DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
AGENCY: Food and Drug Administration, HHS.
21 CFR Parts 314 and 601
New Drug, Antibiotic, and Biological Drug Product
Regulations; Accelerated Approval
[Docket No. 91N-0278]
RIN 0905-AD66
57 FR 58942
December 11, 1992
ACTION: Final rule.
SUMMARY: The Food and Drug Administration (FDA) is issuing final regulations
under which the agency will accelerate approval of certain new drugs and
biological products for serious or life-threatening illnesses, with provisions
for any necessary continued study of the drugs' clinical benefits after approval
or with restrictions on use, if necessary. These new procedures are intended to
provide expedited marketing of drugs for patients suffering from such illnesses
when the drugs provide meaningful therapeutic benefit compared to existing
treatment. Accelerated approval will be considered in two situations: (1) When
approval can be reliably based on evidence from adequate and well-controlled
studies of the drug's effect on a surrogate endpoint that reasonably suggests
clinical benefit or on evidence of the drug's effect on a clinical endpoint
other than survival or irreversible morbidity, pending completion of studies to
establish and define the degree of clinical benefits to patients; and (2) when
FDA determines that a drug, effective for the treatment of a disease, can be
used safely only if distribution or use is modified or restricted. Drugs or
biological products approved under these procedures will have met the requisite
standards for safety and effectiveness under the Federal Food, Drug, and
Cosmetic Act (the act) or the Public Health Service Act (the PHS Act) and, thus,
will have full approval for marketing.
EFFECTIVE DATE: January 11, 1993.
FOR FURTHER INFORMATION CONTACT: Marilyn L. Watson, Center for Drug Evaluation
and Research (HFD-360), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-295-8038.
TEXT: SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of April 15, 1992 (57 FR 13234), FDA published
proposed procedures under which the agency would accelerate approval of certain
new drugs and biological products for serious or life-threatening illnesses,
with provision for required continued study of the drugs' clinical benefits
after approval or for restrictions on distribution or use, where those are
necessary for safe use of the drugs. FDA provided 60 days for public comment,
and, upon request, in the Federal Register of June 18, 1992 (57 FR 27202),
extended the comment period for an additional 30 days until July 15, 1992. The
final rule incorporates all of the provisions of the proposed rule and provides
additional clarification regarding both timing and content of the submissions of
promotional materials and regarding the nature of required postmarketing
studies. The agency has added a new provision clarifying when certain
postmarketing requirements of the rule will be terminated.
Highlights of the final rule are summarized below, followed by a summary and
discussion of the comments.
II. Highlights of the Final Rule
This final rule establishes procedures under parts 314 and 601 (21 CFR parts
314 and 601) under which FDA will accelerate approval of certain new drugs and
biological products for serious or life-threatening illnesses, with provision
for required continued study of the drugs' clinical benefits after approval or
for restrictions on distribution or use, where those are necessary for safe use
of the drugs. These procedures are intended to provide expedited marketing of
drugs for patients suffering from such illnesses when the drugs provide
meaningful therapeutic advantage over existing treatment. The preamble of the
proposed rule (57 FR 13234) provides a description of other mechanisms available
to facilitate access, speed development, and expedite review of therapeutic
products (e.g., treatment investigational new drug applications (IND's), subpart
E, parallel track). Where appropriate, these mechanisms can be utilized in
concert with accelerated approval. The major provisions of the final rule are as
follows:
A. Scope
The new procedures apply to certain new drug, antibiotic, and biological
products used in the treatment of serious or life-threatening diseases, where
the products provide meaningful therapeutic advantage over existing treatment
(21 CFR 314.500 and 601.40).
B. Criteria for Approval
Accelerated approval will be considered in two situations: (1) When approval
can be reliably based on evidence of the drug's effect on a surrogate endpoint
that reasonably suggests clinical benefit or on evidence of the drug's effect on
a clinical endpoint other than survival or irreversible morbidity, pending
completion of studies to establish and define the degree of clinical benefits to
patients; and (2) when FDA determines that a drug, effective for the treatment
of a disease, can be used safely only if distribution or use is modified or
restricted. Drugs or biological products approved under this final rule will
have met the requisite standards for safety and effectiveness under the act or
the PHS Act and, thus, will have full approval for marketing (21 CFR 314.510,
314.520, 601.41, and 601.42). Ordinarily, products used to treat serious or
life-threatening illnesses, for which approval is based on a surrogate endpoint
that is recognized as validated by definitive studies, will be considered for
approval under the traditional process rather than under accelerated approval.
C. Postmarketing Studies
Where a drug's approval under these provisions is based on a surrogate
endpoint or on an effect on a clinical endpoint other than survival or
irreversible morbidity, the applicant will be required to conduct clinical
studies necessary to verify and describe the drug's clinical benefit and to
resolve remaining uncertainty as to the relation of the surrogate endpoint upon
which approval was based to clinical benefit, or the observed clinical benefit
to ultimate outcome. The requirement for any additional study to demonstrate
actual clinical benefit will not be more stringent than those that would
normally be required for marketing approval; it is expected that the studies
will usually be underway at the time of approval. The proposed regulations have
been revised to clarify that required postmarketing studies must also be
adequate and well-controlled (21 CFR 314.510 and 601.41).
D. Restrictions on Use After Marketing
FDA may grant marketing approval of a drug or biological product shown to be
effective where safe use can only be assured if distribution or use is
restricted. Under this final rule, FDA may: (1) Restrict distribution to certain
facilities or to physicians with special training or experience, or (2)
condition distribution on the performance of specified medical procedures. The
restrictions on use will be tailored to the specific safety issue raised by the
particular drug or biological product and agreed to by the applicant at the time
of approval (21 CFR 314.520 and 601.42). FDA expects that the imposition of
these restrictions on distribution will be rare.
E. Promotional Materials
The final rule requires submission of planned promotional materials,
including promotional labeling and advertisements, both prior to approval
(reflecting the initial campaign), and following approval, unless informed by
the agency that such submission is no longer necessary, at least 30 days before
the intended time of initial dissemination of the promotional labeling or
initial publication of the advertisement (21 CFR 314.550 and 601.45).
F. Withdrawal of Approval
The final rule establishes an expedited procedure for the withdrawal of
approval if: (1) Postmarketing clinical studies fail to verify clinical benefit;
(2) the applicant fails to perform the required postmarketing study with due
diligence; (3) use after marketing demonstrates that postmarketing restrictions
are inadequate to ensure safe use of the drug or biological product; (4) the
applicant fails to adhere to the postmarketing restrictions agreed upon; (5) the
promotional materials are false or misleading; or (6) other evidence
demonstrates that the drug or biological product is not shown to be safe or
effective under its conditions of use (21 CFR 314.530 and 601.43).
G. Termination of Requirements
In response to comments, the final rule provides that the requirements set
forth in §§ 314.520, 314.530, and 314.550 for new drugs and antibiotics and §§
601.42, 601.43, and 601.45 for biological products ordinarily will terminate
when FDA determines that the results of required postmarketing studies have
demonstrated that the drug or biological product has clinical benefit, or, where
restrictions on distribution or use have been imposed, when FDA determines that
safe use of the drug or biological product can be ensured without such
restrictions, e.g., through appropriate labeling. FDA will notify the applicant
when these requirements no longer apply (21 CFR 314.560 and 601.46).
III. Effective Date
This regulation will become effective on January 11, 1993.
IV. Comments on the Proposed Rule
FDA received 54 comments on the proposed rule. The comments came from
individuals, specific disease organizations, universities, pharmaceutical
manufacturers, trade associations, health professionals, and professional
societies. The comments reflect broad support and acceptance of the goal of
expediting the approval of drugs intended for the treatment of serious and life-
threatening illnesses. A number of comments asked that the proposal be finalized
expeditiously without change. Many comments posed specific questions and raised
important concerns.
A. General Comments
1. One comment suggested that the term "conditional approval" was less
confusing and ambiguous than the term "accelerated approval." The comment also
referred to the statement in the proposal that "Drugs * * * approved under this
proposal will have met the requisite standards * * * under the (act)" and argued
that because postmarketing conditions may be imposed, this statement can only be
read to say that the requisite standards under the act can only be met by a
lower standard of evidence in hand, combined with assurance that further
evidence will be obtained.
Another comment expressed concern that the proposal appears to establish a
standard for the evaluation of drug product effectiveness that is inconsistent
with the substantial evidence requirement of section 505(d) of the act (21
U.S.C. 355(d)), which means "evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by experts qualified by
scientific training and experience to evaluate the effectiveness of the drug
involved, on the basis of which it could fairly and responsibly be concluded by
such experts that the drug will have the effect it purports or is represented to
have under the conditions of use prescribed, recommended, or suggested in the
labeling or proposed labeling * * *." The comment argued that, with few
exceptions, the agency has consistently interpreted the "substantial evidence"
requirement as an instruction that determinations of effectiveness be based on
data unambiguously reflecting the clinical status of subjects evaluated under
controlled conditions in bona fide clinical experiments. In the absence of
compelling empirical evidence documenting that a drug-induced change in a
surrogate measure reliably and consistently predicts improved clinical outcome,
a surrogate indicator is no more than a hypothetical construct. The comment
asserted that the proposed rule's endorsement of the use of unvalidated
surrogate endpoints, therefore, appears to represent a significant departure
from traditional agency interpretations of "substantial evidence" within the
meaning of the act because it allows belief rather than evidence to serve as the
basis for a conclusion about the effectiveness of a new drug.
Three comments asserted that the new regulations are not needed to approve
drugs intended to treat serious or life-threatening illnesses. Two comments
cited FDA's approval, without new regulations, of didanosine (formerly called
ddi) and zalcitabine (formerly called ddc) in combination with zidovudine
(formerly called AZT) based on a surrogate marker, i.e., an increase in CD4 cell
counts and the "subpart E" procedures at 21 CFR part 312, which address the need
for expediting the development, evaluation, and marketing of new therapies
intended to treat life-threatening or severely debilitating illnesses as
examples of existing mechanisms for the expedited approval of important new
drugs. One comment argued that the act requires that drugs be shown to be "safe"
and "effective," and proof of effectiveness is not limited by the act to
demonstration of an effect on "survival or irreversible morbidity," as the
proposed rule seems to assume. The comment further argued that FDA has
considerable statutory discretion to define what type of data constitutes proof
of effectiveness, and demonstration of an effect on a surrogate marker is one
type of such proof.
The agency believes that what the procedures are called is much less
important than what the procedures are. The shorthand term selected by the
agency reflects the intent of the rule, especially that part related to use of
surrogate markers, which is to make drugs that provide meaningful improvement
over existing therapies for serious illnesses widely available (through
marketing) at the earliest time consistent with the law. The essence of the
proposal is thus acceleration, not the imposition of conditions. Approval under
these procedures is dependent on compliance with certain additional
requirements, such as timely completion of studies to document the expected
clinical benefit. The evidence available at the time of approval under this rule
will meet the statutory standard, in that there must be evidence from adequate
and well-controlled studies showing that the drug will have the effect it is
represented to have in its labeling. That effect will, in this case, be an
effect on a surrogate endpoint that is reasonably likely to predict a clinical
benefit and labeling will refer to the effect on the surrogate, not to effect on
clinical outcome.
While the act does not refer to particular endpoints or state a preference
for clinical, as opposed to surrogate, endpoints, it is well established that
the effect shown in well-controlled studies, must, in the judgment of the
agency, be clinically meaningful. Moreover, the safety standard in the act, that
a drug must be shown to be safe for its intended use, implies a risk/benefit
judgment. The effect shown must be such as to outweigh the risks of the
treatment under the conditions of use. Approval under this rule requires,
therefore, that the effect shown be, in the judgment of the agency, clinically
meaningful, and of such importance as to outweigh the risks of treatment. This
judgment does not represent either a "lower standard" or one inconsistent with
section 505(d) of the act, but rather an assessment about whether different
types of data show that the same statutory standard has been met.
