Envisage

Ethical Evolution

by Elisa Ludwig

June 2007

Legislation that provides incentives for pediatric clinical trials has successfully increased the number of products studied for use in children, but it has not been without controversy. For decades, common wisdom held that testing unproven medicines in children put them in harm’s way. More recently, as biopharmaceutical manufacturers have been encouraged—and sometimes required—to conduct pediatric research on new drugs, they have raised the level of dialogue, increased safety assurances and provided much needed pharmacokinetic information on new therapeutics.

Yet even as the number and quality of pediatric clinical trials has increased, there still are many barriers to pediatric research, due to both the vulnerability of the population and the logistical difficulty of conducting the trials themselves. Researchers still are grappling with many questions about safety and efficacy, says Dr. Elizabeth Garofalo, a pediatric neurologist and adjunct professor at the University of Michigan Medical School, in Ann Arbor, Mich., USA. “It is complicated in children who are growing and developing, and it is difficult to assess whether a drug impacts growth development, cognitive and school functioning,” she says.

In the past, manufacturers and clinicians alike were concerned with the many ethical issues related to exposing pediatric patients to drugs in development, Garofalo says. “Of course, what happened is that the drugs came to market without any information about children [on the label], leaving the pediatrician and the general practitioner to their own devices.” In effect, the experimentation and study of many drugs occurred in clinical practice, she says.

An Unmet Need

Pediatric clinical trials were rare until 1997, when the U.S. Food and Drug Administration (FDA) introduced the voluntary pediatric exclusivity provision of the Food and Drug Administration Modernization Act (FDAMA). This so-called “carrot” of pediatric research extends patent protection to give companies six additional months of marketing exclusivity to conduct studies in children, regardless of whether the research is initiated by the company itself or by request of the FDA. The exclusivity provision was renewed in 2002 under the Best Pharmaceuticals for Children Act.

The accompanying “stick” measure, the Final Pediatric Rule, finalized in 1998 and reinstated in 2003 under the Pediatric Research Equity Act, requires manufacturers of new drugs and biologics likely to be used in a substantial number of children to conduct pediatric studies. These two initiatives have led the FDA to request 760 pediatric studies over the past decade, and have resulted in new information for teenagers and children on the labels of more than 100 drugs. However, both the exclusivity provision and the Pediatric Research Equity Act are due to expire in October 2007.

In the 10 years since the Best Pharmaceuticals for Children Act was enacted in the United States, researchers have ushered in a progressive era for pediatric research, says Dr. Lisa L. Mathis, associate director of the office of new drugs at the Center for Drug Evaluation and Research at the FDA, in Silver Spring, Md., USA. “Without these tools, we would still be in the 1970s in terms of how we treat children,” she says. “This is an era in which people have learned a lot and are now willing to go forward and make the same progress with children as we had for many years with adults.”

As a result, both parents and practitioners understand much more about off-label usage and are better educated about what medications children should or shouldn’t be taking, Mathis says. Although the drug usage in pediatric populations may not have changed considerably, the usage is now more appropriate and the effects more understood. Determining that appropriate usage, however, is still an inexact science subject to the demands of rigorous clinical trials.

Research Barriers

There is no single rule for timing in pediatric clinical trials, since the timing of research is very dependent on the compound of interest. A new drug for a disease that only occurs in children may be studied in a pediatric population sooner than a drug developed for both adults and children, which would first be studied in adults for efficacy and safety data. Yet these are questions that need to be evaluated on a case-by-case basis, Garofalo says. “Many would say that you always need some signal of efficacy and safety data in adults before you expose any children [to a drug], but that could be open to debate,” she says. “It depends on how serious or life-threatening the disease is—you might move faster if it was a more serious situation.”

In the case of neonatal disease, for example, pre-clinical animal models are used to determine toxicity and safety issues. Dogs and other small animals can demonstrate the effect of a drug on a growing being. “Much more attention is being paid to the importance of preclinical models now, particularly when you’re moving into using a drug on a growing child,” says Dr. Robert “Skip” Nelson, a pediatric ethicist in the office of pediatric therapeutics at the FDA. In the area of oncology, for example, banked cancer tissues are becoming an increasingly important model for research on a drug’s impact on the cellular level, he says.

Nelson serves as the FDA’s internal consultant on trial design and other ethical questions regarding pediatric research. The issue of patient consent is of great ethical concern to researchers, Nelson says. Since children cannot truly give informed consent to participate in a potentially harmful trial, their parents must give consent on behalf of the child. If the research doesn’t offer a direct benefit to the child, the risk must be minimal. If the child might benefit clinically from the research, the risks must be balanced with the benefits, and that balance must be comparable with all available alternative treatments, Nelson says.

Although compensating trial subjects is a common occurrence, there’s no official FDA position on compensation for research participation. Compensation often is given to adults who participate in clinical trials for time and missed work. For children, however, compensation becomes more complicated because some see it as an undue influence. “If it’s an intensive study, parents will need to take time off work, so compensation might cover these expenses,” Nelson says. “For a child, there are appropriate tokens of appreciation. If the child is an older adolescent, they might get a minimum wage approach for their time.”

Safety in Design

Another ongoing concern is appropriate placebo use. Although there generally is much less use of randomized placebos in pediatric trials, there are circumstances in which placebo use is necessary, such as when there is no acceptable therapy available or an existing approved drug doesn’t work well. Placebos might also be used if the trial participant would not be denied elements of the standard of care.

