Rigor Vivus

In the post-marketing period, when new drugs “come to life”, a significant and growing amount of clinical research continues to be performed on a drug or device. Indeed recently published information indicates such research volume is rising more rapidly than pre-approval research, albeit from a much smaller base. This trend is all to the good: much important information about therapies and disease can be found by increasing post-marketing research among patients in real-life settings, which cannot be accomplished by the inherent scientific constraints imposed on investigational trials.

Sponsors are increasingly realizing, however, that more rigor needs to be applied to post-approval research – not that there are issues with subject safety, but rather that poor clinical operations process in post-marketing trials means inefficiency and lost opportunity.

There are many reasons why postmarketing studies are conducted differently than investigational trials. Regulations are fewer or non-existent in some circumstances. Research performed under full Good Clinical Practice is very costly. And by definition, once the therapy has passed regulatory muster, the safety and efficacy have already been proven through the exemplary rigor the industry follows. Much post-approval research is initiated and performed by individual investigators (in so-called IITs), who simply have an interest in pursuing a personal hypothesis or want to keep track of patient experience in a manner more organized than is possible in a regular medical practice. Given such circumstances, it is natural for sponsors to take a pragmatic approach to research after a therapy has come to life.

The incidence of post-approval research is particularly high among medical device companies, where many new products are approved as variants of existing devices, and thus are not required to undergo long and complex investigational trials. In these circumstances, rigor in following an approved device seems unnecessary and unproductive to many device companies. It is also true that for those drug companies large enough to have dedicated post-marketing or Phase IV units, physical or organizational separation from the investigational side of the company can lead to a philosophical and tactical separation as well.

Defensiveness doesn’t help

When it is suggested that post-marketing units are not rigorous enough, they often (naturally) react with great defensiveness. But in doing so they are missing the point: it is not a question of patient safety or regulatory compliance, it’s a process problem – a business problem.

Reduced rigor in post-marketing trials runs up against two imperatives. One is increasing regulatory attention, the other is integratability of all sponsored research. Regulators are increasingly asking sponsors to follow their drugs in a systematic manner post-approval, and as has been famously publicized recently in the Wall Street Journal, many of these studies are long delayed. Some of these studies have been a condition of the FDA’s approval of the drug or device. These studies are delayed or incomplete for many reasons, in part because of the inherent difficulties in conducting research in the “live” world, but also because the units charged with conducting this research are not used to operating under investigational research standards.

The internally-driven imperative for more rigor in post-approval studies is more widespread. Increasingly, sponsors are seeking to combine the data, the processes, or the enabling operational technologies (or all three), of both investigational and post-marketing trials. There are several drivers for this. One is the desire to use outside operational assistance (CROs) more judiciously; one way to achieve that is to leverage internal investigational and post-marketing resources to help even out each other’s workload. Another similar driver is the desire to leverage the significant investment companies have made in clinical trial software systems; in doing so they find they need to align processes, or risk confusion and poor control. But the key driver in tearing down the wall between pre- and post-approval research process is to be able to integrate these two rich data sources.

If an IIT or a registry or Phase IV patient experience trial reveals something exciting from a therapeutic or competitive standpoint, it is enormously more cost- and time-efficient for a sponsor to be able to use that data directly, and not have to run a “good process” trial from scratch to reproduce the findings. Sponsors cannot predict when they may want to use post-marketing data for a label extension, secondary indication, or competitive claims. When the opportunity strikes, data units in post-marketing organizations have to scramble to apply rigor retrospectively – something notoriously difficult to do.

The worst thing about a sponsor having two different perceptions of clinical data (pre- and post-approval) is that it creates two groups of staff and two process universes that are incompatible. The skill sets and processes, and therefore the people themselves, are not fungible or shareable. The separate creation of SOPs, training programs, parallel networks of trial monitors, and incompatible overlapping data systems, is highly inefficient.

What does help

We contend that sponsors have nothing to lose and everything to gain by doing all trials to the highest reasonable standards the first time. Rigor might seem more costly, but it is a lot like quality: quality does not cost money, it saves money. Rigor in post-marketing trials cannot compare in cost to the cost of re-running a trial under stricter standards or trying to clean a trial retrospectively. Rigor cannot compare in cost to losing out on a label extension or a competitive claim. Rigor cannot compare to the cost of trying to use an unprepared staff in crisis mode to help with a regulated trial using procedures they are unfamiliar with.

The irony is that what we are talking about here is mostly just good clinical practice, something every sponsor knows well. Post-marketing units need to learn more from their pre-marketing peers. (And while they are talking with each other, maybe investigational trial units can learn from the innovative trial design and technologies which are often first used in the post-marketing environment.)

Technology also helps. If applied properly, the evermore ubiquitous electronic clinical trial tools can help enable rigorous processes. And those tools can make it easier for smaller post-marketing research staffs to do more with less. Equally exciting are electronic tools which enable researchers to reach out into patients’ daily life – electronic patient diaries and similar – so that the experience of patients outside of the clinic, or outside the artificial constraints created by pre-approval trials, can be recorded and analyzed for insights into how to make a good product better, or how to take an alternate tack in a therapeutic strategy.

Not every trial, but more of them

Of course, not all trials post-approval need be run with investigational rigor. By the very nature of the “free enterprise” of science, many of them could not run with investigational rigor even if you wanted to. We also understand full well the usefulness of marketing trials in building provider relationships, enabling “small research” that would never otherwise be funded. And some research, like long-running registries, can only be cost-effective if managed in a lean manner. In all these cases, some research is better than none. With minimum safety and compliance standards met, the only thing being compromised in such examples is the potential scientific value, or perhaps the integratability of the data.

But sponsors are recognizing they need to be more careful about this, and err on the side of rigor rather than laissez-faire. The cost of doing “small research” that is not re-usable, or interferes with the development of an efficient post-approval safety profile, is too high. If necessary, build a “wall” between those who work under pre-approval regulatory requirements and those who support investigator-initiated trials or patient registries. Recognize that these resources will not be fungible. Recognize that the data will not be easily merged, if at all. Recognize all this, and plan accordingly. When there is a hint of wider use of the research results, move it quickly back over the wall to the side of rigor.

Take a long look at how you handle your post-marketing trials. Better processes may be more cost-effective; better science may breathe new energy into those products of yours that have come to life.