Approval based on surrogate endpoints is not new, although the issue has not
previously been considered in regulations. The agency has, in a number of
instances, approved drugs based on surrogate endpoints. For example, drugs for
hypertension have been approved based on their effects on blood pressure rather
than on survival or stroke rate. Similarly, drugs for hypercholesterolemia have
been approved based on effects on serum cholesterol rather than on coronary
artery disease (angina, heart attacks). But, in those cases there was very good
evidence from clinical trials (in the case of hypertension) and from
epidemiologic and animal studies (in the case of hypercholesterolemia) that
improving the surrogate would lead to or is associated with the desired effects
on morbidity and mortality. Even so, there is still today considerable debate
about who will benefit from cholesterol lowering. Controlled trials assessing
effects on clinical endpoints of morbidity and mortality from use of
cholesterol-lowering drugs have been, and are being, conducted.
Reliance on a surrogate endpoint almost always introduces some uncertainty
into the risk/benefit assessment, because clinical benefit is not measured
directly and the quantitative relation of the effect on the surrogate to the
clinical effect is rarely known. The expected risk/benefit relationship may fail
to emerge because: (1) The identified surrogate may not in fact be causally
related to clinical outcome (even though it was thought to be) or (2) the drug
may have a smaller than expected benefit and a larger than expected adverse
effect that could not be recognized without large-scale clinical trials of long
duration. Reliance on surrogate markers therefore requires an additional measure
of judgment, not only weighing benefit versus risk, as always, but also deciding
what the therapeutic benefit is based upon the drug effect on the surrogate.
The sections of the final rule that address approval based upon a drug effect
on a surrogate endpoint specifically clarify the regulatory approval criteria
when the agency relies on a surrogate endpoint that, while "reasonably likely"
to predict clinical benefit, is not so well established as the surrogates
ordinarily used as bases of approval in the past. Postmarketing studies required
to verify and describe actual clinical benefits would also be required to be
adequate and well-controlled studies. Sections 314.510 and 601.41 have been
revised to clarify this point. If, on completion of required postmarketing
studies, the effect on the surrogate is not shown to correspond to a favorable
effect on clinical benefit, the rule provides an expedited means of removing the
drug from the market.
Approval of didanosine and zalcitabine under current procedures does not show
that the rule is of no value. Although approval did rely on a surrogate endpoint
that is of the kind specifically addressed by the rule, the fact that studies to
define clinical benefit were nearly complete and were being conducted under the
auspices of the National Institute of Allergy and Infectious Diseases made it
less crucial to have additional guarantees that such studies would be conducted
promptly. Moreover, the sponsors of didanosine and zalcitabine agreed prior to
approval to expedited withdrawal of the drug from the market if benefit were not
shown. The provisions of the final rule will ensure that appropriate safeguards
exist for timely generation of data on actual clinical benefit, for appropriate
promotional information about labeled indications, and for prompt withdrawal of
the drug from the market if clinical benefit is not confirmed.
2. Pointing to a statement in the preamble to the proposed rule that it is in
the public interest to make promising new treatments available at the earliest
possible point in time for use in life-threatening and serious illnesses, one
comment expressed concern that the proposed rule may lead to the marketing of
large numbers of clinically ineffective, but pharmacologically active, drugs and
this may not be in the interest of the public health. The comment argued that
early access to so-called "promising" drugs is not the same as early access to
safe and effective drugs, and the number of potential markers that may be
advanced as surrogates of clinical outcome is exceedingly large. The comment
suggested that it may be more appropriate to seek adoption of the proposed
requirements through an amendment to the act.
FDA agrees with the contention that providing people who have serious or
life-threatening illnesses with numerous clinically ineffective drugs would not
be helpful. However, the agency does not agree that the rule can be expected to
have this result. Although studies using surrogate endpoints may provide less
assurance of clinical benefit than studies using clinical endpoints, FDA
believes compliance with all of the elements of the accelerated approval program
will not result in the marketing of large numbers of clinically ineffective
drugs. The new procedures apply to a limited group of circumstances, namely, to
drugs intended for serious or life-threatening illnesses when the drugs provide
a meaningful therapeutic benefit over existing therapy. Reliance on a surrogate
endpoint is not equivalent to reliance on any evidence of pharmacologic
activity. The endpoint must be reasonably likely, based on epidemiologic,
therapeutic, pathophysiologic, or other evidence, to predict clinical benefit.
Whether a given endpoint is, in fact, reasonably likely to predict clinical
benefit is inevitably a matter of judgment. FDA, using available internal and
external expertise, will have to make informed judgments in each case presented,
just as it does now. The agency acknowledges that there are well-recognized
reasons for caution when surrogate endpoints are relied on. Certain putative
surrogates have ultimately been shown not to correspond to clinical benefit.
Perhaps the most noteworthy example is the failure of antiarrhythmic agents in
the Cardiac Arrhythmia Suppression Trial (CAST) to improve survival by
depressing ventricular ectopic beats; effective suppression of ectopic beats was
associated with increased mortality.
A sponsor must persuasively support the reasonableness of the proposed
surrogate as a predictor and show how the benefits of treatment will outweigh
the risks. Such presentations are likely to be persuasive only when the disease
to be treated is particularly severe (so that considerable risk is acceptable)
and/or when the surrogate endpoint is well supported. In addition, it will be
the sponsor's clear obligation to resolve any doubts as to clinical value by
carrying out definitive studies.
FDA does not agree that it would be more appropriate to seek an amendment to
the act than to adopt the proposed requirements. As discussed in the preamble to
the proposed rule as well as elsewhere in this preamble to the final rule,
existing provisions of the act and the PHS Act authorize promulgation of the
requirements in the final regulations.
3. One comment expressed concern that because the proposed rule would
establish conditions on a drug's approval, third-party payors may decline
reimbursement because the so-called approval would have attributes of
investigational status.
The agency expects that, because drugs approved under the accelerated
approval process meet the statutory standards for safety and effectiveness, they
would be eligible for reimbursement under State Medicaid programs or other
third-party plans. Drug products granted accelerated approval will not be, under
the law, investigational, as suggested by the comment.
4. One comment asked if all drugs considered for accelerated approval must
be reviewed by an advisory committee. The comment stated that because advisory
committees meet infrequently, waiting for the next meeting may slow down the
approval process.
FDA is not required to consult with an advisory committee before approving an
application under these accelerated approval regulations, or any other
regulation. However, FDA intends to consult the appropriate committee in most
instances. Advisory committee meetings can usually be scheduled to avoid
significant delays in the review process. The agency will consider any request
by an applicant for referral of the application to an advisory committee.
B. Scope
5. Four comments asked for further clarification of what diseases are covered
by the rule. One comment stated that the terms "serious," and "life-
threatening," are defined in the proposal by reference to 21 CFR 312.34,
followed by a brief statement explaining the role of judgment and examples of
diseases that are currently judged to be serious. The comment asked that FDA
also describe: (1) Diseases that are not currently included in the category of
"serious," (2) examples of diseases that are currently judged "life-
threatening," and (3) examples of diseases that are not currently included in
the category "life-threatening."
One comment contended that the statement in the preamble that "seriousness of
a disease is a matter of judgment, but generally is based on its impact on such
factors as survival, day-to-day functioning, or the likelihood that the disease,
if left untreated, will progress from a less severe condition to a more serious
one" too narrowly limits diseases covered by the proposed rule (57 FR 13234 at
13235). The comment argued that some "less severe" diseases, even if treated,
may progress to a more serious state, and that these diseases should also be
covered by the rule. On the other hand, two comments argued that the language in
the preamble that classifies diseases as "serious" was overly broad and
subjective and far too large a number of illnesses could be eligible as being
"serious."
FDA discussed the meaning of the terms "serious" and "life-threatening" in
its final rules on "treatment IND's" (52 FR 19466 at 19467, May 22, 1987) and
"subpart E" procedures (54 FR 41516 at 41518-41519, October 21, 1988). The use
of these terms in this rule is the same as FDA defined and used the terms in
those rulemakings. It would be virtually impossible to name every "serious" and
"life-threatening" disease that would be within the scope of this rule. In FDA's
experience with "treatment IND's" and drugs covered by the "subpart E"
procedures there have not been problems in determining which diseases fall
within the meaning of the terms "serious" and "life-threatening," and FDA would
expect no problems under this accelerated approval program. The likelihood of
progression to a serious condition with available treatments would also be
considered in assessing whether the disease is within the scope of the final
rule. The preamble to the proposed rule (57 FR 13234 at 13235) referred to
chronic illnesses that are generally well managed by available therapy, but can
have serious outcomes for certain populations or in some or all of their phases.
Applicants are encouraged to consult with FDA's reviewing divisions early in the
drug development process if they have questions about whether their specific
product is within the scope of this rule.
The concerns expressed in these and other comments about considering too
many illnesses eligible for consideration under the accelerated approval
procedures may arise from the underlying fear that reliance on surrogate
endpoints will become routine, the "normal" way drugs are brought to the market.
This fear is groundless. The vast majority of drugs are directed at symptomatic
or short-term conditions (pain, heart failure, acute infections,
gastrointestinal complaints) whose response to drugs, if it occurs, is readily
measured and where there is no need to consider or accept surrogate endpoints.
Surrogates, with few exceptions, are of interest in the following situations:
(1) Where the clinical benefit, if there is one, is likely to be well in the
future; and (2) where the implications of the effect on the surrogate are great
because the disease has no treatment at all or the drug seems to treat people
with no alternative (e.g., because they cannot tolerate the usual effective
treatment). In the first case, great care is needed, and would be given, as
there would generally be no experience linking an effect on the surrogate to
clinical success, and there have been conspicuous examples of lack of linkage
(CAST, referred to above; drugs that increase cardiac output in patients with
heart failure but that decrease survival; imperfect agreement of effects on
coronary artery patency and effects on survival in patients with myocardial
infarction; lack of beneficial effect on bone fracture rate despite favorable
effects on bone density in patients with osteoporosis). FDA and outside experts
will be aware of these examples as proposed surrogates are considered. The
implications are especially great when considering prophylactic therapy, i.e.,
treatments to prevent chronic illness (coronary artery disease, cancer), in an
essentially well population. In the second case, there will generally have been
experience (with the standard therapy) to evaluate in considering linkage of the
surrogate to benefit; this was, for example, the case with didanosine, where
evidence from zidovudine studies of the relationship of an effect on CD4
lymphocytes and clinical outcome could be assessed. Similarly, there is
considerable experience to show that durable complete responses in many cancers
correspond to improved survival, so that an agent inducing them in refractory
illness or in primary
disease that had previously been poorly responsive would generally be seen as
reasonably likely to provide a clinical benefit.
6. One comment stated that epilepsy is a serious and life-threatening
condition and asked that it be included within the scope of the proposal. The
preamble cited, among other illnesses, depression and psychoses as examples of
chronic illnesses that can have serious outcomes even if they are generally well
managed. One comment asserted that neither depression nor psychosis is a
disease, nor is either one serious or life-threatening. The comment stated that
depression and psychosis are diagnoses. The comment urged the agency to remove
them from the definition of life-threatening "illnesses" or "diseases."
With respect to epilepsy, FDA notes that in the "treatment IND" final rule
(52 FR 19466 at 19467, May 22, 1987), the agency listed "certain forms of
epilepsy" as an example of a disease or stage of disease that would normally be
considered "serious." Certain forms of epilepsy may also be considered "serious"
under the accelerated approval program. It is unlikely, however, that a
surrogate endpoint would be utilized in such a case, as seizure frequency, a
clinical endpoint, is readily measured.
FDA's reference to depression and psychoses was intended to give examples of
conditions or diseases that can be serious for certain populations or in some or
all of their phases. While drugs for the treatment of depression and psychosis
would be examples of those that could be covered by the accelerated approval
program, it is not the use of surrogate endpoints that would be expected; the
symptoms and signs of these diseases are readily studied. On the other hand,
some of these drugs have been quite toxic (e.g., clozapine for refractory
psychoses) and might be considered for approval with restrictions to ensure safe
use.
