criteria. A description of the Randomization start rule is incomplete without a listing of these rules. Their presence in the data would make it unnecessary to repeat them in an SDRG.

So what is the answer to our initial question? If data standards and their implementation were adequate, we would not need an SDRG. That fact that we need SDRGs today should be a sign our study datasets still lack important meaning that analysts need to interpret/analyze the data. It implies that more standards development and better implementation of standards are needed to increase semantically interoperable data exchange. The SDRG should eventually not be needed and should disappear. I think I'm not alone in wishing for the SDRG's eventual demise.

Please share your thoughts and ideas. 



Rules in Study Protocols

When you read a study protocol, your are bombarded by rules. Some are explicitly stated. Many are implicit and must be teased out. Rules are extremely important in ensuring that protocols are conducted correctly. Rules are critical for a good study outcome. Unfortunately, we don't have a good way to standardize protocol rules. This makes it challenging to automate study conduct activities and quickly analyze if a study "followed the rules."

Let's dissect the components of a rule. A rule basically looks like this:

IF {condition A} THEN {Do B} ELSE {Do C}

the ELSE clause is optional and it is assumed to default to "do nothing" if condition A is not met. 
Rules can be complex :

IF {condition A} THEN {
(IF {condition E} THEN {Do F} ELSE {Do G} }

Evaluating a Rule is an Activity whose outcome is binary:  either the condition(s) is/are met ("true") or not met ("false"). One could argue for a 3rd category, not applicable, for cases where the reason to have a rule in the first place doesn't apply (e.g. when to conduct a pregnancy test in a male) 

In clinical studies, rules often depend on other activities. I call these prerequisite activities (PA). For example:
IF {migraine occurs} THEN {take study drug}
or a more precise way of expressing it:
IF {headache assessment = MIGRAINE} THEN {take study drug} 

In this case the prerequisite activity is a headache assessment and the condition is met when the headache assessment outcome indicates that a migraine is present. 

Regarding how prerequisite activities are evaluated, sometimes it is sufficient that the PA simply has begun (PA status = started) or completed (PA status = complete) or, more commonly, completed with a specific expected outcome (PA expected outcome = migraine). 

When looking at rules more closely, they can be expressed as start rules for other activities. Let's call these target activities (TA). 

Target Activity: Study Drug Administration_01
Start Rule: MigrainePresent_01 -- Prerequisite Activity:  HeadacheAssessment_01
                                                       PA Expected ActivityOutcome:  MIGRAINE

StudyDrugAdministration_01 is a planned activity that just sits there, waiting to be performed. As soon as the headache assessment is performed and whose outcome is a documented MIGRAINE, the rule outcome is set to TRUE and the target activity can begin. 

One can add qualifiers in the rule to describe exactly when the target activity is performed. for example a delay = 30 minutes means wait exactly thirty minutes after the condition is met before starting the activity. maxdelay = 60 minutes means wait no more than 60 minutes before starting the activity. mindelay = 30 minutes means wait a minimum of 30 minutes before starting the activity. 

I have tried this paradigm in multiple scenarios and so far it seems to work (randomization, eligibility determination, delayed start, assessments). 

In a future post, I'd like to explore how these rules can be expressed computationally using the RDF. 


Is Death an Adverse Event?

Throughout the course of a drug's marketing life cycle, it is critical that sponsors and regulatory agencies understand if a drug administration is associated with the death of the patient, but is death an Adverse Event? I argue that death is not an adverse event but instead may be the outcome of an AE. I think that it's important to draw this distinction to improve AE reports and automate death/causality analyses.

Here is my argument. First, let's review some definitions.

The U.S. Code of Federal Regulations (21 CFR 312.32) defines an adverse event as
  • any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. 
The bolded text is mine, as I want to consider how to interpret these terms.

Untoward is an adjective meaning unexpected, inappropriate, inconvenient. (Oxford Dictionary). Synonyms include inconvenient, unlucky unexpected, surprising, unusual.

