Development delays lead to new trends in clinical trials industry

Trial experts discuss recent research trends

In 2005, major pharmaceutical companies are estimated to have spent $45-$50 billion on research and development. Yet only 17 drugs were approved for marketing by the FDA, says Dan McDonald, vice president of Thomson CenterWatch in Boston.

In fact, the pipeline of drugs in development has grown rapidly in recent years with a greater than 10% annual increase. This has combined with other market pressures to force new trends in the clinical trial industry, experts say.

"We're seeing an absolute explosion in the pipeline of drugs in clinical research and moving toward the market," McDonald says. "Most of this is due to new drug discovery technologies and science that make the process at the discovery, pre-clinical phase much more efficient. But on the cusp of that we're seeing an impact on our ability to get drugs to the market faster."

Ten years ago, there were nearly 70 drugs approved for market in one year, but the recent numbers have been low, averaging below 20 annually, except for the 30 drugs that were approved in 2004, McDonald says. "That year is looking like an anomaly," he adds.

"Industry in the clinical trial process is not very efficient," McDonald says. "So we have a lot in the pipeline, but they're not pushed through to the final phases."

The biggest problem is poor recruitment in phase II and III clinical trials, he adds. "The process has slowed down so much that 90% of clinical trials are delayed by at least a month because of an inability to recruit patients," McDonald explains.

Going global

Primarily for this reason, pharmaceutical companies have flocked to other countries to find new clinical trial sites, experts say. In recent years, U.S. companies have sent increasing numbers of clinical trial contracts to international sites, says Norman M. Goldfarb, CRCP, managing director of First Clinical Research and editor of The Journal of Clinical Research Best Practices. Goldfarb also is the chairman of the Model Agreement Group Initiative and chairman of the Clinical Research Relief Organization.

In 2002, about 76% of the 1,572 contracts that investigators sign with the FDA to conduct studies were submitted by U.S. investigators. Two years later, U.S. investigators submitted 62% of the FDA's 1,572 contracts, and that same percentage was submitted by U.S. investigators in 2005, Goldfarb says.

"My guess is that the plateau is temporary," Goldfarb says. "Studies aren't moving to Japan and England; they're moving to Poland, Brazil, India, and places like that where the costs are lower and, more importantly, it's easier to recruit subjects."

There always will be clinical trials conducted in the United States because the U.S. market constitutes 60% of the global pharmaceutical market, says Vijai Kumar, MD, global medical director for Neeman Medical International of Raleigh, NC.

About 80% of clinical trials are conducted in the U.S., and less than 5% are done in non-traditional geographies, including South America, Asia, Africa, and Eastern and Central Europe, Kumar says. "The rest are in Western Europe," Kumar adds. "However, the trend is moving towards trials outside the U.S."

U.S. investigators will continue to have as many clinical trials as they can handle, but pricing and offshoring trends may force them to become more efficient and produce trials faster with lower costs, the experts predict.

"U.S. investigators who are competing with other investigators in their area will now have to compete on a global scale," McDonald says. "Companies won't take a trial and put it all in one location; there will be sites in India, the U.S., Eastern Europe, and elsewhere."

U.S. clinical trial sites will continue to do a majority of post-marketing studies because pharmaceutical companies want to conduct these in the countries where doctors write prescriptions, and the U.S. has a high prescription rate, Goldfarb notes.

Also, the U.S. has a more diverse population than do many other countries, and pharmaceutical companies need to show drug efficacy in the ethnic groups that will be using the drug, he says.

"You can't find African Americans in Africa, for example," Goldfarb says. "The diets, etc., are different, so the ethnicities are different."

Cost, timeliness, and quality are the three main reasons pharmaceutical companies are moving more trials off shore, Kumar explains.