7. Two comments asked how FDA will decide that a drug is eligible for
accelerated approval. One comment asserted that the decision should be an option
for the applicant to consider, not a decision for FDA to make unilaterally.
Pointing to a statement in the preamble (57 FR 13234 at 13235) that FDA reserves
the right not to apply accelerated approval procedures when it believes in good
faith that the drug's foreseeable use is reasonably likely to be outside the
scope of "life-threatening diseases without meaningful therapeutic benefit over
existing therapy," the comments argued that, if there are patients with life-
threatening conditions that can benefit from expedited approval, the needs of
the patients should determine the procedures used to approve the drug. One
comment contended that applicants of products considered candidates for
accelerated approval may have their drug or biological product "forced" into the
accelerated approval process and be forced to conduct a program of studies to
substantiate that surrogate endpoints actually predict significant clinical
benefits.
The medical reviewing divisions within FDA's Center for Drug Evaluation and
Research (CDER) and Center for Biologics Evaluation and Research (CBER) will
determine the type of regulatory review that FDA may apply to an application.
FDA encourages sponsors to meet with FDA early in the drug development process
to discuss the applicability of the accelerated approval program to their
product; however, FDA reserves the discretion to determine whether these
procedures are applicable to a specific product.
With respect to the preamble statement cited by one comment, the comment
misreads the preamble statement, which does not say that FDA will, in all cases,
apply FDA's traditional approval mechanisms rather than this accelerated process
for drugs where a majority of the drug's foreseeable uses are outside the scope
of "life-threatening" diseases without meaningful therapeutic benefit over
existing therapy. The statement merely informs applicants that FDA will consider
the possible impact of widespread use of a drug for uses other than the one
supporting accelerated approval; drugs approved under this program would often
have only small safety data bases so that widespread off-label use might have
serious implications. The agency does not believe that such a situation would
regularly lead to exclusion from these provisions.
FDA does not agree that applicants seeking approval to market drug and
biological products that would be candidates for accelerated approval will be
forced to use the accelerated approval mechanism. It is true, however, that
some proposed surrogate endpoints would not be considered acceptable bases for
approval without assurance that the clinical studies to show clinical benefit
will be conducted. A sponsor that wishes the application to be considered under
the traditional approval process may request and receive such consideration.
The agency wishes to clarify the circumstances in which the accelerated
approval regulations will apply. Sections 314.500 and 601.40 describe aspects of
the scope of these regulations. Moreover, these regulations are intended to
apply to applications based on surrogate endpoints whose validity is not fully
established, to applications based on clinical endpoints that leave unanswered
major questions about the product's effect on ultimate outcome, and to
applications for products whose safe and effective use requires limitations on
distribution or use. In all other situations, accelerated approval requirements
will not apply.
Where approval is based on a surrogate endpoint that is accepted as validated
to predict or correlate with clinical benefit, the product will be considered
under the traditional process, and the postmarketing requirements under
accelerated approval will not apply. Approvals of products for serious or life-
threatening illnesses based on clinical endpoints other than survival or
irreversible morbidity will usually also be considered under traditional
procedures. Approvals based on such clinical endpoints will be considered under
the accelerated approval regulations only when it is essential to determine
effects on survival or irreversible morbidity in order to confirm the favorable
risk/benefit judgment that led to approval. Applications for products for
serious or life-threatening illnesses that provide a meaningful therapeutic
benefit over existing therapy will receive a priority rating and expedited
review, even when not considered under the accelerated approval procedures.
The agency also wishes to clarify that whenever an application is approved
under § 314.510 or § 601.41, postmarketing studies confirming the product's
clinical benefit will thus be required. Therefore, in order to eliminate
potential confusion, the agency has amended §§ 314.510 and 601.41 to clarify
these points.
FDA also recognizes that over time a particular surrogate, once acceptable as
a basis for approval only under the accelerated approval regulations, could
become recognized as validated by definitive studies (just as high blood
pressure, for example, over time became validated as a surrogate with clinical
significance). In such cases, a future application relying on such a surrogate
would not require postmarketing studies confirming the surrogate's clinical
benefit and the application would be considered under traditional procedures.
8. Two comments asked for clarification of the phrase "meaningful
therapeutic benefit over existing therapy" as used in the description of what
drugs the accelerated approval program should apply to. Specifically, pointing
to an example described in the preamble that a new therapy would be eligible for
accelerated approval if there was "a clear improvement" over existing therapy in
being more effective or better tolerated, one comment urged FDA to clarify the
meaning of "clear improvement" to discourage applicants of "me-too" products
from wasting the agency's time and resources by applying for accelerated
approval of such products. The comment also asked that FDA specify that if a new
drug is approved under the accelerated approval provisions because the drug
exhibits a "clear improvement" over an existing drug that was also granted
accelerated approval, then specific restrictions will be placed on the prior
approved drug to limit its use only to patients who cannot tolerate the new
drug, or whose physicians assess that a change to the new drug might involve
significant risks to the patient that outweigh the benefits. One comment asked
that the term "meaningful therapeutic benefit over existing therapy" be
interpreted and consistently applied to both drugs and biological products.
FDA believes that the examples given to help clarify the phrase "meaningful
therapeutic benefit over existing therapy" (ability to treat unresponsive or
intolerant patients or improved response compared to available therapy) are
readily understood illustrations of the intent of the requirement. A drug that
is essentially the same as available treatment (what the comment refers to as a
"me too" drug) will not have a credible claim to a meaningful therapeutic
benefit over that existing treatment and this should be easily detected.
With respect to restricting use of a drug previously approved under
accelerated approval procedures when a new drug granted accelerated approval is
a clear improvement over the prior approved drug, this would rarely be
appropriate. Although, in some instances, certain therapies are identified as
"second-line," this requires essentially unequivocal evidence of an advantage of
alternative therapy, not likely on the basis of a surrogate endpoint. Labeling
for both drugs will be accurate, however, allowing physicians to prescribe both
the newly approved drug and the prior drug properly.
9. One comment asked if a change in the route of administration would be
considered as a meaningful benefit and within the scope of the proposal.
A change in the route of administration may be a candidate for accelerated
approval depending upon the particular evidence presented.
10. One comment asked if subpart E drugs currently under investigation will
be considered for accelerated approval. The comment assumed that new drug
applications (NDA's) and supplemental NDA's considered for accelerated approval
will have the highest priority for review.
Subpart E drugs will be considered for accelerated approval if they satisfy
both eligibility criteria for accelerated approval, i.e., if they are being
developed for the treatment of serious or life-threatening illnesses and the
products will provide meaningful therapeutic benefits to patients over existing
treatment. As discussed above, applicants should consult with FDA early in the
development process to determine the nature of the regulatory review. Early
consultations are a critical part of subpart E procedures. Drugs being reviewed
under accelerated approval procedures will receive high priority review.
However, applications for drugs for acquired immunodeficiency syndrome (AIDS)
and human immunodeficiency virus (HIV)-related conditions will receive the
highest priority review.
C. Criteria for Approval
11. Two comments expressed concern that the proposal did not provide enough
detail on what constitutes an appropriate surrogate endpoint. One comment
recommended that FDA adopt specific criteria for what constitutes an appropriate
surrogate endpoint. The comment suggested that such criteria should include: (1)
The surrogate endpoint must be biologically plausible in that it must be
consistent with what is known about the pathophysiology and pathogenesis of the
disease; (2) the surrogate endpoint must be present or abnormal in a large
percentage of people who have the disease; (3) the surrogate endpoint must be a
good predictor of the disease progression and should correlate closely with the
significant clinical endpoint; (4) there should be a correlation between the
quantitative aspect of the surrogate endpoint and the progression of the disease
(e.g., the more severe the disease, the more deviant the surrogate endpoint from
normal); (5) the regression of the surrogate endpoint should be significantly
associated with clinical improvement (e.g., those with the greatest improvement
in the surrogate endpoint should also show the greatest clinical effects);
conversely, the lack of regression of the surrogate endpoint should be commonly
associated with a lack of clinical improvement; and (6) the incidence of
regression or improvement in the surrogate endpoint should be significantly
greater in treated than untreated patients.
One comment asked if the use of microalbuminuria data is a surrogate for
diabetic nephropathy and if all drugs relying on surrogate endpoints would be
eligible for accelerated approval, e.g., an angiotensin receptor antagonist with
potential utility for treatment of congestive heart failure. The comment also
asked what would happen if postmarketing studies demonstrate beneficial changes
of surrogate endpoints but not beneficial clinical endpoints. The comment also
asked if FDA will consider publishing guidelines on which surrogate endpoints
would be appropriate for the diseases that may be affected by the proposed rule.
Another comment expressed the belief that there is no evidence that surrogate
endpoints are necessarily good indicators of therapeutic benefit. The comment
stated that a drug may have an effect on a surrogate endpoint, but will not make
any clinical difference because the advanced stage of the patient's disease
precludes any effective therapy or the surrogate marker is not synchronous with
the patient's clinical condition.
Another comment asserted that the requirement to base an approval on a
surrogate endpoint that is "reasonably likely, based on epidemiologic,
therapeutic, pathophysiologic, or other evidence, to predict clinical benefit
other than survival or irreversible morbidity" is not restrictive enough to
assure adequate consumer protection. Terms like "reasonably likely" and "or
other evidence" allow drug manufacturers too much latitude for claiming that
there is a correlation between surrogate endpoints affected by their drugs and
clinical endpoints. The comment argued that until a correlation between a
surrogate endpoint and a clinical endpoint has been established, a particular
surrogate endpoint should only be used to approve subsequent drugs, without
adequate clinical evidence, if there is a very strong effect of the drug on the
surrogate marker or, if the effect is not sufficiently strong, there is an
additional surrogate marker which corroborates the results of the first.
FDA intends to publish informal guidance concerning surrogate endpoints, but
does not believe specific requirements for an appropriate surrogate should be
specified by regulation. Any given specifications may not be applicable to a
particular case. For example, the thoughtful suggested criteria supplied by the
comment would rarely, if ever, be applicable to the first effective drug for a
disease, because criterion 5 requires that regression of the surrogate endpoint
be associated quantitatively with clinical improvement. If there had never been
effective treatment, this would never be known. Yet the surrogate could be
persuasive on other grounds, such as a well-documented etiologic relation. In
general, it is likely that one or another strongly supportive piece of evidence
might outweigh gaps in other areas.
In developing informal guidance on surrogate endpoints, FDA will consider the
suggestions in this comment. Interested persons will have an opportunity to
comment on any guidance documents in this area developed by the agency. In some
cases, new or revised drug class, or disease-specific, clinical guidelines may
refer to surrogate endpoints. FDA is not prepared, at this time, to comment on
the acceptability of an endpoint that it has not specifically considered, e.g.,
microalbuminuria.
The final regulations make it clear that not all drugs submitted for approval
based on surrogate endpoint data are eligible for accelerated approval (§§
314.500 and 601.40). The drug in question must be for a serious or life-
threatening condition and must provide meaningful therapeutic benefit over
existing therapy. In the case of an angiotensin receptor antagonist posed by the
comment, there is existing documented life-prolonging treatment for congestive
heart failure. An application for a new agent, to be eligible for accelerated
approval, would have to show potential benefit over available therapy as well as
identify a reasonable surrogate endpoint. This is problematic since no accepted
surrogate endpoint for studies to treat congestive heart failure has been
identified to date. For example, some drugs with favorable effects on
hemodynamic measures in heart failure patients have been clinically ineffective.
The regulations are clear in requiring that, for drugs approved under these
provisions based on surrogate endpoints, the postmarketing studies must show
clinical benefit, not just the previously shown effect on the surrogate (§§
314.510, 314.530, 601.41, and 601.43).
Surrogates, or proposed surrogates, are not always good, nor necessarily bad,
indicators of therapeutic benefit and must be judged on a case-by-case basis.
