of the program in improving information about important pediatric uses
for approved drugs.
The program has
been ineffective in improving information about drugs used in pediatric
cancer, since little research in pediatric cancer has been stimulated.
speak for themselves. Current FDA data indicate that the agency has
issued only two written requests for pediatric cancer studies to date,
and these came after almost a year of aggressive advocacy by pediatric
cancer advocates. Further, industry has made only five efforts to obtain
pediatric exclusivity over the two-and-a-half years in which the statute
has existed. These disappointing results clearly indicate that the program
has failed for pediatric cancer unlike its success in other disease
We believe that
the pediatric exclusivity program has failed for children with cancer
because of a series of overly restrictive interpretations and actions
by the FDA, which are described below. We believe it is essential that
greater industry resources are allocated to timely and effective research
on pediatric cancer. Accordingly, we are committed to working with industry,
FDA, NCI and the pediatric oncology community to ensure that innovative,
high quality clinical trials in pediatric cancer result in the eradication
of these diseases and would urge FDA reconsideration of its interpretation
of Section 111 in the case of pediatric cancers.
a. FDA, in interpreting
the statute, has imposed requirements not intended by Congress and not
provided for in the statute.
Section 111 requires
only that sponsors agree to requested studies that "may produce
health benefits in the pediatric population." Rather than requesting
pediatric studies proposed by pharmaceutical sponsors in consultation
with experts in pediatric cancer research, it is our understanding from
industry representatives that FDA has in effect imposed the complications,
delay and expense of filing a new drug application (NDA) or supplemental
new drug application (SNDA).
FDA currently maintains
that an NDA or SNDA is not an explicit requirement to qualify for exclusivity.
However, the "Pediatric Cancer Therapeutics: Letter of Interest"
posted on the FDA website indicates that, to obtain pediatric exclusivity
for oncology drugs, a sponsor must commit to studies effectively leading
to an NDA or SNDA. Congressional sponsors of the legislation that became
Section 111 have confirmed to patient advocates, and we believe to FDA
as well, that the requirement of filing an NDA or SNDA was not intended
by Congress nor supported by the statutory language.
FDA's basis for
imposing additional requirements on sponsors seeking pediatric exclusivity
seems to be a reference in the statute to the fact that studies, after
the request has been issued by FDA, must be "reported in accordance
with the requirements of the Secretary for filing." Because NDAs
and SNDAs must be "filed," FDA takes the position that the
requirements for NDAs and SNDAs are to be superimposed on Section 111,
which features no such requirements. This statutory construction ignores
the fact that the concept of "filing" appears numerous times
in the Act with almost no overlap in meaning.1 The only consistency
is that, wherever "filing" is mentioned, it is in accordance
with the common language meaning of the word, which is to submit a package
of information to an agency or other recipient. Reference to "filing"
in Section 111 cannot, standing alone, reasonably result in imposition
of the entire set of responsibilities accompanying NDAs or SNDAs.
the drafters of Section 111 intended to impose SNDA requirements, they
did so explicitly, in contrast to the above reference to "filing."
Elsewhere in Section 111, a second six-month exclusivity period can
be awarded for sponsors who successfully file a "supplemental application." Rules of statutory interpretation dictate that, if a requirement is specifically mentioned in one part of a statute but omitted from another, the omission cannot be ignored. Moreover, if a supplemental NDA must
be filed in connection with the first set of studies, which theoretically
results in six months additional exclusivity, the second exclusivity
period appears to be rendered meaningless. It is also a rule of statutory
construction that a statute should be interpreted so that every part
of it is given effect.
of the statute in this manner has real consequences for pediatric cancer.
A disease like cancer, where the course of the disease is likely to
be different in adults and children, is effectively discriminated against
as a result of FDA's interpretation. Congress intended to stimulate
private sector investment equally across all diseases by offering incentives
for pediatric studies that "may produce health benefits" for
drugs used in children. However, requiring pediatric studies of cancer
drugs to meet NDA or SNDA standards for cancer drug approvals effectively
imposes highly burdensome requirements. We believe that this interpretation
has dampened industry interest in taking advantage of the incentive.
b. FDA's interpretation
of the statute has not taken account of the standards and practices
of pediatric oncology research.
