Moving beyond rote case reporting: demonstrating a believable commitment to patient safety

The complexity of case reporting compliance
Assuming you have an hour or two to spare, and a mind for detail, ask someone in the business of pharmacovigilance and safety about case reporting. If they are so inclined, you may get a story involving nuances about tight deadlines, adherence to detail, differing interpretations of complex regulations, and the differences between event, outcome, seriousness and severity. Safety specialists may be the only people in the world who can tell you with a straight face that they know of someone who suffered a “mild” death. They will allow that death is always serious, but not necessarily severe.

Such arcane distinctions, and the reality of dealing with a vast array of differing safety regulations around the world, have made safety case reporting a very complex task. Compliance with “the rules” is very important, and in many companies consumes all their efforts.

However, what are the real expectations? If safety is an academic assignment, what is the rubric used to grade one’s compliance?

Acting on newfound knowledge
At a recent FDA public meeting, which included many of the international safety regulators, a representative from the EMEA confided to me over coffee that compliance with case reporting should be considered the bare minimum – your “passing grade.” To earn top marks, it is much more important to understand what was done with the knowledge gained from the process. The idea proposed by this regulator was that we just have the pharma companies send the regulatory agencies every single case as soon as they get it, so reporting timelines and regulatory nuances are minimized. That way, companies could focus on acting on their newfound knowledge.

Similarly, in the wake of recent drug withdrawals, the public and legislators have taken a second look at an industry that possesses a high level of trust, and decided they didn’t like what they saw. For the most part, people understand and tolerate that problems with medicines are sometimes discovered only over a period of time. By and large, they accept the risks involved in order to attain the benefits of many medicines. But what society finds hard, is not being able to understand what responsible actions were carried out when a manufacturer first hears inklings that all may not be well.

Indeed, the recent Food and Drug Administration Amendments Act (FDAAA) of 2007 places special burdens on regulators and industry alike to be more transparent about clinical trials – whether positive or otherwise – and to be more proactive in their pharmacovigilance and risk management efforts. With the objective of regaining the trust of patients, regulators will be looking for what they’ve always been looking for: a demonstrated commitment to safety that goes beyond mere compliance. 

Compliance is a start
Whether we like it or not, regulators do tend to singularly focus on whether the rules were followed. Although, as my conversation with the EMEA regulator shows, they recognize that sometimes compliance can be an enemy of doing the right thing.

While the rules may seem arcane, numerous and somewhat arbitrary, they are not mitigating factors in explaining non-compliance. We cannot do away with compliance because, human nature being what it is, things would settle quickly to the lowest common denominator. We need to embrace the commitment that says “compliance is just the start.”

The compliance gap
The reason for the divergence between compliance and commitment can be found in the difficulty in codifying ideal behavior in laws, regulations and guidelines. We have to deal with safety across different stages:  during clinical trials, when data quality is arguably at its best because of its controlled circumstances, and during post marketing, when data quality is arguably at its worst.  

With so many rules, we are tempted to simply make ourselves a checklist, and if we can check off every item, we feel we’ve achieved compliance. But earning top marks – the “A” grade – means going beyond mere compliance.

Single-case scenarios
Let’s take the example of individual case reports. Such a report needs to be reported to the authorities within certain defined timeframes, depending on the facts of the case.

The rules tell us what those timeframes are. Without going into too much detail, a case needs to be “expedited” (hurried along in a matter of days) if it is “serious.” In a jurisdiction using ICH standards, an event is “serious” if it (a) results in death; (b) is life-threatening; (c) requires hospitalization or prolonged hospitalization; (d) results in persistent or significant disability/incapacity; (e) is a congenital anomaly/birth defect; or (f) is a medically important event or reaction.

It is this last item that can take us beyond compliance and move us toward a true commitment to safety. While the regulations say we must expedite the case if it is “medically important,” and there is some attempt to define what that means, it actually implies the conscientious use of medical and scientific judgment.
Such judgment cannot be measured from a pure compliance perspective – there is always room for reasonable disagreement as to medical or scientific conclusions. Disagreement is alright, however, as long as reasonable judgment is actually exercised. But in order to know whether there has been compliance with regard to the exercise of the judgment, it must be seen to have been exercised and that means documenting the thought process and conclusions.
In other areas of the industry, it has long been an axiom: if it is not documented, it did not happen.

Our documentation, therefore, must not just track that the case was put through the various steps appropriately, but that in each of those steps, the “right thing” was done.

But things can get tricky. An initial report may not need to be expedited based on the evidence available – it may not have been “serious.” To conclude that it was not “serious” implies exercising the judgment we just talked about. If information is later received that makes us reconsider our assessment, we need to be able to document our initial judgment, and our new judgment. How do you record the fact that you correctly did nothing, then subsequently and correctly did something?

