A et ready to start reading about some congressional efforts to strengthen the FDA’s authority to order drug companies to conduct pediatric clinical trials.
Two pediatric drug-testing laws, approved by Congress in 2002 and 2003, contain a “sunset” provision and will expire on September 30, 2007, unless action is taken to extend them. It’s a good bet that Congress will make, and President Bush will sign, improvements to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA).
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These two laws work in concert. Their chief claim to fame is that the BPCA authorizes the FDA to offer drug companies an extra six months of marketing exclusivity in return for performing clinical trials in children.
On March 27, 2007, Senator Hillary Clinton (D-N.Y.) introduced a bill that would create some changes around the edges of those two laws. Senator Chris Dodd (D-Conn.) has been passing around a much more extensive reform bill whose most controversial provision would decrease the six-month additional exclusivity period. He and other congressional critics, while noting the major gains in clinical information on pediatric drugs—which have led to numerous and important labeling changes—argue that six months’ time is much too large a carrot to offer companies that sell blockbuster drugs. The additional profits far outweigh the costs of actually conducting the pediatric clinical trials.
But even the current carrot does not persuade all companies to perform pediatric trials when the FDA offers the incentive. According to the Government Accountability Office (GAO), 214 requests were made to conduct trials between June 2002 and December 2005, and during that time, the drug companies declined to conduct trials 41 times. In those instances, the FDA can refer the drugs to the Foundation for the National Institutes of Health (FNIH), a nonprofit corporation. Although the FNIH is supposed to perform the trials, this hasn’t happened.
Of the 41 written requests that the drug sponsors had declined, the FDA referred nine of them to the FNIH, which had not funded the studies as of December 2005. In April 2006, the FNIH agreed to allocate all $4.13 million it had raised for pediatric drug studies under the BPCA to fund half the cost to study one on-patent drug—baclofen (Drug Lioresal, No-vartis), a muscle relaxant.
The NIH and the FNIH identified bac-lofen as the highest-priority, on-patent drug that a drug sponsor had declined to study. The NIH requested proposals for the study of this drug and selected a contractor to perform the studies. The NIH expects the baclofen study to cost about $7.8 million over three years and has agreed to cover the costs that exceed the contribution from the FNIH. Table 1 presents the estimated costs to study a number of on-patent drugs.
Table 1 Estimated Costs of Funding the Study of On-Patent Drugs Referred to the Foundation for the National Institutes of Health (NIH) under the Best Pharmaceuticals for Children Act
|On-patent Drug||Disease or Condition to Be Studied||Estimated Cost|
|Generic Baclofen (Lioresal) Bupropion canadian (Wellbutrin generic) Dexrazoxane (Zinecard)Eletriptan (Relpax) Hydroxyureab (Droxia) Metoclopramide (Generic Reglan) MorphineSevelamer tablet (Renagel generic) Zonisamide (Zonegran)||Spasticity in children with cerebral palsy DepressionUsed to block cardiac effects of the anticancer
drug doxorubicin (Adriamycin) Migraine headaches Sickle cell disease Gastroesophageal reflux disease Analgesia Renal failure
Refractory partial seizures
|$7.8 million $7.4 million_________________ a
$8 million—$10 millionc
$8.7 million $2.7 million $8.4 million
|Total||$43 million—$45 milliond|
|aThe NIH did not provide cost estimates.b Hydroxyurea is available in on-patent and generic (or off-patent) formulations. According to NIH officials,after the written request was referred to the FNIH for funding, the NIH determined that a study funded by its National Heart, Lung, and Blood Institute would provide much of the needed information for appropriate use. In 2005, NIH’s National Institute of Child Health and Human Development agreed to co-fund the study.
cThe NIH has not made a formal cost estimate, but an initial estimate ranged from $8 million to $10 million. dThe total estimated cost is for the six drugs, for which an estimated cost is available.
Adapted from the U.S. Government Accountability Office, Report No. GAO-07-557, Pediatric Drug Research, March 2007.
Because the FNIH has committed all of its BPCA funds to the study of baclo-fen, no resources remain for the FNIH to fund the study of any other drugs. That leaves eight drugs—and maybe more— that need funding for pediatric clinical trials. It is not clear why the FDA referred only nine of the 41 drugs that the companies declined to evaluate.
Not conducting those clinical trials puts kids at risk; the GAO has indicated that about 87% of the drugs that are granted pediatric exclusivity under the BPCA have required labeling changes. In many cases, the pediatric drug studies have found that the children might have been exposed to ineffective drugs, ineffective dosing, overdosing, or previously unknown side ef fects.
Even when the pediatric trials did turn up evidence of the need for labeling changes, however, it took quite a while to implement those changes. It took from 238 to 1,055 days for information to be reviewed and labeling changes to be approved for 18 drugs (about 40% of the total of 53 drugs that received exclusivity during the 2.5-year period). It took more than a year to implement seven of those labeling changes.
Although Senator Dodd has signaled that he is most interested in reducing the six-month exclusivity incentive— albeit only for yet-to-be defined blockbuster drugs—the larger need may be to convince drug companies to conduct more pediatric trials and to have the results of these trials translated into final labeling language much more quickly than is now the case.
Senator Clinton’s bill partly addresses this need. Under the BPCA, the FDA can require a pediatric study, but there are so many hoops to jump through that the agency has never used that authority. Senator Clinton would add language to the PREA that would streamline the BPCA’s authority and at the same time would preserve the ability of companies to have a fair review of the agency’s decisions. silagra uk
However, the bigger question—unfortunately, it probably won’t be answered— is why the FDA does not have the authority to require pediatric testing of all drugs, given that 87% of the labels eventually end up needing to be changed.