Rigor Vivus

When new products come to life in the postmarketing period 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 preapproval research, albeit from a much smaller base.1 This trend is all to the goodmuch important information about therapies and diseases can be found by increasing postmarketing 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 postapproval researchnot that there are issues with subject safety, but rather that poor clinical operations process in postmarketing trials means inefficiency and lost opportunity.

For many reasons, postmarketing studies are conducted differently than investigational research. Regulations are fewer or nonexistent 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 postapproval research is initiated and performed by individual investigators (in so-called IITs), who simply have an interest in pursuing a personal hypothesis, or who 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 postapproval research is particularly high among medical device companies, where many new products receive approval 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 drug companies, which are large enough to have dedicated postmarketing or Phase 4 units, physical or organizational separation from the investigational side of the company can lead to a philosophical and tactical separation as well.

Defensiveness doesnt help
When it is suggested that postmarketing units are not rigorous enough, those units often (naturally) react with great defensiveness. But in doing so they are missing the pointit is not a question of patient safety or regulatory compliance, its a process problem. Its a business problem.

Reduced rigor in postmarketing 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 postapproval, 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 FDAs 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 postapproval studies is more widespread. Increasingly, sponsors seek to combine the data, the processes, or the enabling operational technologies (or all three), of both investigational and postmarketing trials. There are several drivers for this. One is the desire to use outside operational assistance (such as that provided by CROs) more judiciously; one way to achieve that is to leverage internal investigational and postmarketing resources to help even out each others 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 they risk confusion and poor control. But the key driver in tearing down the wall between pre- and postapproval research processes is to be able to integrate these two rich data sources.

If an IIT, a registry, or Phase 4 subject 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 postmarketing data for a label extension, secondary indication, or competitive claims. When the opportunity strikes, data units in postmarketing organizations have to scramble to apply rigor retrospectivelysomething notoriously difficult to do.

The worst thing about a sponsor having two different perceptions of clinical data (pre- and postapproval) 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 helps
I 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 qualityquality does not cost money, it saves money. The cost of rigor in postmarketing trials cannot compare to the cost of rerunning a trial under stricter standards or of trying to clean a trial retrospectively. The cost of rigor cannot compare to that of losing out on a label extension or to a competitive claim. Neither can the cost of rigor compare to the cost of asking an unprepared staff in crisis mode to help with a regulated trial using procedures with which they are unfamiliar.

The irony is that what we are talking about here is mostly just good clinical practice, something every sponsor knows well. Postmarketing units need to learn more from their premarketing 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 postmarketing 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 postmarketing research staffs to do more with less. Equally exciting are electronic tools which enable researchers to reach out into patients daily lifeelectronic subject diaries and similar toolsso that the experience of patients outside of the clinic, or outside the artificial constraints created by preapproval 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 postapproval need be run with investigational rigor. By the very nature of the free enterprise of science many of them could not be run with investigational rigor even if you wanted to do so. Marketing trials can be useful in building provider relationships and in 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 reusable, or that interferes with the development of an efficient postapproval safety profile, is too high. If necessary, build a wall between those who work under preapproval 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 postmarketing trials. Better processes may be more cost-effective. Better science may breathe new energy into those products of yours that have come to life.

References
1. CenterWatch Editorial, Clinical Grants Market Decelerates, CenterWatch 1 (April 2003).