Postmarket Clinical Studies: The Era of Outsourcing Is Here

GUIDE TO OUTSOURCING

Now that CDRH has started to get more stringent with medical device manufacturers about postmarket surveillance, conducting postmarket clinical trials properly has never been more important. And because many device companies use contract research organizations (CROs) to run postmarket studies, it is also critical to select the right CRO. Along with that, device makers must ensure a clear division of labor and maintain communication with the research organization.

Because FDA has only just come out with its plan for enhancing postmarket surveillance, industry is unsure how the plan will affect business. Therefore, CROs aren't seeing a huge upswing in demand to run postmarket studies just yet. But they are seeing device companies take postmarket studies more seriously than they used to. If your company is not doing so, it risks needless trouble with the agency.

“In the old days, postmarket trials were very, very informal,” says Helen Colquhoun, CEO of Pleiad, a CRO based in Cambridge, MA. “Often a sponsor's marketing group would run them. Now, they are set up like premarket clinical trials.”

With this in mind, device makers must put significant thought into developing a postmarket study. To that end, CROs may be able to lend their expertise. First, however, device makers should understand the advantages of outsourcing a postmarket study. And they should learn how to choose a CRO and how to build a strong relationship.

Why Outsource a Postmarket Study?

There are three major types of postmarket studies that a device manufacturer may have to undertake, according to Bill Morton, president of Medical Device Consultants Inc. (MDCI; North Attleboro, MA). They are

For the first two, a device company has input, perhaps even marching orders, from FDA as to goals and end points. For the third, the firm must figure out for itself what needs to be accomplished and what methodologies to use. CROs might be able to help in that regard.

All kinds of postmarket studies differ from premarket studies in that they “do not typically require as much monitoring,” says Linda Alexander, CEO of Minneapolis-based CRO Alquest Inc. This is because during a premarket study, not much is known about how a device works on humans, so researchers must be prepared for anything. By the time a postmarket study rolls around, the safety profile of the device is already established and unpleasant surprises are less likely. Indeed, the goal of most postmarket studies is to examine only one or two issues, making such studies a less costly enterprise than premarket studies.

And, says David West, PhD, vice president of medical device development for Quintiles Consulting (Rockville, MD), while premarket studies tend to be confined to a small number of clinical sites and investigators, postmarket trials typically involve more sites, more patients, a wider geographical range, and a longer period of study. “There are three things that a CRO has going for it that a device company might not: the ability to cover a wide geography and perform tasks consistently across it, the ability to see trends across multiple product lines, and [the ability to assess] economies of scale,” he says.

These factors make a postmarket study as much a data-gathering project as a clinical pursuit, and thus make it an obvious target for outsourcing.

“[Outsourcing to CROs] can free up space to let your internal staff focus their efforts on the tasks that are more important to them, such as getting the next product to market,” says Alexander. And, she adds, small companies may not have enough people and resources to conduct postmarket studies at all.

A product's volume can also play a role in the decision of whether to outsource. “When you have a product like drug-eluting stents where many thousands are being used, the case for using a CRO is more obvious,” says Michael Feldstein, PhD, MDCI's vice president of clinical studies. “But there are other Class III devices where the number in use may be in the hundreds at most. In that case, sponsors could conceivably navigate such a project themselves.”

The Right CRO

So how does one find the appropriate CRO for a postmarket study? One way is to use the same CRO that was used for the product's premarket study, because it will be versed in the product and its potential risks. “If a company has done premarket work for you, it will be familiar with the nature of the existing product data,” says Feldstein. “It will also be familiar with the databases used to support those data.”

But if the premarket study was conducted in-house or was not required (which, says Morton, is the case for many Class II devices), a CRO search will be necessary. Here are some questions device makers should ask CROs:

“Approach [the process] as you would if you were checking out almost any other service that a device company would outsource,” says West. “Obtain capability statements and seek information on the background and experience of the people that would be assigned to your study. That includes getting their curriculum vitae and résumés.”

A good practice, CROs say, is to get quotes from at least three potential vendors, but make sure that the same information is given to all of them, so that the quotes can be compared apples-to-apples.