Even very good surrogates may not be perfect: Blood pressure lowering has been a
better predictor of effect on stroke than on coronary artery disease,
cholesterol lowering has had a clearer effect on coronary artery disease than on
survival. Moreover, a surrogate may be persuasive for a phase of disease with
short expected survival but much less so in an earlier phase of the disease.
Caution is always appropriate in evaluating surrogate endpoints and the
particular therapeutic setting should always be considered. The agency believes
that the evaluation of surrogate endpoint data and the safeguards built into
these accelerated approval procedures will provide adequate consumer protection.
12. One comment expressed concern that if there is no accepted surrogate
endpoint, an applicant's only option is to conduct a study using some clinical
event as an endpoint, which may result in long, large studies that delay
approval to the detriment of patients and sponsors. One comment suggested as an
alternative that FDA permit approval of a drug based on a study using a clinical
endpoint, but accept a less rigorous standard of statistical significance, e.g.,
0.20 or 0.15 instead of 0.05. The comment further suggested that the sponsor
could then complete postmarketing studies to establish statistical significance
at conventional levels. The comment argued that this alternative is totally
consistent with FDA's willingness to accept greater uncertainty in approving
drugs for serious and life-threatening illnesses.
The intent of the rule is to allow FDA to utilize a particular kind of
evidence, an effect on a surrogate endpoint, as a basis for approval, and, where
appropriate, to ensure that remaining doubts about the relationship of the
effect on the surrogate to clinical benefit are resolved by additional adequate
and well-controlled studies with clinical endpoints. The rule is not intended
to place into the market drugs with little evidence of usefulness. Although
there is no statutory requirement for significance testing of any particular
value, there are well-established conventions for assessing statistical
significance to support the statutorily required conclusion that the well-
controlled studies have demonstrated that a drug will have the effect it is
represented to have. There is nothing about serious or life-threatening diseases
that make them uniquely difficult to study. A meaningful effect on survival or
morbidity where there is no effective therapy should be readily discerned. Such
studies need be long and large only when the effect is small or difficult to
detect. In that event, proper assessment of benefit, and valid weighing of its
relation to risk, is especially critical.
13. One comment asked that FDA clarify that one study could be the basis of
approval and that one postmarketing study should be all that is needed to
establish the link between the endpoint used for approval and some relevant
clinical benefit.
FDA interprets the statute, and good science, as requiring at least two
adequate and well-controlled studies to establish effectiveness. In some
instances, drugs have been approved on the basis of a single well-controlled
study; this has been done where the study was of excellent design, showed a high
degree of statistical significance, involved multiple study centers, and showed
some evidence of internal replicability, e.g., similar effects in major study
subsets. FDA encourages applicants to discuss with FDA early in a drug's
development the basis for the applicant's choice of a specific endpoint and,
where applicable, the basis for its belief that a single study would be a
sufficient basis for approval. With respect to postmarketing studies, FDA
anticipates that the requirement will usually be met by studies already underway
at the time of approval. As stated in the proposed rule, the requirement for any
additional study to demonstrate actual clinical benefit will not be more
stringent than those that would normally be required for marketing approval of
the same drug for the same claim.
14. One comment expressed concern that the preamble to the proposed rule
implied that a sponsor of an AIDS drug might have to do a postmarketing study to
establish an effect on survival after showing an effect on such endpoints as
weight or incidence of opportunistic infection (57 FR 13234 at 13235-13236). The
comment stated that FDA's own advisory committee indicated that it was pleased
to see an effect from a nucleoside analogue on the incidence of opportunistic
infections with AIDS patients but did not suggest that further work should be
done to show an effect on mortality. The comment argued that in some cases
direct correlation with clinical endpoints such as mortality is difficult to
prove and urged FDA to be flexible on this issue to encourage sponsors to go
through the accelerated approval process.
Ordinarily, an effect on a meaningful clinical endpoint, e.g., on rate of
opportunistic infections in AIDS, is a sufficient basis for approval without
need for followup studies. Other endpoints, however, might leave major questions
unanswered. For example, a modest effect on weight gain in AIDS without other
demonstrated benefit, if considered an adequate basis for approval, while a
clinical endpoint, might leave sufficient doubt as to the ultimate value of the
effect so that further studies would be necessary. FDA intends to interpret this
provision of the regulations with flexibility. This provision should also serve
as a reminder, however, that for life-threatening diseases, the ultimate aim of
therapy is improved survival as well as improved symptoms.
15. One comment asked FDA to clarify what a sponsor's obligation is to
continue supplying medication on a compassionate basis if clinical efficacy is
not demonstrated to FDA's satisfaction in postmarketing studies but individual
patients appear to be benefiting from use of the drug.
Sponsors are not obligated to supply drugs on a "compassionate basis."
Whether, if clinical studies did not show effectiveness, further availability of
the drug would be appropriate under any mechanism would be determined case-by-
case.
D. Promotional Materials
16. Three comments asserted that requiring advance submissions of promotional
materials is both beyond FDA's statutory authority and is unnecessary. Although
FDA stated in the proposal that it does not intend specifically to approve
promotional materials, two comments contended that is the likely effect of
advance submission. The comment cited section 502(n) of the act (21 U.S.C.
352(n)), which provides that no regulation promulgated under that provision
shall require prior FDA approval of the content of any advertisement "except in
extraordinary circumstances," and asserted that the "extraordinary
circumstances" language would not apply to drugs approved under the accelerated
approval program. One comment argued that submission of promotional material
prior and subsequent to approval is unwarranted when dealing with treatments for
serious or life-threatening illnesses where dissemination of the most current
and timely information is important to the treating physician. One comment
questioned why there would be any greater likelihood of misleading promotional
claims for products approved under the proposed accelerated approval process
than for drugs intended to treat serious or life-threatening diseases that are
approved under the normal NDA procedures. The comment also expressed the hope
that the proposed requirement for advance submission of promotional materials
was not based upon an assumption that promotional materials for drugs intended
to treat serious diseases are more likely to be misleading than promotional
materials for other types of drugs because any such assumption would be
unfounded. One comment argued that if an advertisement or labeling is
inaccurate, the product is misbranded and FDA could then obtain injunctive
relief, seize the product, and/or initiate criminal proceedings. Another comment
considered requiring advance submission of promotional materials unreasonable
because companies are not required to do so now. One comment questioned the
legal authority for requiring presubmission of promotional material following
approval of a drug product, and the reason for the requirement.
The agency believes that the requirements for submission of promotional
materials in the context of accelerated approval are authorized by statute.
Subsections 505(d)(4) and (d)(5) of the act provide that, in determining whether
to approve a drug as safe and effective, the agency may consider not only
information such as data from clinical studies but also "any other information"
relevant to safety and effectiveness under the proposed conditions of use. Such
information would include information about how the drug would be promoted. In
determining whether the drug's proposed labeling would be "false or misleading"
under section 505(d)(7) of the act, the agency is similarly authorized to
evaluate "all material facts" during the approval process, including the facts
about promotion.
FDA is also authorized by section 505(k) of the act to require reporting of
information subsequent to approval necessary to enable the agency to determine
whether there may be grounds for withdrawing the approval. Among the grounds for
withdrawal specified in section 505(e) of the act are that the evidence reveals
the drug is not shown to be safe and effective under its conditions of use. In
addition, drug approval may be withdrawn if information shows the labeling to be
false or misleading. Information on how the drug will be promoted is again
relevant to whether the drug's marketing approval should be withdrawn. Section
701(a) of the act (21 U.S.C. 371(a)) generally authorizes FDA to promulgate
regulations for the efficient enforcement of the act.
For biological products, additional authority in section 351 of the PHS Act
(42 U.S.C. 262) authorizes the promulgation of regulations designed to ensure
the continued safety, purity, and potency of the products. The content of
promotional materials is important to the continued safe and effective use of
biologicals.
Therefore, the provisions of the final rule requiring submission of
promotional materials prior to approval under the accelerated approval
procedures and subsequent to such approval are authorized by statutory
provisions. FDA might also invoke the authority of section 502(n) of the act (21
U.S.C. 352(n)) to require prior approval of the content of any prescription drug
advertisement in "extraordinary circumstances." Whether FDA could appropriately
rely on section 502(n) of the act in promulgating §§ 314.550 and 601.45 need not
be determined, however, because FDA is not relying upon section 502(n) of the
act as legal authority for these (or any other) sections of the accelerated
approval regulations.
The agency believes that advance submissions of promotional materials for
accelerated approval products are warranted under the accelerated approval
circumstances. The special circumstances under which drugs will be approved
under these provisions and the possibility that promotional materials could
adversely affect the sensitive risk/benefit balance justify review of
promotional materials before and after approval. For example, if the promotional
materials exaggerate the known benefits of the drug, wider and inappropriate use
of the drug could be encouraged, with harmful results.
Similarly, high risk drugs that are approved based on postmarketing
restrictions would not have been approved for use without those restrictions
because the risk/benefit balance would not justify such approval. If promotional
materials were to undermine the postmarketing restrictions, the health and
safety of patients could be greatly jeopardized.
Although there is potential harm from any misleading promotion, and there is
no reason to believe improper promotion is more likely in this setting than in
others, the risk/benefit balance is especially sensitive in this setting. The
relatively small data base available and the minimal published information
available also can contribute to making the physician and patient populations
particularly vulnerable under accelerated approval circumstances.
Reliance on court actions (such as seizures, injunctions, and criminal
prosecutions) can be effective in ending false promotions, but can only be
initiated after the fact, when harm has already occurred. Corrective efforts can
be helpful but are always somewhat delayed. Under the circumstances of
accelerated approval, FDA believes that it is far preferable to avoid problems
by reviewing the promotional materials in advance of drug approval and of
dissemination of the materials.
17. Two comments supported the provision about submission of promotional
materials. One comment urged the agency to require that specific patient
information be included in promotional materials to indicate the fact that the
drug's clinical benefit has not yet been established. For drugs approved under
the restricted use provision, the comment recommended that the labeling specify
in detail the exact restrictions placed on the drug. In both cases, the comment
recommended that this patient information appear as boxed warnings.
Section 502(n) of the act and regulations at § 202.1(e)(1) (21 CFR
202.1(e)(1)) require prescription drug advertisements (promotional material) to
contain, among other things, a true statement of information in brief summary
relating to side effects, contraindications, and effectiveness, which would
include warnings, precautions, and limitations on use. The information in brief
summary relating to side effects, contraindications, and effectiveness is
required to be based solely on the approved labeling. Therefore, to the extent
that a drug's labeling reflects the extent of clinical exposure and includes
appropriate warnings, a drug's promotional material would also include this
information.
FDA regulations governing prescription drug labeling (21 CFR 201.56 and
201.57) require that serious adverse reactions and potential safety hazards, as
well as limitations in use imposed by them, be included in the "Warning" section
of the labeling. In the case of approval based upon effect on a surrogate
endpoint, the "Indications and Usage" section of the labeling would reflect the
nature of the demonstrated effect. If the approval is based on use restrictions,
the label would also specify the restrictions.
FDA may require boxed warnings if there are special problems associated with
a drug, particularly those that may lead to death or serious injury (21 CFR
201.57(e)). The agency does not agree that information related to clinical
benefit or use restrictions for accelerated approval drugs would necessarily
always require a boxed warning.
As indicated by §§ 314.550 and 601.45 of the final rule, applicants will be
required to submit promotional materials prior to approval and in advance of
dissemination subsequent to approval whether the product is a new drug, an
antibiotic, or a biological product.
18. One comment contended that FDA review and approval of all promotional
pieces before their use will indefinitely delay product marketing campaigns and
other patient and physician educational activities, which are essential to
market a product, thereby significantly diminishing the advantage of securing an
early approval for the applicant. The comment further contended that the
requirement to submit "all promotional materials * * * intended for
dissemination or publication upon marketing approval" will be overly burdensome
for FDA and will unnecessarily slow down the process for review of all
materials, not just those for products subject to this proposed rule. The
comment recommended that FDA only request for review the primary advertising
pieces, such as the introductory letter to physicians, the main detail piece,
and the main journal advertisement, but not the secondary materials, e.g., a
letter to pharmacists, of the initial promotional campaign.