Sometimes it’s necessary to make special efforts to record the action that did not result in visible effects, and not just those actions that did. Our current systems tend to be biased towards the latter.

Proving a lack of inaction
Another example of having to document apparent inaction is in the literature safety reviews. In such journal articles and trade publications, there are often reports of safety cases that occur. Companies are expected to survey for such literature cases – indeed in Europe, the frequency of such review is mandated by legislation.

When a case is found, the mere act of recording and tracking and reporting it in the company safety system proves that you did the legally mandated and ethically required review in the first place. But, as is often the case, you will find nothing during a review. Nothing is pretty hard to track. Unless your safety system allows for it, it will yield no documentation that you ever looked, unless there was an actual finding.

Therefore, it is more important than ever that your systems allow you to track actions whether they yield reportable cases or not.

Word of the day: provenance
For people to look back and be able to trust that you did the right thing, you need provenance – proof of its source or origin.
Just as a painting or antique furniture piece requires a provenance to stand up to a buyer’s scrutiny and attests to a seller’s claims, so does a company’s handling of a safety issue.

And, of course, a safety issue is not necessarily or likely to be equivalent to a single safety case.

What is a safety issue?
In reality, an actual safety issue can arise from multiple sources. It may constitute a whole series of documented safety cases, or a single unusual or medically significant safety case. Or it can, in fact, consist of no actual identifiable cases at all – at least none that meet the regulatory minimum criteria of: a patient, an event, a reporter and a product.

However it arises, we need to be able to track a safety “issue” regardless of the actual number of safety “cases.” Whether an issue arises from a rumor in the hallways, or an article in the mass media or from one or more well-defined safety reports, we need to be able to start tracking the issue from day one, and be able to document all associated cases and reports, all discussions we hold, all analyses we perform, and ultimately, the actions we take in order to mitigate any safety risks discovered and substantiated.

Case series vs. safety issues
Because we need to track all the associated cases, such safety issues are often currently referred to as “case series.” The very nomenclature implies the association of one or more cases with the issue.  However, this terminology can be misleading in the event of safety issues arising from sketchy data or non-canonical reports, where no identifiable or reportable cases may be involved.

Cases or no cases, we need to signal our awareness of the issue, and lay out a documented plan of action, and track against it.

The three dimensions of case-issue management
A “case series” is more properly a defined set of criteria relating to the people at risk, the products involved and the adverse event itself.
As one looks at the case series, you quickly realize that the definition of each of these dimensions often needs to be refined as a series of analyses is performed, to truly get to the bottom of what is happening. A safety issue is therefore likely to consist of multiple associated case series (plural).
It is already well-established that safety issues are often defined not just by a single medical term, but are better defined by a set of medical terms, due to the way in which the associated events are manifested and diagnosed.

A start has been made to define some such sets – the MedDRA Standardized Medical Queries or SMQs are designed for use in just such inquiries. But the reality is that SMQs are not yet comprehensive, and the medical view of certain issues may move faster than the SMQs are able to be adapted.
Consequently, companies are looking to be able to define their own “standardized queries,” not just for event terminologies, but also for demographic sets and product groupings – all of which need to adjust over the lifetime of investigation of a safety issue.

Iterative analysis both good and bad
Consider for example, the case of a drug reputed to cause a particular adverse effect. A straight analysis of the specific product and specific event, in narrowly defined terms, will not necessarily yield useful information. However, an analysis of all products in the same pharmacological class and all events that could feasibly be confounded with the original will likely yield more useful information. Since we will likely be working with these broader sets of data again and again, it is useful to be able to define shorthand queries for these groups of products and events.

At the same time as we battle with the dimensions and scope of our analysis, we will no doubt pursue fruitless as well as fruitful lines of inquiry. Whether they make sense at the time they are initiated, the results we gain from our analysis must be documented for posterity, along with the basis for our research.

Demonstration + Documentation = Commitment
Once we have done our research, which is well beyond the scope of case reporting compliance, we then have to act to mitigate any safety concerns. And, if there are no concerns, and hence no obvious actions, we need to also document that fact.

Only once our systems and processes allow us to transparently document our knowledge, judgments and actions (and of course, assuming we are making good judgments and taking good actions) will we be in a position to expect and earn that coveted “A” grade –and, more important, regain the trust of the public we serve.

Mark Loudon is the director of regulatory compliance at Aris Global LLC (www.arisglobal.com), a leading provider of integrated software solutions for pharmacovigilance and safety, regulatory affairs, clinical research and medical information. He can be reached at mloudon@arisglobal.com.