To make the incentive
meaningful for childhood cancer, FDA should have implemented the pediatric
exclusivity provision after thorough consultation with experts in the
pediatric oncology community. Decisions about the priority of clinical
trials for pediatric exclusivity purposes through Section 111 should
be based upon advice by "experts in pediatric research," as
the statute requires. Their input would have increased the chances that
the exclusivity program would have yield a greater number of appropriate
studies for pediatric cancer with the result that children with cancer
would benefit from the incentive.
The successes in
treating childhood cancer over the past 15-20 years have been accomplished
independently of FDA's labeling requirements. Drugs used to treat pediatric
cancer are approved for the treatment of cancer in adults. These drugs
are then evaluated through NCI pediatric cooperative group and cancer
center studies and used off label for cancer in children. Pediatric
oncologists regard the initial approval of an oncology drug or biological
product as a license to use it in practice, guided by the considerable
peer-reviewed literature reporting clinical studies. Advances in cancer
therapies proceed by the rapid translation of new scientific findings
into clinical practice. The practice of pediatric oncology, which is
responsible for real and dramatic increases in survival rates over the
past two decades, should be enhanced by the availability of Section
111 and not hindered by delays inherent in the process of reviewing
NDAs and SNDAs.
have openly stated that, for many compounds in current use, dosing and
side-effects data would add significant information that would improve
the treatment of children with cancer. However, such data, by FDA's
current process, could be gathered only as part of a development plan
to obtain a labeled indication for a drug, i.e., full approval. Full
approval would require efficacy trials according to FDA's usual adult
standards, where the incidence and type of disease are very different
from pediatric cancer. Even when a drug is known to be effective based
on studies by the pediatric oncology cooperative groups, FDA seems to
be requiring additional efficacy studies. Obtaining exclusivity for
drugs in current use is especially problematic because of the nature
of the efficacy trials FDA usually requires for NDA or SNDA purposese.g.,
single agent studies to show the individual contribution of a compound.
Such studies are likely be unethical in pediatric cancer because it
has been well established that no single agent alone is expected to
show efficacy in this disease setting. Pediatric "gold standard"
efficacy trials, which have established the standard of care through
the pediatric oncology cooperative groups, typically do not satisfy
FDA's approval standards.
funding in pediatric cancer could offer new hope for childhood cancers
for which treatment advances have lagged. New approaches are desperately
needed for pediatric solid tumors, including most types of brain tumors.
Pediatric oncologists desire access to promising new agents, which are
most often developed by industry. Section 111 offers a targeted incentive
that could stimulate studies in these difficult to treat pediatric cancers.
However, FDA requirements that studies be sufficient for labeling undermine
the potential of the incentive for industry to study these diseases.
c. FDA delays
and inconsistencies in implementing the pediatric exclusivity program
for pediatric cancer have further undermined its potential.
of the mandated "list" has been characterized by inconsistencies
and delays that have been especially disadvantageous for pediatric cancer.
The first list published by the agency in March 1999 contained a substantial
number of cancer drugs targeted for pediatric studies. However, in May
1999, the agency issued a replacement list that contained only a few
relatively marginal drugs, apparently based on its conclusion that the
list should include only drugs where the disease was the same in adults
as in children. This requirement unduly limits studies of drugs that
might yield benefits for children.
with pediatric oncology research experts could have created a meaningful
list of priority drugs for study in pediatric cancer and would have
increased the pace of pediatric cancer research. At present, there is
no meaningful list of cancer drugs that might be studied for the purpose
of demonstrating health benefits in children. Further, to the confusion
of many, the agency has maintained that the list is only an internal
tool for determining how the agency's resources should be employed rather
than a list of priorities, as the statute required.
Contrary to this
view, the list mandated by Congress has a very important function outside
of the governmentthat is, notifying private sector companies of
research opportunities that may be eligible for the incentive of extended
exclusivity. Absent the list, companies may not know the research opportunities
and will not step forward to fund important projects.
d. FDA's interpretation
has imposed unrealistic time lines on prospective sponsors and thus
undermines the incentive for pediatric cancer research.