As previously discussed in this preamble, FDA will be reviewing an
applicant's planned promotional materials both prior to approval of an
application (reflecting the initial campaign) and subsequent to approval to
ascertain whether the materials might adversely affect the drug's sensitive
risk/benefit balance. Because all promotional materials, including those
referred to by the comment as "secondary" materials, can have significant
adverse effects if they are misleading, the agency does not agree that such
materials should, as a matter of course, not be requested for review. Insofar as
such materials may be directly derived from the introductory letter to
physicians, or other materials characterized by the comment as "primary"
materials, the additional time to review the derivative materials should not be
extensive.
The agency does not agree with the comment's contention that the requirement
to submit all promotional materials prior to and subsequent to approval will
indefinitely delay marketing campaigns and educational activities or be overly
burdensome to FDA reviewers. FDA is committed to rapid review and evaluation of
all drugs considered for approval under this rule and will promptly review the
promotional materials.
19. One comment suggested a passive, time-limited clearance system for review
of advertising after the initial promotional campaign such as that used for
review of IND's, which would allow the sponsor to proceed to use promotional
materials after an allotted timeframe, such as 30 days, unless otherwise
notified by FDA.
As indicated by this comment and others, additional clarification regarding
both timing and content of the submissions of promotional materials seems
useful. Therefore, the agency is revising proposed §§ 314.550 and 601.45 to make
it clear that, unless otherwise informed by the agency, applicants must submit
during the preapproval review period copies of all promotional materials
intended for dissemination or publication within the first 120 days following
marketing approval. The initial promotional campaign, sometimes referred to as
the "launch campaign," often has a significant effect on the climate of use for
a new product. As discussed elsewhere in this preamble, the risk/benefit balance
of accelerated approval products is especially sensitive, and inappropriate
promotion may adversely affect the balance with resulting harm.
There may be some instances in which promotional materials that had not been
completed and submitted by the applicant prior to approval would be beneficial
in fostering safe and effective use of the product during the first 120 days.
Under revised §§ 314.550 and 601.45, FDA would have the discretion to consider
such materials at a later time. An applicant who requested permission to include
additional materials among those disseminated within the first 120 days
following product approval would be notified of FDA's determination. If FDA
agreed that dissemination of such materials was acceptable, the materials could
then be disseminated or published upon notification.
For promotional materials intended for dissemination subsequent to the
initial 120 days under §§ 314.550 and 601.45 FDA would review the submitted
materials within 30 days of receipt. This 30-day period is meant to be time-
limited, so that the applicant will be assured of no unnecessary delay. It will
be important for the applicant to identify the materials being submitted
appropriately, so that it is clear that the materials are subject to the 30-day
review period. The agency intends to review all such materials promptly, and to
notify the applicant of any identified problems as soon as possible. The agency
expects that, if the agency notifies the applicant of significant objections to
the proposed materials, no materials will be disseminated or published until the
agency's objections are resolved. The applicant should plan to allow sufficient
time after receiving FDA's comments for resolving differences and incorporating
requested changes in the submitted materials prior to dissemination or
publication.
When FDA removes the requirement for advance submission of promotional
material, the agency will continue to offer a prompt review of all voluntarily
submitted promotional material.
E. Postmarketing Restrictions
FDA received many comments on the proposed requirement to limit distribution
to certain facilities or physicians with special training or experience, or
condition distribution on the performance of specified medical procedures if
such restrictions are needed to counterbalance the drug's known safety concerns.
20. Several comments questioned FDA's authority to impose restrictions on
distribution or use after an approved drug is marketed. Two comments disagreed
with the statutory provisions cited by FDA in the proposed rule as its authority
to impose restrictions on distribution or use stating that they refer only to
FDA's general authority to ensure that drugs are not misbranded, which is an
entirely separate issue. Another comment argued that section 503(b) of the act
(21 U.S.C. 353(b)) contemplates that the issues warranting a restriction as to
distribution are not factors in whether a drug product is "safe" for purposes of
approval, but rather only whether the product must be limited to prescription
status. Two comments said that, in the absence of specific statutory authority,
the courts clearly have refused to permit FDA to impose restrictions on
distribution and cited American Pharmaceutical Association (APhA) v. Weinberger,
377 F. Supp. 824, 829 n. 9 (D.D.C. 1974), aff'd sub nom. APhA v. Mathews, 530
F.2d 1054 (D.C. Cir 1976), a case concerning conditions placed on the approval
of the drug methadone.
Some comments asserted that placing restrictions on the distribution of an
approved drug to only certain facilities or physicians, or restricting use to
certain medical procedures interferes with the practices of medicine and
pharmacy, which the comments contended FDA does not have the authority to
regulate.
The agency believes that the restrictions to ensure safe use contemplated for
approvals under §§ 314.520 and 601.42 are authorized by statute. As discussed in
the preamble to the proposed rule (57 FR 13234 at 13237), sections 501, 502,
503, 505, and 701 of the act provide broad authority for FDA to issue
regulations to help assure the safety and effectiveness of new drugs.
The agency does not agree with the comments' contention that the misbranding
provisions of the act are irrelevant. Section 502(a) of the act prohibits false
or misleading labeling of drugs, including (under section 201(n) of the act)
failure to reveal material facts relating to potential consequences under
customary conditions of use. Section 502(f) of the act requires drugs to have
adequate directions for use and adequate warnings against unsafe use, such as
methods of administration, that may be necessary to protect users. In addition,
section 502(j) of the act prohibits use of drugs that are dangerous to health
when used in the manner suggested in their labeling. Each of these misbranding
provisions is intended, at least in significant part, to protect consumers
against the marketing of drugs that would not be safe under certain conditions
of use. Section 701(a) of the act authorizes FDA to issue regulations for the
efficient enforcement of the act. The restrictions on use contemplated by §§
314.520 and 601.42 help to ensure that products that would be misbranded under
section 502 of the act are not marketed.
The restrictions on use imposed under section 503 of the act, which relate to
prescription use limitations, primarily concern whether a drug is safe for use
except under the supervision of a licensed practitioner. While the agency agrees
that the restrictions imposed under §§ 314.520 and 601.42 concerning
distribution to certain facilities or physicians with special training or
experience would be in addition to ordinary prescription limitation, FDA
believes these restrictions are consistent with the spirit of section 503 of the
act, as well as the other provisions of the act referred to, in ensuring safe
use.
New drugs may be approved under section 505(d) of the act only if they are
safe for use under the conditions prescribed, recommended, or suggested in the
proposed labeling. In addition, for approval, a drug's labeling must not be
false or misleading based on a fair evaluation of all material facts, which
would include details about the conditions of use. For biological products,
section 351(d) of the PHS Act also authorizes the imposition of restrictions
through regulations "designed to insure the continued safety, purity, and
potency" of the products.
The agency disagrees with the comments' implication that the courts' rulings
in American Pharmaceutical Association (APhA) v. Weinberger mean there is no
statutory authority to impose restrictions on distribution for accelerated
approval drugs. The situation considered in that case is readily distinguishable
from the situation addressed in §§ 314.520 and 601.42 of the accelerated
approval regulations. The APhA case concerned a regulation that withdrew
approval of NDA's for methadone, but permitted distribution to certain
maintenance treatment programs and certain hospital and community pharmacies.
Because methadone is a controlled substance within the provisions of the
Controlled Substances Act, which is implemented by the Drug Enforcement
Administration with the Justice Department, the district court concluded that
the question of permissible distribution of the drug was within the jurisdiction
of the Justice Department, not FDA. The Court of Appeals determined that the
type of misuse associated with methadone, i.e., misuse by persons who have no
intent to try to use drugs for medical purposes, differed from safety issues
contemplated for control under section 505 of the act. In contrast, the
restrictions contemplated under §§ 314.520 and 601.42 are precisely those deemed
necessary to ensure that section 505 criteria have been met, i.e., restrictions
to ensure that the drug will be safe under its approved conditions of use. It is
clearly FDA's responsibility to implement the statutory provisions regarding new
drug approval.
Nor does FDA agree that the provisions placing restrictions on distribution
to certain facilities or physicians, or conditioned on the performance of
certain medical procedures, impermissibly interfere with the practice of
medicine and pharmacy. There is no legal support for the theory that FDA may
only approve sponsors' drugs without restriction because physicians or
pharmacists may wish to prescribe or dispense drugs in a certain way. The
restrictions under these provisions would be imposed on the sponsor only as
necessary for safe use under the extraordinary circumstances of the particular
drug and use. Without such restrictions, the drugs would not meet the statutory
criteria, could not be approved for distribution, and would not be available for
prescribing or dispensing. The agency, as a matter of longstanding policy, does
not wish to interfere with the appropriate practice of medicine or pharmacy. In
this instance, the agency believes that rather than interfering with physician
or pharmacy practice, the regulations permit, in exceptional cases, approval of
drugs with restrictions so that the drugs may be available for prescribing or
dispensing.
21. One comment asserted that postmarketing restrictions on distribution to
certain facilities or physicians with certain training or experience should be
limited to rare occasions in cases of extreme hazard to patient safety in which
toxicity of a particular drug may require it, but should not be applied because
of insufficient efficacy data. Some comments argued that safety issues in the
context of drug use should be addressed through patient management and effective
product labeling, not through restricted distribution. In support of this
argument, the comments cited the labeling of oncologic drugs, which provides
physicians with adequate warnings and recommendations for their use without
limiting distribution.
FDA agrees with these comments in part and intends to impose restrictions on
distribution or use under this rule only in those rare instances in which the
agency believes carefully worded labeling for a product granted accelerated
approval will not assure the product's safe use. As stated in the preamble to
the proposed rule (57 FR 13234 at 13237), FDA believes that the safe use of most
prescription drugs will continue to be assured through traditional patient
management by health professionals and through necessary safety warnings in the
drug's labeling.
22. Two comments asked who will determine if restricted distribution should
occur and what facilities or physicians with special training or experience will
participate. Several comments expressed concern that restricted distribution
and/or conditional use may not include all health care professionals who should
participate in safe and effective patient care. Two organizations representing
pharmacists asked that FDA develop functional and objective criteria that
clearly establish the activities of pharmacists, physicians, and others in the
care of patients receiving a drug under restricted distribution. The comments
asserted that any health care professional that met these criteria should be
allowed to participate in distribution of the drug and care of the patient. One
comment recommended that any postmarketing restrictions on distribution or use
of a drug approved under the accelerated approval process be developed by
appropriate FDA advisory committees or panels expanded to include physicians and
pharmacists with expertise in the therapeutic area being considered and in
relevant drug distribution systems. Where appointment of pharmacists to these
committees or panels is not feasible, the comment recommended that FDA use
pharmacists in a consultant capacity. Another comment argued that current
systems for drug distribution incorporate "checks and balances" such that
prescribers and pharmacists work together to assure safe use of a drug by a
patient. Two comments would oppose any restricted distribution system that
allows manufacturers exclusively to deliver prescription drugs directly to
patients. One comment asked whether FDA or the applicant would monitor the
criteria for restricted distribution sites or physicians.
The medical reviewing divisions within FDA's CDER and CBER will determine if
restricted distribution or use should be imposed. FDA will usually seek the
advice of outside expert consultants or advisory committees before making this
determination, and will, of course, consult with the applicant.