Just look at the statistics of U.S.-conducted trials, he says:

  • 15%-20% of clinical trials conducted in the U.S. have zero enrollment, and 30% enroll just 5% of the patients, Kumar says.
  • Another 20% of clinical trial sites are average performers, and 30% enroll 75% of the patients, Kumar adds.
  • The amount of time a new drug or device spends in the clinical phase of research has increased from 31 months in the period of 1982 to 1999 to more than 70 months today, McDonald says. "So the process involved in testing drugs has become more extensive and complicated."
  • Clinical trials cost $50,000 a day on average to operate the trial, and the opportunity costs — measuring how much money is lost in potential drug sales as the product is delayed in making it to the market — is more like $1 million per day, McDonald says.
  • Pharmaceutical company spending on phase III trials through bringing a new drug to the FDA for approval has had greater than 20% increases over the last three years, due, in part, to increasing recruitment costs and replacing investigators, McDonald says.
  • At least one measure of clinical trial quality shows that the U.S. lags behind developing countries: In the U.S., clinical trial sites average 15 queries per 100 pages, while in some developing countries the number of queries is an average of five per 100 pages, Goldfarb says.
    "The research team is more motivated, and the compensation is relatively higher, so they can afford to spend the time on documentation," Goldfarb explains.
  • Patient retention in phase 2 and 3 studies is 70%, which is very low, Kumar says.

In developing countries, there is less mobility among populations, and this contributes to a higher subject retention rate, Goldfarb notes.

"Each patient who is lost costs a pharmaceutical company $45,000 a day," Kumar says. "Therefore the drivers for off-shoring clinical trials are increasing patient costs, delays and drop-outs in the United States, and quality is slipping. It's a vicious cycle because everyone goes to the experienced investigators; so they're kept busy, and you have to find new investigators who are not as experienced and who don't have the same level of quality."

Are changes in order for US trials?

These problems may contribute to clinical trial outsourcing, but they also indicate a need for changes in how trials are conducted in the U.S., the experts say.

"Less than 3 to 5% of the entire U.S. population participates in clinical trials," Kumar says. "We really have to go out to the community and find out why they're not participating."

This will require broad public education about clinical trials, but also education that targets community physicians, who could be discussing research with more patients, but are not, Kumar suggests.

"Most new investigators in the U.S. are tourists," Goldfarb says. "They think research looks interesting, and they have the impression it will be easy money."

Then they start a trial and reality strikes.

"They do a study or two and find out it's a lot harder than they thought and more of a headache, and they lose a lot of money," Goldfarb says.

This trend accounts for 60% to 70% of investigators who do one or two studies and then drop out, never returning to clinical trial research, McDonald says.

Giving incentives to investigators and clinical trial professionals to become certified is one way to improve education and training, Goldfarb says.

If sponsors were to reward sites with certified personnel by selecting them over competitors and paying a token amount above the average contract budget, it would pay for the training and certification and be a very inexpensive way to improve clinical trial quality, Goldfarb says.

Then there are the problems related to poor training of new investigators, particularly when it comes to the management and budgeting of clinical trials.

In CenterWatch's 2005 annual survey of research sites, there was a major shift in what those surveyed reported as their number one cause of delay, McDonald says. "Contract and budget negotiation and the approval process are the main causes of delay in clinical trial sites at this point in time."

Previously, budget negotiation was listed as the second or third cause of delay, McDonald says. New investigators often make the mistake of accepting the first budget a sponsor puts forth, and those typically are the inexperienced sites that will have difficult with subject accrual, Goldfarb says.

A logical solution would be for sponsors to keep track of the good performers versus the poor performers, but that does not always happen.

"I'm sure there are a lot of sponsors that are aware of this problem and attempt to cultivate relationships with good sites," Goldfarb says. "But I can also tell you that sponsor study personnel are very focused on the current research project, because that's what they're paid to do."

For example, when Goldfarb ran a clinical trial site, sponsors commonly would ask him if he'd ever done a study for them before, and he might be running another trial for that very same company at that time, and they weren't aware of it.

"It's very fragmented on the service provider side. Most research sites are small, part-time, and not long for the industry," Goldfarb says.

One trend that may improve this situation is the pharmaceutical industry's outsourcing to contract research organizations (CROs) for conducting clinical trials, McDonald suggests.

"CROs have the expertise to find the right doctors with the right patients or to venture into territory outside the United States," McDonald says. "We're seeing about 21% of research and development outsourced to CROs [including those in developing countries] today, and that will grow to close to 30% in the next four years."