Drug safety has become an integral part of CT research from start to finish

More jobs, more focus on pharmacovigilance

Pharmaceutical companies and clinical research institutions have adhered to drug safety regulations and standards for decades. But in recent years there has been a trend of increasing attention paid to pharmacovigilance, with drug safety staffs increasing rapidly at research institutions and clinical research organizations (CROs).

Regulatory pressure has contributed to the trend.

For instance, the European Union now requires every drug submitted for marketing authorization to have a risk management plan, says Edward A. Kelly, MD, vice president of Global Pharmacovigilance at Quintiles Transnational Corp., in Durham, NC. Quintiles is a CRO and provides research support to the pharmaceutical industry.

Also, the FDA requires certain high-risk drugs to have a risk management action plan (Risk MAP). And the FDA has been granted by Congressional legislation new punitive power to force companies to conduct post-approval studies for the purpose of assessing drug safety, says Axel K. Olsen, PhD, MS, executive director of Global Pharmacovigilance at Quintiles Strategic Research and Safety, Quintiles Transnational Corp.

Quintiles' staff in Global Pharmacovigilance has doubled in size within the past 18 months due to growth in both marketed product safety programs and studies and pre-approval studies, Olsen says.

"A broader view is that companies are increasing the number and type of studies that they're doing on marketed products, and there is an in-crease in the epidemiologic investigations being conducted," Olsen adds.

Drug safety is big news

Another impetus to the heightened focus on drug safety is the media. Newspaper headlines regularly feature articles about drugs that are recalled or are relabeled because of drug safety issues.

In a recent example, a front page story in The New York Times, dated Oct. 20, 2007, discussed an FDA panel's recommendation to ban cold and cough medicine marketed to children younger than age 6.1

"The main difference now is that the issue of drug safety is much more apparent because of the media," says Esther King, BS, a safety surveillance associate III at the Duke Clinical Research Institute (DCRI) of Duke University in Durham, NC.

"The question is whether there were enough studies conducted prior to getting the drug approved," King says. "We follow patients, but there's not that much long-term data—beyond 12 months—in most studies."

Also, when drugs make it to the market they typically are used in a wider patient population than what they were indicated for, King notes.

"The physician can prescribe the drug for anybody, so you want to make sure the drug is truly safe," she adds.

The drug safety group at Duke also has doubled in size within the past couple of years, King says.

Even small sponsors who previously handled all drug safety work on their own are now asking for assistance from DCRI, King notes.

"We have 12 people now and will hire again soon," she says. "Our workload has doubled in size."

The safety group has been available to researchers and clinical trial sites affiliated with Duke University for years, but people are paying more attention to its services now.

"Maybe with all of the black box warnings coming out and with the closer scrutiny, I think we would certainly err on the side of caution and perhaps consult with the safety surveillance group more frequently now than we have in the past," says Peggy Arias, project leader at the Duke Clinical Research Institute.

Increasingly complex therapies

As medications have become more complex, sponsors and research sites have had to be more diligent than they might have been in the past, Olsen notes.

"The complexity of trials also is increasing, and we have the added shift toward the biological compounds," Olsen explains. "We are dealing with a very different kind of situation because the biologic response is more of a systemic response and can be quite sudden."

For example, a research disaster occurred during the phase I clinical trial of a biological compound studied by TeGenero AG of Wurzburg, Germany, in March, 2006. Six healthy participants in London, England, simultaneously were given the study drug, a humanized agonistic anti-CD28 monoclonal antibody called TGN1412, and they became violently ill immediately. All six men were hospitalized, including one man who remained in critical care at Northwick Park Hospital for weeks.

Unpredictable events sometimes happen with biologic compounds, Kelly says. "The main thing you worry about with biologic and humanized antibody [drugs] is anaphylaxis," Kelly says.

"An antibody can have a target that no one understands," he adds.