There have been
additional barriers to the successful implementation of the exclusivity
incentive. Data released by FDA do not disclose the average time required
to navigate the process before a sponsor may receive a request for pediatric
exclusivity studies. Anecdotal information from the trade press indicates
that it may take well over a year before a sponsor is able to reach
closure with the agency on the requirements necessary to obtain pediatric
with the agency and receipt of the formalized request, sponsors must
then conduct studiesmore than one as required in the NDA and SNDA
process. With the small number of patients affected by different childhood
cancers, such studies typically take three to four years. Adding the time to negotiate with FDA on requirements for the studies,
a sponsor would face about five years to qualify for exclusivity. It
is important to note that the entire period of exclusivity available
to a new drug (without patent protection) under the Hatch-Waxman legislation
is five years. Thus, by the current method of implementing Section 111,
it seems practically impossible for such a drug to benefit from pediatric
exclusivitythe original exclusivity will probably expire before
FDA's requirements to study drugs in pediatric cancer can be satisfied.
2. Adequacy of
the pediatric exclusivity incentive.
As the statistics
concerning pediatric studies stimulated by Section 111 clearly reflect,
the incentive is inadequate in pediatric cancer.
It is possible that
six months additional exclusivity could be a significant incentive for
sponsorship of pediatric research, in cancer as in other diseases, but
only if the incentive is reasonably attainable. If the burdens imposed
on prospective sponsors are perceived to outweigh the potential benefits
to them, the incentive will not work.
Many believe that
an incentive greater than six months might be necessary to increase
industry involvement in pediatric cancer research. This perception may
require further investigation for verification. However, regardless
of the nature of the incentive, its implementation must be timely, efficient
and consistent with the standards and practices of pediatric oncology.
3. Economic impact
of the pediatric exclusivity program on taxpayers and consumers.
There is a negative
impact on the well-being and future productivity of childhood cancer
patients who might have benefited, but little if any impact on taxpayers
The negative impact
on the productivity and well-being of those children who would have
been helped by advances in pediatric oncology research must be noted.
There is broad consensus in the pediatric oncology community that incentives
are necessary to stimulate much needed private sector research to hasten
the development of effective treatments for childhood cancers.
As a test case,
the Section 111 incentive has failed to generate progress in pediatric
cancer research, and consequently failed to improve the potential of
the lives of children diagnosed with cancer.
With respect to
the impact on taxpayers and consumers, concern for the availability
of generic drugseven over an extension of only six monthsis
appropriate in most circumstances. However, patients facing life-threatening
diseases understandably place a higher priority on incentives for research
than on access to lower cost versions of drugs. Research may produce
new and more effective therapies than lower cost drugs with known but
In cancer therapies,
whether for adults or children, the availability of generic drugs has
little or no direct impact on consumers. The insulation of patients
from drug pricing considerations flows from the fact that drugs are
generally components of global payments made either to physicians or
hospitals. Payments by, or on behalf of, patients are usually the same
regardless of whether generic or innovator drugs are used.
With respect to
taxpayer impact, the result is not much different. Current reimbursement
systems for both physician and hospital administration of chemotherapy
drugs do not distinguish between generic and innovator drugs. Thus,
cancer patients as consumers or taxpayers typically do not gain an advantage
by the earlier availability of generic alternatives.
for FDA action.
Given the self-evident
failure of the Section 111 incentives to benefit pediatric cancer, FDA
should reconsider its interpretation in implementation of the statute
by creating an exception for pediatric cancer studies (and possibly
studies for other childhood life-threatening diseases).
for modifications will be forthcoming to Congress.
We support reauthorization
of the pediatric exclusivity incentive but with modifications that will
make it meaningful for all pediatric diseases, and especially childhood
cancer. Our understanding of the congressional intent in Section 111
was that it would provide an incentive, beyond FDA's regulatory authority
in the "Pediatric Rule," to encourage private sector support
for pediatric research. If the incentive of six months additional exclusivity
is to be meaningfulat least for pediatric cancerit must
be independent of the discretion of FDA to add requirements or limitations
that effectively undermine the incentive. Further, it must be implemented
consistent with the general conduct of pediatric oncology researcha
strategy that has yielded unprecedented advances in cancer treatment.
As the life-span
of the statute draws to a close, Congress should consider legislative
measures that either (1) restrict FDA discretion to limit the incentive,
or (2) provide a separate incentive for childhood cancer and other life-threatening diseases, where research is sorely needed to improve treatment options
and save the lives of children. We will provide specific legislative
suggestions to the Congress.