A Trio of Reports Discuss the Benefits of the Pediatric “Carrot and Stick” Statutes, the Orphan Drug Act, and Hatch-Waxman

By Kurt R. Karst –      

Last week, as Congress, FDA, and industry continue to ramp up debate on what changes or modifications should be made to the FDC Act and PHS Act as part of a user fee package of bills expected to be enacted later this year, three reports were issued discussing the various benefits of three long-standing areas of interest – pediatrics (under the Pediatric Research Equity Act (“PREA”) (FDC Act § 505B) and the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A)), orphan drugs (under the Orphan Drug Act), and generic drugs (as a result of the Hatch-Waxman Amendments).

After holding a series of meetings going back to December 2010, the Institute of Medicine (“IOM”) issued a 300-page report, titled “Safe and Effective Medicines for Children: Pediatric Studies Conducted Under BPCA and PREA.”  The report, which was called for by Congress, documents improvements in the availability of evidence about the safety and efficacy of drugs in children following the enactment and FDA’s implementation of the BPCA and PREA (and their predecessor policies).  The report also considers the incentives for pediatric studies of biologics under the Biologics Price Competition and Innovation Act of 2009.  The IOM reports follows a May 2011 U.S. Government Accountability Office report on the effects of the BPCA and PREA on the study and labeling of drug and biological products for pediatric use (see our previous post here), and a February 2012 House Energy and Commerce Committee hearing at which the reauthorization of both laws was a major topic of discussion. 

After reviewing and assessing a representative sample of labeling changes and other FDA actions related to BPCA-requested or PREA-required pediatric studies (for the period from July 1, 1998, through December 31, 2010) and considering other data and information, a committee appointed by the IOM reached several broad conclusions detailed in the report:

• Pediatric studies conducted under BPCA and PREA are yielding important information to guide clinical care for children.  Information from pediatric studies sometimes supports and sometimes runs counter to expectations about the efficacy, safety, and pharmacokinetics of a drug in children of different ages.
• Some studies requested under BPCA or required under PREA do not achieve their full potential.  Reasons vary and may include the inability of sponsors to recruit sufficient numbers of children, the use of weak study designs and underpowered samples, the lack of dose-ranging studies to guide efficacy trials, and the omission of relevant study information from labeling.  FDA has taken steps to address many of these problems.
• More timely planning, initiation, and completion of pediatric studies would benefit children. European requirements for the submission of plans for pediatric studies apply at a stage of drug development that may be somewhat premature, whereas U.S.  requirements apply later than may be warranted. Delays in sponsor completion of required studies also warrant further attention.
• Pediatric drug studies remain particularly limited in certain areas, including the use of medications with neonates and the long-term safety and effectiveness of drugs for all pediatric age groups.  The frequent lack of information about the long-term safety of drugs used with children is a special worry—both for drugs that may be used for decades for chronic conditions and for drugs for which short-term use may have adverse consequences on a child’s development months or years later.  Many drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.
• Congress has significantly expanded public access to information from recent pediatric studies conducted under BPCA and PREA and has thereby enhanced the value of these studies.  Limitations still exist, however, particularly for products with PREA-related labeling changes that occurred prior to September 2007.
• The reauthorization processes for BPCA and PREA have improved policies promulgated under both acts, but frequent reauthorizations create uncertainties for industry and FDA.
• Pediatric studies of biologics conducted under PREA have generated valuable information.  The 2010 expansion of BPCA to cover biologics has potential to expand knowledge further, but it is too early to assess its effects.  Almost 90 percent of biologics that the committee investigated have been the subject of some study with children.  Of the dozen biologics that have not been studied with children, most were approved for indications that are not diagnosed or very rarely diagnosed in children.  Given the applicability to biologics of long-standing policies such as the 1984 Orphan Drug Act and PREA and given the range of existing pediatric research on many biologics, the incentives of BPCA may have a valuable but more modest effect in encouraging studies of biologics than they did for small-molecule drugs.

Among the suggestions and options the IOM committee says Congress and FDA should  consider as the BPCA and PREA are debated during the 112th Congress are the following:

• Expand public access to information from pediatric studies conducted under BPCA and PREA;
• Improve the timeliness of certain pediatric studies;
• Strengthen pediatric studies requested under BPCA or required under PREA; 
• Address areas of limited pediatric investigation under BPCA and PREA, including neonatal studies and long-term safety studies;
• Increase the clarity and understanding of FDA judgments about pediatric studies; and
• Continue to encourage pediatric studies of biologics.

The American Academy of Pediatrics (“AAP”) applauded the IOM report in a press release, saying that many of the IOM committee’s findings, “including the need to plan pediatric studies earlier and promote these studies in younger age groups,” are consistent with AAP’s priorities for reauthorization of the BPCA and PREA. 

In a second report, this one titled “What the Orphan Drug Act Has Done Lately for Children With Rare Diseases: A 10-Year Analysis” and published in the journal Pediatrics (2012;129:516–521), the authors (Chandana Thorat, et al.) scoured data and information provided to them by FDA on orphan drug designations and approvals from January 1, 2000 to December 31, 2009 to discern what effect the Orphan Drug Act has had on improving drug availability for children with rare diseases.  According to the authors, the Orphan Drug Act has “led to increased product availability for [rare diseases] overall, with an increasing number of marketing approvals for children this past decade.”  Specifically, say the authors, from January 1, 2000 to December 31, 2009:

1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases.  The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second.  More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup.  The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972.  Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%).

In recent years, FDA’s Office of Orphan Products Development has developed a policy under which the Office has determined, for orphan drug designation purposes, “that pediatric patients constitute a unique population that is eligible for orphan designation if the prevalence of the pediatric population with the disease or condition is less than 200,000.”

In a third report, titled “Drug Pricing: Research on Savings from Generic Drug Use,” the GAO “summarizes the findings of peer-reviewed articles, government reports, and studies by national organizations, including trade and nonprofit organizations” on estimates of cost savings from the use of generic drugs in the United States.  The report research was undertaken in response to a request from Senator Orrin Hatch (R-UT). 

The GAO’s review identified various articles that used different approaches to estimate the savings associated with generic drug use in the United States and places them into three groups.  (The GAO did not independently assess the methodologies of the articles, including the reliability of data used as a basis for them.)  “One group of studies estimated the savings in reduced drug costs that have accrued from the use of generics. . . .  A second group of studies estimated the potential to save more on drugs through greater use of generics. . . .  A third group of studies estimated the effect on health care costs of using generic versions of certain types of drugs where questions had generally been raised about whether substituting generic drugs for brand-name drugs was medically appropriate.”   “Unlike the other two groups which focused on savings on drugs only” (and showed significant savings from generic drug use), the third group of articles, says GAO, “had mixed results regarding the effect of using these generics in that some found they raised health care costs, while others found they led to cost savings.”  The difference in findings of the third group of articles, comments GAO, may be attributable to the fact that the studies were generally limited to certain types of drugs, such as narrow therapeutic index drugs like Anti-Epileptic Drugs (“AEDs”).   As we previously reported, questions have been raised as to whether there are increased risks to patients who are switched from a brand-name AED to an approved, bioequivalent generic version.