The agency does not agree that FDA should develop criteria that clearly
establish the activities of health care professionals in the care of patients
receiving a drug approved under this rule and for which restricted distribution
has been imposed. Any postmarketing restrictions required under this rule will
impose an obligation on the applicant to ensure that the drug or biological
product is distributed only to the specified facilities or physicians. FDA will
seek the advice of outside consultants with expertise in distribution systems or
advisory committees when necessary in determining the need for or type of
restricted distribution. The limitations on distribution or use imposed under
this rule, including specific distribution systems to be used and the
applicant's plan for monitoring compliance with the limitations, will have been
agreed to by the applicant at the time of approval. The burden is on the
applicant to ensure that the conditions of use under which the applicant's
product was approved are being followed. As appropriate, FDA may monitor the
sponsor's compliance with the specified terms of the approval and with the
sponsor's obligations.
23. One comment recommended that proposed § 314.520 be modified to include
therapeutic outcomes monitoring as a third example of a permissible
postmarketing restriction. The comment defined therapeutic outcomes monitoring
as the systematic and continual monitoring of the clinical and psychosocial
effects of drug therapy on a patient which achieves the objective of preventing
problems with drug therapy. Some comments argued that through therapeutic
outcomes monitoring, a physician, a pharmacist, and a patient can work together
to prevent problems with drug therapy by being constantly alert to signs of
trouble. One comment said that indicator data can be routinely reported to a
central collection point for utilization review by health care professionals,
followed by educational programs to further improve the efficacy of drug
therapy.
The postmarketing restrictions set forth in the proposal and in this final
rule are intended to enhance the safety of a drug whose risks would outweigh its
benefits in the absence of the restriction. Therapeutic outcomes monitoring does
not contribute to that enhancement, and would not be required under this rule.
24. Some comments asked that FDA clarify how products will move from
restrictive status to a regular prescription drug status. The comments asserted
that all conditions associated with accelerated approval should automatically
terminate following completion of confirmatory clinical trials; one comment
urged FDA to explicitly state this in the final rule. One comment asserted that
restrictions should automatically be removed 180 days after a supplemental
application containing the data from the postmarketing study has been filed if
FDA has not yet acted upon the supplemental application and the product should
be deemed approved as if by "traditional" procedures and all other provisions of
the act should apply, e.g., the applicant must have a formal hearing before
removal of the product from the market.
FDA will notify the applicant when a particular restriction is no longer
necessary for safe use of the product. In the case of drugs approved with a
requirement for postapproval studies, FDA would expect that all of the
postapproval requirements set forth in this rule, i.e., submission of
promotional material and use of expedited withdrawal procedures, would no longer
apply after postmarketing studies have verified and described the drug's
clinical benefit. Concurrent with the review of the postmarketing studies, if
requested, FDA will also review the need to continue any restrictions on
distribution that have been imposed. In the case where restrictions on
distribution or use have been imposed, such restrictions would be eliminated
only if FDA determines that safe use of the product can be assured without them,
through appropriate labeling. In some cases, however, that assurance could not
be expected and the nature of the specific safety issue raised by the product
might require continued restrictions. FDA has added new §§ 314.560 and 601.46 to
state when postapproval requirements will no longer apply and state that the
applicant may petition the agency, in accordance with 21 CFR 10.30, at any time
to remove specific postapproval requirements.
With respect to the suggested time period for removing restrictions on
distribution or use following submission of a supplemental application
containing the data from a postmarketing study, FDA does not believe it should
prescribe any specific time period. These applications will receive a priority
rating and FDA is firmly committed to expedited review of an application
considered for accelerated approval and all data submitted from a postmarketing
study to verify clinical benefit and believes most reviews will be completed and
action taken within 180 days.
25. One comment argued that, as proposed, it is not clear how accelerated
approval would apply to drugs which fall under the conditions described in §§
314.520 and 601.42, which state the postmarketing restrictions on distribution
or use that FDA may apply, because the language of these sections explicitly
states that the sections apply to products "shown to be effective," which are
already adequately covered by the act. To the comment, the language "shown to be
effective" implies that full Phase 3 efficacy trials have been conducted,
assessed, and deemed to demonstrate that the drug is effective for its proposed
use. If the clinical data demonstrate that the product has an acceptable safety
profile, the safe use of the drug should be addressed in the product labeling.
Thus, the comment argued that §§ 314.520 and 601.42 should not be included in
new subpart H of part 314 and subpart E of part 601, respectively, which deal
with accelerated approval because these sections explicitly apply to products
shown to be effective under a full drug development program.
Sections 314.520 and 601.42 apply not only to drugs and biological products
approved on the basis of an effect on a surrogate endpoint but also to drugs and
biological products that have been studied for their safety and effectiveness in
treating serious or life-threatening illnesses using clinical endpoints and that
have serious toxicity. In either case, if the products are so potentially
harmful that their safe use cannot be assured through carefully worded labeling,
FDA will approve the products for early marketing only if postmarketing
restrictions on distribution or use are imposed. The phrase "shown to be
effective" was not intended to distinguish drugs approved under new subpart H
from drugs approved under any other subpart of the regulations. All drugs
approved will have had effectiveness demonstrated on the basis of adequate and
well-controlled studies, whether the endpoint of the studies is a surrogate
endpoint or a clinical endpoint.
26. One comment expressed concern that the proposed restricted distribution
or use provisions would restrict or eliminate the wholesale distribution of
drugs approved through the accelerated approval process.
The limitations on distribution or use required under this rule are imposed
on the applicant. Therefore, the burden is on the applicant to ensure that the
conditions of use under which the applicant's product was approved are being
followed. This rule does not specify how a manufacturer will distribute its
product to those receiving the product under the approval terms. FDA will only
determine which facilities or physicians may receive the drug, and the applicant
will have agreed to this limitation on distribution or use.
27. One comment expressed concern that the proposed postmarketing restriction
provision does not preclude a physician to whom restricted distribution applies
from prescribing drugs approved under the accelerated approval process for
unapproved (off-label) uses.
The comment is correct that this rule does not itself prevent a physician
from prescribing a drug granted accelerated approval for an unapproved use.
Under the act, a drug approved for marketing may be labeled, promoted, and
advertised by the manufacturer only for those uses for which the drug's safety
and effectiveness have been established and that FDA has approved. Physicians
may choose to prescribe the drug for a condition not recommended in labeling.
Such off-label use would, of course, be carried out under the restrictions
imposed under this section. FDA also believes that physicians will be cognizant
of the product's special risks and will use such drugs with particular care. The
labeling of products approved under this rule will include all necessary
warnings and full disclosure labeling would generally reflect the extent of
clinical exposure to the drug.
F. Postmarketing Studies
28. Three comments argued that FDA does not have the authority to require
postmarketing studies to be performed as a condition of approval based on a
"surrogate" endpoint. One comment stated that it is widely accepted that the act
empowered the agency to define the type and extent of efficacy data necessary to
approve a product application. If a surrogate marker can be shown to be
sufficiently related to actual patient benefit, then, the comment asserted, data
regarding the effect of a drug on a surrogate marker constitute acceptable proof
of efficacy under the act. Two comments urged FDA to continue to ask applicants
to agree voluntarily to perform postmarketing studies when medically warranted
as is the current policy under the traditional approval process. One comment
expressed concern that requiring postmarketing studies may become the norm
rather than the exception.
The agency's response to comment 1. explained the circumstances in which FDA
might conclude that a drug should be marketed on the basis of an effect on a
surrogate endpoint reasonably likely to predict clinical benefit only if studies
were carried out to confirm the presence of the likely benefit. As discussed in
the preamble to the proposed rule (57 FR 13234 at 13236), FDA believes that it
is authorized by law to require postmarketing studies for new drugs and
biological products. Section 505(d) of the act provides for the approval of new
drugs for marketing if they meet the safety and effectiveness criteria set forth
in section 505(d) of the act and the implementing regulations (21 CFR part 314).
As discussed in the proposed rule, to demonstrate effectiveness, the law
requires evidence from adequate and well-controlled clinical studies on the
basis of which qualified experts could fairly and responsibly conclude that the
drug has the effect it is purported to have. Under section 505(e) of the act,
approval of a new drug application is to be withdrawn if new information shows
that the drug has not been demonstrated to be either safe or effective. Approval
may also be withdrawn if new information shows that the drug's labeling is false
or misleading.
Section 505(k) of the act authorizes the agency to promulgate regulations
requiring applicants to make records and reports of data or other information
that are necessary to enable the agency to determine whether there is reason to
withdraw approval of an NDA. The agency believes that the referenced reports can
include additional studies to evaluate the clinical effect of a drug approved on
the basis of an effect on a surrogate endpoint. Section 701(a) of the act
generally authorizes FDA to issue regulations for the "efficient enforcement" of
the act.
With respect to biological products, section 351 of the PHS Act provides
legal authority for the agency to require postmarketing studies for these
products. Licenses for biological products are to be issued only upon a showing
that they meet standards "designed to insure the continued safety, purity, and
potency of such products" prescribed in regulations (42 U.S.C. 262(d)). The
"potency" of a biological product includes its effectiveness (21 CFR 600.3(s)).
The agency notes that it has in the past required postmarketing studies as a
prerequisite for approval for some drugs (see 37 FR 201, January 7, 1972; and 37
FR 26790, December 15, 1972).
29. One comment recommended that FDA require that specific timelines for
completion of the required postmarketing studies be included in the marketing
application. The comment further suggested that, if the sponsor fails to meet
its timelines, approval of its application be withdrawn, or in the event it is
difficult to withdraw approval of drugs for serious or life-threatening
diseases, FDA should establish substantial fines and penalties for sponsors that
deliberately withhold information from FDA regarding the preliminary results and
the progress of their postmarketing studies, or delay the completion of such
studies. The comment also urged FDA to publish in the Federal Register
identification of manufacturers who are not meeting their obligation to complete
the required postmarketing studies on time. These recommendations were prompted
by the comment's concern that once a manufacturer is granted approval for its
product, the manufacturer will have little incentive to complete postmarketing
studies in a timely manner, especially if the preliminary results of such
studies indicate that the drug may not be safe and/or effective. Another comment
urged FDA to include in the final rule language that requires the participation
of pharmacists in postmarketing studies because pharmacists can serve as an
additional source of information on therapeutic outcomes of patients taking
drugs approved under this rule and monitoring for such drugs.
The agency expects that the requirement for postmarketing studies will
usually be met by studies already underway at the time of approval and that
there will be reasonable enthusiasm for resolving the questions posed by those
studies. The plan for timely completion of the required postmarketing studies
will be included in the applicant's marketing application. In addition, in
accord with the annual reporting requirements at § 314.81(b)(2)(vii) (21 CFR
314.81(b)(2)(vii), an NDA applicant is required to provide FDA with a statement
of the current status of any postmarketing studies. FDA declines to impose the
sanctions suggested by the comment for failure of an applicant to meet its plans
for completion of a postmarketing study. FDA believes this rule applies
appropriate regulatory sanctions. Under the proposed rule and this final rule,
FDA may withdraw approval of an application if the applicant fails to perform
the required postmarketing study with due diligence.
FDA believes that it is not within the scope of this rule to establish the
role of pharmacists in postmarketing studies. That role should more properly be
defined by the clinical investigator and each institution or facility at which a
postmarketing study is conducted.
30. One comment asserted that the proposal sets forth an inherent
contradiction between the way FDA evaluates the benefit and risk for drugs today
and the way the proposal contemplates. The comment argued that now, if
postmarketing data raise questions about the risk associated with a drug
product, FDA considers that data along with the other data known about the
product, and determines whether, based on the overall knowledge about the drug,
there is a need to seek withdrawal of approval. Under this proposal, if the
postmarketing study data raised questions about the risk of the product, FDA
would seek withdrawal of approval, whether or not the new data really made a
fundamental difference to what is known about the benefit and risk of the
product.
FDA does not agree that the contradiction described by the comment exists.
Under the circumstances of accelerated approval, approval would be based on a
weighing of the benefit suggested by the effect on the surrogate endpoint
against known and potential risks of the drug. Should well-designed postapproval
studies fail to demonstrate the expected clinical benefit, the benefit expected
at the time of approval (reasonably likely to exist) would no longer be expected
and the totality of the data, showing no clinical benefit, would no longer
support approval. This evaluation of the data is not different from
considerations that would apply in evaluating data in the case of a drug
approved under other provisions of the regulations.