A medical occurrence is more difficult to define. I take it to mean a medical condition: i.e. disease, disorder, injury, or transient physiological state that impairs or may impair health.

Taking all of this into consideration, my working definition of an Adverse Event is any unexpected medical condition (disease, disorder, injury, transient physiological state) that impairs or may impair health and emerges or worsens after a medical intervention (e.g. drug use).

Notice that I broaden the definition to medical interventions such as medical device use, or medical procedure, because AEs in those scenarios are equally relevant from a public health perspective.

With these definitions in mind,  I think one of the pitfalls in causality assessments is wrong use of the term adverse event. I believe Adverse Events are medical conditions. Medical conditions fluctuate over time. An AE can remain stable, improve, or resolve over time. It can also worsen to the point where the patient dies. All of these are potential outcomes of an AE.

Here is a hypothetical case of crazy conclusions that can emerge if our definitions are not precise. Imagine that one is developing software to automate AE causality assessments. 

Consider an 13 y/o male on chronic treatment with Drug X for seizures. Over the course of the year, he grew 4 inches and gained 25 lbs, yet his dose of anti-convulsant medications did not change to keep pace with his increased body mass. Towards the end of the year, he was having breakthrough seizures with a documented low therapeutic level of Drug X in his blood. A computer program may select the following concepts for further causality assessment:
Suspect Drug:  Drug X

Adverse Events:  Seizures, Weight Gain

A computer program would look at this and ask did Drug X cause weight gain and seizures in this case? On a superficial level, it is a fair question since the subject was on Drug X when those events happened.

But wait a minute. A human assessor immediately recognizes the frivolity of such a question in this case. Clearly the growth and weight gain are consistent with puberty-associated growth spurt. The problem is the dose of Drug X wasn't increased in response to the increased body mass. 

The fact that the causality question even arises is a misinterpretation of an Adverse Event. Applying our working definition of an AE, Seizure is not an Adverse Event in this case. It's in fact the Indication, a medical condition that is the target of a medical intervention (i.e. anticonvulsant therapy).  But, you say, it's also a medical condition that worsened with treatment. The key here is that it didn't unexpectedly worsen. A sub-therapeutic dose of an anticonvulsant can be expected to result in breakthrough seizures. 

How about weight gain? Again, this is not an AE. It's an observation, well technically it's an analysis of two (or more) observations, body weight, over time. Is it indicative of an AE? Not necessarily. In this case, it is the consequence of normal growth. Obesity, on the other hand, would be an AE depending on how it's defined. There is no evidence in this report of obesity.

So what is the causality assessment for this case?  The assessment cannot be done. There is no adverse event.

Here's another case:  A person takes Ambien, gets drowsy and drives a car and is involved in a motor vehicle accident.
Suspect Drug:  Ambien
Adverse Event: Motor Vehicle Accident (MVA)

Based on our definition, an MVA is not an Adverse Event since it is not a medical condtion. The AE here is  drowsiness. The MVA is a consequence/outcome of the AE.

So let's get back to death? It's commonly listed as an AE in safety reports. Is it a Medical Condition? No. Death marks the end of a complex physiologic process we call Life and it happens to all living organisms. Death (like an MVA, or a bad fall) is or may be a consequence/outcome of a Medical Condition. In the case of Death we call it the Cause of Death. The cause of death may or may not be an AE.

This reminds me of the clinical data lifecycle:  Observations lead to Assessments/Adjudications to diagnose/assess Medical Conditions (including AEs) which leads to Interventions to (treat, mitigate, cure, prevent) those conditions, which leads to more Observations.  In turn Medical Conditions have consequences/outcomes sometimes beyond our control, like Death (or Falls, or Motor Vehicle Accidents).

These information buckets are well established and distinct in clinical medicine. We save a lot of confusion and misinterpretation of clinical data when we classify them appropriately. We need to do a better job of distinguishing AEs from observations, and not confusing the consequence(s) of an AE from the AE itself. Recognizing this distinction is important to automate adverse event assessment, including those resulting in death.