The long-running antidepressant SSRI studies, which in 2004 led the FDA to direct manufacturers to include a boxed warning and expanded warning statements for all antidepressant drugs, are an example of trials that relied on placebos, Nelson says. The research successfully demonstrated the increased risk of suicidality in younger patients. “In that case, the only way you could see that safety signal was by using placebos,” he says. “But the important thing was that the trial design set safety boundaries by excluding children with severe depression who needed treatment from enrolling.”

Due to design and implementation challenges, pediatric trials also can be logistical quagmires, particularly in the area of trial enrollment. Although adult studies can examine a drug’s effect on consenting subjects who are healthy, in pediatric studies, children are not exposed to the risk of research unless they are sick. “You’ll usually have lower enrollment in pediatric trials,” Mathis says. “You need a multi-institutional setting and maybe a multinational setting.”

Formulating adult medicines for children’s usage is another barrier in pediatric drug development. In her work on anti-convulsives, Garofalo saw firsthand that adapting a new formulation is an exceedingly difficult process. “It took five years to produce a pediatric formulation of [the anticonvulsant drug] Neurontin. We need to have a lot of focus to help the regulators understand what the realities are and help industry get more sophisticated at producing them,” she says.

Early Fears

These barriers to pediatric research have deep roots. For years, the development of pediatric products was not only beset with logistical difficulties, it also showed little financial benefit, given the significant risks involved. Since most children in Western countries generally do not suffer from chronic conditions requiring continued medication as many adults do, there is both a limited population for trial enrollment, and a limited market in which to ultimately sell the products. Many pediatric cancers, for instance, affect too few children to attract drug development. Historically, the drugs that were most consistently studied in children were limited to those that had the biggest market potential, such as cold and cough medicines, antibiotics and vaccines.

Sponsors also feared that exposing children to clinical trials would open up a chasm of legal risks. “No one wanted to study drugs because they knew that any time a kid got hurt they would get sued,” Mathis says. A clinical trial gone wrong potentially could result in negative publicity and sinking stock prices.

As a result of industry’s concerns, the majority of drugs approved by the FDA by the mid-1990s did not contain labeling for children. In 1992, for instance, there were 19 new molecular entities approved by the FDA, and 15 of them were not labeled for pediatric use. Pediatricians and general practitioners often withheld treatments without pediatric labeling from children. In other cases, they “dosed down,” adjusting adult doses for off-label use in their smaller and younger patients. With no centralized repository for dosing information from which to draw, the process involved some trial and error, and the possibility of putting patients at risk.

“Fifteen years ago, when I was in training, I didn’t know what off-label use was,” Mathis says. “I didn’t realize that these drugs had not been studied in kids or that they were being prescribed without a full understanding of the doses.”

But due in large part to the legislation, there has been an evolution of ethical thinking in regards to conducting clinical research in children, Garofalo says. “Now the likelihood of getting pediatric data when it’s needed is much higher than it has ever been.”

The exclusivity rule has even affected Mathis’s practice as a pediatrician, she says. “My experience has been very positive,” she says. “I have been able to base how I treat my patients on facts rather than guessing. I really hope we continue to have this mechanism to gain data for children. We owe it to them.”

Knowledge Sharing

Pediatric legislation similar to the United States’ exclusivity provision took effect in the European Union in January 2007. “Every time a doctor in Europe writes a prescription for a child for an untested, unauthorized product, that doctor cannot be sure the medicine will be effective, cannot be sure what dose is appropriate and cannot predict what adverse reactions the child may suffer,” says Dr. Agnes Saint Raymond, the London, U.K.-based head of scientific advice and orphan drugs at the EMEA. In addition to the lack of safety and efficacy data, many new therapies are denied to children due to restrictive laws of some member states, she says. “Innovative medicines may and do save lives, and the children of Europe deserve at least the same access to such innovation as that enjoyed by adults.”

Like the FDA, the EMEA is now offering a six-month patent extension to companies that conduct clinical trials for new products on children, regardless of whether a pediatric indication is ultimately authorized. For orphan medicines designed to treat rare conditions, the agency offers a two-year extension of market exclusivity and data protection for off-patent medicines. A committee with representatives from each EU member state will review pediatric investigation plans that manufacturers will have to submit with all future market authorization applications for drugs that might eventually be prescribed to children.

From a regulatory perspective, the EMEA legislation poses a different kind of challenge. For multinational companies, coordinating pediatric trials in Europe and the United States may be more complicated by having two agencies to whom they must answer. “Sponsors used to focus primarily on what the FDA was asking, but now we will need to create our pediatric drug development while taking both [agencies] into consideration,” Garofalo says.

For these reasons, the FDA and EMEA will be working together to smooth the process, Saint Raymond says. “There is no requirement that only data generated in Europe can be used to support an application,” she says. The EMEA and the FDA are already engaged in a dialogue to exchange information and make the regulatory requirements on both sides compatible with global development, she says.

In the United States, some are concerned that the success of pediatric exclusivity to date is based on large pharmaceutical companies with blockbuster drugs, Nelson says. “Most companies are making much less money [from the exclusivity provision], so looking at past experience, it is difficult to anticipate what the future will hold as we drill down and look at drugs with less market value,” Nelson says. “There’s some suggestion that the number of sponsors declining written requests for pediatric trials have increased, and it may be because companies that stood to make a lot of money have already done so.”

Still, the imminent expiration of the legislation could pose a threat to the progress that has been made, and some fear that without it, pediatric clinical research may regress to pre-1990s frequency. “There needs to be new legislation passed, and there’s a lot of interest in what the new legislation will look like,” Garofalo says. “There’s great hope that it will maintain both the mandatory piece and the incentive piece.”

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