31. Two comments expressed the view that the proposed requirement for
postmarketing studies may raise important ethical questions because once a drug
product is approved, it may be unethical, depending on the circumstances, for a
physician to conduct a study using a placebo control. One comment also contended
that a postmarketing study requirement could compromise the NDA holder's ability
to enroll sufficient numbers of patients in the study when the new approved drug
and possible alternative therapies are widely available to patients.
Usually, and preferably, because of problems suggested in the comment, the
requirement for postmarketing studies will be met by studies already underway at
the time of approval, e.g., by completion of studies that showed an effect on
the surrogate. FDA recognizes that ethical considerations will play a central
role in the type of study carried out, a choice that will depend upon the type
and seriousness of the disease being treated, availability of alternative
therapies, and the nature of the drug and the patient population. There often
are alternatives to use of a placebo control, including active control designs
and dose-response studies that can satisfy both the demands of ethics and
adequacy of design.
32. One comment contended that the term "postmarketing study" is used
inconsistently in the proposed rule. The comment argued that "postmarketing
study" is an accepted regulatory term of art which, to this point, has referred
to studies conducted to confirm safety (not efficacy), after an approval has
been granted, whereas in this proposal, a "postmarketing study" refers to a
study required to establish clinical efficacy (i.e., a Phase 3 study), but not
necessarily safety, although safety data will be collected. To prevent confusion
and to differentiate between these required postmarketing confirmatory efficacy
studies and safety studies traditionally conducted after approval and to clarify
that products granted accelerated approval have been approved on the basis of
Phase 2 (surrogate endpoint) data, the comment suggested changing the term
"postmarketing study" to "Phase 3 study" in this rule except where traditional
postmarketing studies are intended. The comment also suggested that the term
"Phase 3 study" be defined as a study required to confirm findings of efficacy
based upon surrogate data collected in Phase 2, which will be conducted after an
accelerated approval has been granted and will be required before restrictions
set forth in § 314.520 are removed.
The agency does not believe that the comment has accurately described
accepted meanings of various terms. The term postmarketing study does not refer
to any particular kind of study, but to studies carried out after a drug is
marketed, often as part of an agreement by a sponsor to do so. These have
included pharmacokinetic, drug-drug interaction, and pediatric studies, studies
of dose-response or of higher doses, and studies of new uses. The term is not
limited to safety studies. Moreover, Phase 2 and 3 studies are not distinguished
by the endpoints chosen. Phase 3 hypertension studies, for example, still
measure blood pressure, not stroke rate. The agency believes that the use of the
"postmarketing study" in the final rule is appropriate and consistent.
G. Withdrawal of Approval
33. One comment supported the proposed withdrawal of approval procedure.
Other comments asserted that the proposed procedure does not provide the
applicant with the procedural safeguard of a formal evidentiary hearing
guaranteed by section 505 of the act and the Administrative Procedure Act (APA).
As an example, the comments said that based on a finding of a single study
failing to show clinical benefit or misuse of any promotional material, an
approved new drug would be subject to withdrawal from the market with only a
minimal opportunity for the NDA holder to be heard. The comments argued that
section 505(e) of the act guarantees applicants "due notice and opportunity for
a hearing" on withdrawal of an NDA in compliance with APA hearing standards,
thus FDA must conduct hearings on withdrawals of NDA's using the formal
adjudicatory procedures of the APA. One comment asserted that, under the
proposed procedure, there is the absence of a discernible legal standard, an
inability to cross-examine, the prosecuting attorney and judge are one and the
same person, and there is a lack of even minimal formal evidentiary procedures.
The comment expressed doubt that the proposed procedure would be sufficient to
create a record suitable for review by a Court of Appeals, which must be able,
on the basis of such a record, to determine whether the approval is supported by
"substantial evidence."
FDA believes the withdrawal procedures set forth in proposed §§ 314.530 and
601.43 and in this final rule are consistent with relevant statutes and provide
applicants adequate due process. As stated in the proposed rule, in issuing its
general procedural regulations, FDA decided to afford NDA holders an opportunity
for a formal evidentiary hearing even though the courts had not decided that
such a hearing was necessarily legally required (see 40 FR 40682 at 40691,
September 3, 1975). In promulgating its procedural regulations, FDA also
determined that a formal evidentiary hearing is not required before withdrawing
approval of biological products, but that it would be appropriate to apply the
same procedures to biological products as to drug removal (see 40 FR 40682 at
40691).
Through the hearing process in this final rule, as in the proposed rule,
applicants will be afforded the opportunity to present any data and information
they believe to be relevant to the continued marketing of their product. The
proposed process also would have permitted the presiding officer, the advisory
committee members, a representative of the applicant, and a representative of
the Center that initiates the withdrawal proceedings to question any person
during or at the conclusion of the person's presentation. As discussed below in
response to a comment, FDA has decided to allow up to three representatives of
the applicant and of the Center to question presenters. Participants could
comment on or rebut information and views presented by others. As with ordinary
21 CFR part 15 hearings, the hearing will be transcribed. Subsequent to the
hearing, the Commissioner of Food and Drugs would render a final decision on the
matter. The agency believes that the administrative record created through this
process would be sufficient for judicial review.
The agency emphasizes that, as part of the approval process under this rule,
applicants will have agreed that these withdrawal procedures apply to the drug
for which they seek approval; applicants objecting to these procedures may
forego approval under these regulations and seek approval under the traditional
approval process. Under such circumstances, applicants would not have the
benefit of accelerated approval; if the drug were subsequently approved,
however, before withdrawal of the approval, the applicant would have an
opportunity for a 21 CFR part 12 hearing.
34. One comment noted that the "imminent hazard" provision of section 505(e)
of the act allows FDA to suspend approval of a product, immediately, if it is
found to pose an imminent hazard to the public health. As an alternative to the
proposed withdrawal procedure or in addition to the "imminent hazard" statutory
provision, the comment suggested that, when confronted with a dangerous product
on the market, FDA could request that the applicant voluntarily withdraw its
product, and most applicants would comply if a legitimate hazard exists.
As noted in the proposed rule, FDA and applicants have often reached mutual
agreement on the need to remove a drug from the market rapidly when significant
safety problems have been discovered. However, applicants usually have been
unwilling to enter into such agreements when doubts about effectiveness have
arisen, such as following the review of effectiveness of pre-1962 approvals
carried out under the Drug Efficacy Study Implementation (DESI) program. For
drugs approved under the accelerated procedure regulations, the risk/benefit
assessment is dependent upon the likelihood that the surrogate endpoint will
correlate with clinical benefit or that postmarketing restrictions will enable
safe use. If the effect on the surrogate does not translate into a clinical
benefit, or if restrictions do not lead to safe use, the risk/benefit assessment
for these drugs changes significantly. FDA believes that if that occurs, rapid
withdrawal of approval as set forth in this rule is important to the public
health.
35. Under the proposed withdrawal procedures, in addition to other persons,
one representative of the Center that initiates the withdrawal proceedings may
question participants at a withdrawal of approval hearing. One comment objected
to limiting the Center to one representative because detailed knowledge about a
drug product is likely to be available from several scientists.
The proposed limitation of questioning to single representatives of the
initiating Center and the applicant was intended to make the proceedings
manageable. On further consideration, the agency has determined that it would be
appropriate and manageable to allow up to three persons to be designated as
questioners for the applicant and for FDA. Sections 314.530(e)(2) and
601.43(e)(2) have been revised accordingly.
36. Some comments questioned FDA's ability to withdraw approval under the
proposed procedures efficiently or effectively because of: (1) The lack of
assurance that the results of postmarketing studies will be promptly provided to
FDA; (2) limited agency resources to review study results and act upon them
promptly; (3) the difficulties associated with establishing that an approved
drug is "ineffective;" and (4) political pressure not to rescind the approval of
NDA's for drug products that may lack evidence of effectiveness, especially if
no clearly effective alternative treatments are available. One comment offered
the opinion that where a drug shows only modest evidence of benefit, perhaps on
a surrogate endpoint, and only shows equivocal evidence of clinical efficacy in
postmarketing studies it would be difficult and socially disruptive to withdraw
approval and remove the drug from the market if the drug has become well
established and accepted, and there is no issue of toxicity. Another comment
believed it would be difficult to withdraw approval of a drug that may be
beneficial in a subpopulation but which, in fact, has not been shown to be
efficacious in broader patient population studies. The comments suggested the
need for a lesser sanction.
Another comment suggested that expediting removal of a product from the
market could be accomplished by using a procedure like the "imminent hazard"
provision of the act, i.e., immediate removal of the drug from the market if any
of the conditions listed in proposed § 314.530 were met followed by a hearing.
Although the potential difficulties cited by the comments are real, they are
not fundamentally different from determinations FDA regularly must make in
carrying out its responsibilities. The new regulations provide for an expedited
procedure to withdraw approval; they do not guarantee that results of studies
will be wholly unambiguous or that FDA will always be able to prevail in its
view as to the need for withdrawal, any more than current withdrawal procedures
do. The studies being carried out under these provisions will be conspicuous and
important and their completion will be widely known. There is no reason to
believe their results would or could be long hidden. A study that fails to show
clinical effectiveness does not prove a drug has no clinical effect but it is a
study that, under § 314.530, will lead to a withdrawal procedure because it has
failed to show that the surrogate endpoint on which approval was based can be
correlated with a favorable clinical effect. This may have occurred because the
study was poorly designed or conducted; while FDA will make every effort to
avoid this, the commercial sponsor has the responsibility for providing the
needed evidence confirming clinical benefit. As previously discussed, §§ 314.510
and 601.41 have been revised to clarify that required postmarketing studies must
also be adequate and well-controlled. The possibility that an ineffective drug
has become "accepted" is not a basis for continued marketing. FDA intends to
implement the provisions of § 314.530 as appropriate; data that are ambiguous
will inevitably lead to difficult judgments.
A drug with clear clinical effectiveness in a subset of the population, but
not in the population described in labeling, would have its labeling revised to
reflect the data. Withdrawal would be inappropriate under such circumstances.
If an imminent hazard to the public health exists, the Secretary of Health
and Human Services may suspend approval of an application and then afford the
applicant an opportunity for an expedited hearing. In the absence of a
significant hazard requiring immediate withdrawal, FDA believes the expedited
procedure described in the rule satisfies the need for prompt action while, at
the same time, allowing opportunity for discussion and debate before withdrawal.
37. One comment noted that the proposed rule would allow FDA to withdraw
approval for failure to perform the required postmarketing studies with due
diligence. The comment asserted that the act does not permit FDA to withdraw
approval on this ground. Another comment, however, suggested that because
proposed §§ 314.530 and 601.43 cite grounds for withdrawal of approval that are
not grounds under the act, the language of these proposed sections should be
revised to use language that closer aligns to that used in the act, e.g.,
describe a "postmarketing study" in statutory language.
FDA reaffirms the position expressed in the preamble to the proposal (57 FR
13234 at 13239) that there is adequate authority under the act to withdraw
approval of an application for the reasons stated under proposed §§ 314.530 and
601.43, which include failure of an applicant to perform the required
postmarketing study with due diligence. Section 505(e) of the act authorizes the
agency to withdraw approval of an NDA if new information shows that the drug has
not been demonstrated to be either safe or effective. Approval may also be
withdrawn if the applicant has failed to maintain required records or make
required reports. In addition, approval may be withdrawn if new information,
along with the information considered when the application was approved, shows
the labeling to be false or misleading.
For biological products, section 351(d) of the PHS Act authorizes approval of
license applications under standards designed to ensure continued safety,
purity, and potency. "Potency" for biological products includes effectiveness
(21 CFR 600.3(s)). The PHS Act does not specify license revocation procedures,
except to state that licenses may be suspended and revoked "as prescribed by
regulations."