Once a selection is about to be made, it is a good idea for a device company to obtain references and contact former clients. In some cases, it may also be a good idea to audit the CRO to ensure it follows good clinical practices, and to ask to see the CRO's standard operating procedures.

“We like being audited,” says Colquhoun. “It gives us a chance to show that we are good at what we do.”

Clear Communication

Once a sponsor has selected a CRO, it is important to map out responsibilities and how communication will occur. “In the old days, companies were content to let the postmarket trial run itself, and then have the sales reps look at the data,” Colquhoun says. “Now there is more active monitoring. We often go to the sites and make sure the data are being collected correctly. To be blunt, sales reps do not have that kind of training. I mean no disrespect to their work, but even in a registry, the least formal way of gathering data, there is still a need to have someone trained to make sure the data are being collected correctly. Because if your input is not good, your output won't be, either.”

The first thing to do, she says, is to make sure that the CRO understands the key issues being investigated. “Has FDA brought up any issues you must address? Are there issues marketing people are concerned about?” The databases should be organized around these data points, and they must be compliant with 21 CFR Part 11, which covers electronic records and signatures, says Feldstein.

Then, Colquhoun says, make sure the CRO knows whether there are any investigators that the sponsor wants to make sure are included in the trial. “If there is a valued opinion leader or a big user of your products that you want to be sure is on board, you may want to design your trial in such a way that they will want to participate,” she says. From there, the rest of the investigators should be a mix of clinicians with expertise in the field and those that the marketing department wants to use.

Then it is time to divide responsibilities. That task should take into account the capabilities of the in-house staff and the CRO staff, as well as the budget the sponsor has available. There is no strict formula for the division of labor; it depends on the product, the objectives of the trial, and the size and capabilities of both parties. An important consideration here, says Feldstein, is, “How can you get any piece of data out at any point in time?”

However, it is best to make the sponsor responsible for keeping FDA in the loop, because, says Colquhoun, “it needs to own the regulatory piece. It is [the manufacturer's relationship] with FDA that is important and [it is] its product that will sink or swim” based on what happens in the trial.

And, says Alexander, “Even if the CRO is responsible for reporting to FDA, it should always report problems to the sponsor as well, so that there are no questions about whether the sponsor has been fully informed. Problems should never be a surprise for a sponsor.”

The sponsor and CRO also need to determine what sorts of events need to be reported to FDA immediately and which can be identified in the next scheduled report to the agency. Colquhoun says device companies should use the same reporting standards that they do when they detect problems with a device in the field. Some CROs have staff members who are experienced with spotting adverse events and with recalls. This is the stage to find out how to leverage that experience if the postmarket study turns up something troubling.

“What needs to be reported depends on the classification of the device,” says West. “For Class II devices, it is driven by the medical device reporting regulation. If it's a Class III device, you may find additional guidance pursuant to the conditions of the PMA.” If there are still areas a device manufacturer is not sure about, it should consult with FDA, says Morton.

Before the trial is to begin, the device company and the CRO need to put together a plan that dictates the lines of communication between the two firms. The ideal situation is for each company to designate a single point person. “The CRO will have a project manager that organizes all services that are being contracted,” West says. “So the medical device manufacturer ought to appoint someone with the same task.” These two people should talk regularly, and everyone else should know that all information needs to be shared with the designated individuals.

“You need to know who to keep up on the progress and who to pass on info to if new issues come up,” says Colquhoun. “I suggest talking on a weekly basis. The success of the project will depend on the success of the relationship between those two people.” The sponsor must feel it has input into the trial, and the CRO must know who to go to at the sponsor if problems occur.

Conclusion

The days of considering postmarket studies as nothing more than marketing enterprises are gone. The days of FDA scrutinizing postmarket studies as rigorously as premarket studies are not yet here. But they are coming, and medical device firms should not be caught unprepared. One of the best ways to be prepared is to pair up with a CRO with the appropriate expertise for the product line and scope of the trial.

Copyright ©2007 Medical Device & Diagnostic Industry