In studies of riskier or more unpredictable drugs, a pharmacovigilance best practice would be to start the pharmacovigilance plan in the pre-clinical phase, Kelly suggests.

"One of the critiques of the TeGenero situation is there were enough signals out there that there could be problems with the drug in humans," Kelly says.

No one suggested that when human subject trials began that the process begin slowly with even smaller doses and, perhaps, one person taking the drug and having his health monitored before the next person is given the drug, Kelly explains.

"Now, our best practices is to have a pharmacovigilance plan that pulls all safety information together at any stage of development and say, 'What are we looking at in risks, and what can we do to mitigate those risks?'" Kelly adds.

Quintiles has had preliminary discussions with pharmaceutical companies about providing a pre-clinical drug safety plan, but this practice has not yet caught on, Kelly says.

"I think we will over time see more and more of that," he says.

Ideally, a pharmacovigilance plan would be put in place from the pre-clinical research to the post-approval stage, Olsen says.

"You should broadly apply the same principals in pre-approval to post-approval," he adds.

Risk MAPs for high-risk products

Risk MAPs already are being used to save lives among consumers of high-risk products.

For example, the medication natalizumab (Tysabri®) has a risk MAP that is required by the FDA, Kelly says.

The drug is used to treat patients with Crohn's disease and multiple sclerosis.

"Data came in after the drug was on the market that it was associated with three cases of potentially fatal brain infection," Kelly says.

The opportunistic viral infection of the brain called progressive multifocal leukoencephalo-pathy (PML) was observed in two patients with multiple sclerosis and one patient with Crohn's disease, according to the "Dear Healthcare Professional" letter, dated in July, 2006, by Biogen Idec Inc. and Elan Pharmaceuticals Inc.

The risk MAP enabled the sponsors to quickly learn of the three cases and determine that PML is a true risk of taking the medication, Kelly says.

They also found that what placed patients at greater risk was being prescribed a second immune modulator in addition to natalizumab, he says.

The risk MAP also came up with these precautions, as outlined in the "Dear Healthcare Professional" letter:

  • Natalizumab is available only through a special restricted distribution program that includes distribution of the drug solely by authorized sites;
  • Health care professionals are advised to monitor patients on the drug for any new sign or symptom that could be suggestive of PML and dosing should be withheld immediately at the first sign or symptom;
  • The manufacturer provided education to health care providers about how concurrent use of natalizumab with antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML;
  • All physicians prescribing the drug and their patients are enrolled in a Tysabri registry.

The risk MAP for natalizumab has been a success story, Kelly says.

Since putting the drug back on the market 18 months ago there have been no additional cases of PML, he says.

"The good news is that, through expert drug safety management, a drug of great therapeutic value for patients with a potentially devastating disease was kept in the market," Kelly says.

Although the FDA doesn't require risk MAPs for all drugs, global pharmaceutical companies create risk management plans similar to risk MAPs because every drug marketed in Europe now needs one as part of the marketing application, Kelly notes.

These risk management plans require sponsors to identify the product's risks and explain what will be done about those risks, Kelly said.

"The risk might be a headache, and you won't have to do that much about it other than routine pharmacovigilance monitoring," Kelly explains. "But some risks may be more substantial, and you're obligated to say what the risks are and what the safety profile is and what you'll do about it."

What clinical trial site professionals and investigators need to keep in mind is that the research industry is focused on safety concerns, Olsen says.

"We need to engage the entire segment of the life sciences sector into this process," Olsen says. "That's a theme we're seeing from the pharmaco-vigilance and pharmaceutical industry, and we're broadly promoting it to the life sciences sector."

All clinical trial staff should understand what their own responsibilities are with regard to patient involvement in clinical trials, he adds.

"I would encourage investigators to see themselves as members of a team that has an important mission to bring helpful medicine to the public and to protect the public safety," Kelly says.


  1. Harris G. FDA panel urges ban on medicine for child colds. New York Times Oct. 20, 2007:page 1.