For drugs approved under § 314.510, FDA will have determined that reports of
postmarketing studies are critical to the risk/benefit balance needed for
approval; if those reports are not forthcoming, then, under authority of section
505(d) of the act, the drug cannot on an ongoing basis meet the standards of
safety and efficacy required for marketing under the act. Therefore, it is
important to ensure that the applicant make a good faith effort to complete any
required postmarketing studies in a timely manner so that FDA can rapidly
determine whether the surrogate endpoint upon which the drug was approved has
been confirmed to correlate with clinical benefit. Failure to submit the study
results in a timely fashion would also constitute failure to make a required
report. Similarly, without submission of the information from required
postmarketing studies on biological products approved under these procedures,
the biological product is not assured of continued safety and effectiveness.
The license application may, therefore, appropriately be revoked as described in
§ 601.43.
FDA does not find the statements of the grounds for withdrawal of approval
under §§ 314.530 and 601.43 of this rule inconsistent with statutory language or
ambiguous. The agency notes that, in the event none of the grounds for
withdrawal specifically listed in § 314.530 or § 601.43 applies, but another
ground for withdrawal under section 505 of the act or section 351 of the PHS Act
and implementing regulations at 21 CFR 314.150 or 601.5 does apply, the agency
will proceed to withdraw approval under traditional procedures.
38. Two comments expressed concern that it may be difficult for the agency to
enforce the requirement that postmarketing studies be pursued with due
diligence. The comments asked what would happen if a sponsor using due diligence
is unable to recruit enough patients, or if the sponsor questions the validity
of the data from the required postmarketing study, and would clumsy data
management be seen as sufficient reason to rescind approval for a marketed drug?
Another comment stated that once a product is approved and, by definition,
provides a "meaningful therapeutic benefit over existing therapies," study
accrual may drop off dramatically as patients may refuse to receive the "old"
therapy or placebo, or physicians may consider it unethical not to treat all
patients with the approved indication with the new drug or biological product.
Under these circumstances, the comment expressed the opinion that neither the
sponsor nor the product should be penalized, nor should there be a threat to
withdraw approval. Based on FDA's past history in postmarketing studies, which
one comment characterized as resulting in poorly done studies, studies conducted
much later than agreed upon, or not at all, the comment expressed the opinion
that the "due diligence" with which applicants are expected to carry out
postmarketing studies may be an overly great expectation. One comment asked FDA
to give examples of when it may withdraw approval if "other evidence
demonstrates that the drug product is not shown to be safe or effective under
its conditions of use" (proposed §§ 314.530(a)(6) and 601.43(a)(6)).
FDA does not agree that it will be difficult to enforce the "due diligence"
provision of this rule. The "due diligence" provision was designed to ensure
that the applicant makes a good faith effort to conduct a required postmarketing
study in a timely manner to confirm the predictive value of the surrogate marker
or other indicator. Any requirement for postmarketing studies will have been
agreed to by the applicant at the time of approval, and if the study is not
conducted in a timely manner as agreed to by the applicant, approval of the
applicant's application will be withdrawn. FDA will expect any required
postmarketing study to be conducted in consultation with the agency. Therefore,
should the applicant encounter problems with subject enrollment in a study or
ethical difficulties about the type of study to conduct, FDA expects the
applicant to discuss these problems with the agency and reach agreement on their
resolution.
Examples of other evidence demonstrating the drug product is not shown to be
safe and effective could include further studies of the effect of the drug and
the surrogate endpoint that fail to show the effect seen in previous studies,
new evidence casting doubt on the validity of the surrogate endpoint as a
predictor of clinical benefit, or new evidence of significant toxicity.
39. Some comments objected to withdrawal of approval of a drug product
approved under the accelerated approval process because of perceived misconduct
by the applicant, such as failure to perform a required postmarketing study with
due diligence or use of promotional materials that are false or misleading. The
comments argued that the primary purpose of the accelerated approval process is
to provide improved treatments to desperately ill patients at the earliest
possible time, and withdrawal of approval of the new treatments for reasons not
directly related to safety or efficacy undermines the purpose of the proposed
rule. Two comments suggested that correction of the promotional material without
interruption of access to the drug would be a better approach. Another comment
suggested that there may be circumstances where continued access to the drug, if
accompanied by informed consent, would be appropriate even if substantial
questions arise about a product's safety and effectiveness. One comment urged
that anticipated withdrawal of approval be preceded by measures to ensure that
patients and their physicians will have an uninterrupted supply until
alternative treatment arrangements can be made.
The need for "due diligence" in conducting the agreed to postmarketing
studies is discussed in paragraph 37. The reasons for concern about misleading
promotional materials are discussed under paragraph 16. With respect to
promotional materials, FDA expects that, in most cases, any disagreements
between the applicant and FDA will be resolved through discussion and
modification of the materials, so that the drug or biological product can
continue to be marketed. If, however, FDA concludes that the promotional
materials adversely affect the risk/benefit conclusion supporting the drug's
marketing, the agency intends to minimize the risk to the public health by
removing the product from the market through the withdrawal procedures in this
rule.
40. One comment expressed concern that the proposed withdrawal procedure may
give the appearance of bias or preconceived notions on the part of the agency
because the final decision to withdraw approval of a drug would be made by the
Commissioner of Food and Drugs and the intention to withdraw approval of the
drug will already have been determined by the agency.
Under the withdrawal provisions of this rule, FDA's CDER or CBER, rather than
the Commissioner, will initiate the withdrawal proceedings. The withdrawal
process will begin with a letter from CDER or CBER notifying the applicant that
the Center proposes to withdraw marketing approval and stating the reasons for
the proposed action. Although separation of functions will not apply under the
provisions of §§ 314.530 or 601.43, the Commissioner's decision regarding
withdrawal would not occur until after the applicant had an opportunity for
hearing as described in those sections. The Commissioner would then expect to
review the issues with objectivity and fairness having had the benefit of the
presentations and discussions at the hearing and of the advisory committee's
recommendations.
H. Safeguards for Patient Safety
41. One comment asked if drugs approved under the accelerated approval
process will be held to the same standards concerning postmarketing safety as
drugs approved by the traditional process.
As discussed in the preamble to the proposed rule, applicants gaining
approval for new drugs through the accelerated approval procedures will also be
expected to adhere to the agency's longstanding requirements for postmarketing
recordkeeping and safety reporting (see 21 CFR 314.80 and 314.81). Information
that comes to FDA from the applicant or elsewhere that raises potential safety
concerns will be evaluated in the same manner that such information is evaluated
for drugs approved under the agency's traditional procedures. If the
postmarketing information shows that the risk/benefit assessment is no longer
favorable, the agency will act accordingly to remove the drug from the market.
42. One comment urged FDA, if the proposed rule were adopted, to require
written informed consent so that patients would know that the drugs with which
they were being treated had risks and that the benefits had not been adequately
established.
The agency does not agree that patients using drug products approved under
the accelerated approval regulations should be asked to provide written informed
consent. Drugs approved under these provisions are not considered experimental
drugs for their approved uses. Like all approved drugs, drugs approved under
these provisions will have both risks and benefits. As previously discussed in
this preamble, for drugs approved based on studies showing an effect on a
surrogate endpoint, the approved labeling will describe that effect. In
addition, the labeling will contain information on known and potential safety
hazards and precautionary information. As with all prescription drugs, the
physician has the responsibility for appropriately advising the patient
regarding the drug being prescribed.
43. One comment asked that FDA require manufacturers to maintain an updated
list of names, addresses, and phone numbers of physicians prescribing their
products approved under this rule, and in the case of recall or withdrawal of
approval, require manufacturers to contact these physicians and encourage them
to notify their patients.
FDA does not believe such a procedure is necessary. Furthermore, maintaining
such a registry for drugs prescribed through pharmacies would be very difficult.
Agency experience with recalls and product withdrawals indicates that the
methods of notification that have been developed for such circumstances are
adequate.
44. One comment recommended that FDA require patient package inserts (PPI's)
for all drugs granted accelerated approval that would state the specific
restrictions placed on a drug product and/or the reason for requiring
postmarketing studies. In addition, the comment recommended that FDA require the
manufacturer to include an adverse drug reaction "hotline" phone number in the
PPI along with an FDA phone number. The PPI should inform the patient to report
immediately any adverse drug reaction experienced to his or her doctor, the
manufacturer, and FDA, and the manufacturer should be required to contact FDA
immediately after receiving a report of a serious adverse reaction.
FDA concludes that patient package inserts are not routinely needed for drugs
granted accelerated approval, although if circumstances made one appropriate,
one would be developed for a particular drug. As with any prescription drug, the
approved labeling for a product granted accelerated approval will contain
information about the safe and effective use of the product, including all
necessary warnings and the extent of clinical exposure. In addition, the
conditions of use will be carefully worded to reflect the nature of the data
supporting the product's approval. Physicians have the responsibility to inform
patients about the safe and effective use of an approved product. Labeling
includes suggestions to the physician concerning information to be provided to
patients.
The agency notes that in this final rule limited editorial changes have been
made to the wording of the proposed rule. The agency has determined that these
changes do not affect the intent of the proposed rule.
V. Economic Impact
In accordance with Executive Order 12291, FDA has carefully analyzed the
economic effects of this final rule and has determined that it is not a major
rule as defined by the Order. Indeed, because firms will not be forced to use
the accelerated approval mechanism, applicants will most probably choose to take
advantage of the program only where its use is expected to reduce net costs,
Similarly, the final rule does not impose a significant economic impact on a
substantial number of small entities so as to require a regulatory flexibility
analysis under the requirements of the Regulatory Flexibility Act of 1980.
VI. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action is of a
type that does not individually or cumulatively have a significant effect on the
human environment. Therefore, neither an environmental assessment nor an
environmental impact statement is required.
VII. Paperwork Reduction Act of 1980
This rule does not contain new collection of information requirements.
Section 314.540 does refer to regulations that contain collection of information
requirements that were previously submitted for review to the Director of the
Office of Management and Budget (OMB) under section 3504 of the Paperwork
Reduction Act of 1980 (Adverse Drug Experience Reporting, OMB No. 0190-0230).
List of Subjects
21 CFR Part 314
Administrative practice and procedure, Confidential business information,
Drugs, Reporting and recordkeeping requirements.
21 CFR Part 601
Biologics, Confidential business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public Health
Service Act, and under authority delegated to the Commissioner of Food and
Drugs, 21 CFR parts 314 and 601 are amended as follows:
PART 314 -- APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
1. The authority citation for 21 CFR part 314 continues to read as follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 706 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355,
356, 357, 371, 376).
2. Subpart H consisting of §§ 314.500 through 314.560 is added to read as
follows:
Subpart H -- Accelerated Approval of New Drugs for Serious or Life-
Threatening Illnesses
Sec.
314.500 Scope.
314.510 Approval based on a surrogate endpoint or on an effect on a clinical
endpoint other than survival or irreversible morbidity.
314.520 Approval with restrictions to assure safe use.
314.530 Withdrawal procedures.
314.540 Postmarketing safety reporting.
314.550 Promotional materials.
314.560 Termination of requirements
Subpart H -- Accelerated Approval of New Drugs for Serious or Life-
Threatening Illnesses
§ 314.500 Scope.
This subpart applies to certain new drug and antibiotic products that have
been studied for their safety and effectiveness in treating serious or life-
threatening illnesses and that provide meaningful therapeutic benefit to
patients over existing treatments (e.g., ability to treat patients unresponsive
to, or intolerant of, available therapy, or improved patient response over
available therapy).
§ 314.510 Approval based on a surrogate endpoint or on an effect on a
clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a new drug product on the basis of
adequate and well-controlled clinical trials establishing that the drug product
has an effect on a surrogate endpoint that is reasonably likely, based on
epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict
clinical benefit or on the basis of an effect on a clinical endpoint other than
survival or irreversible morbidity. Approval under this section will be subject
to the requirement that the applicant study the drug further, to verify and
describe its clinical benefit, where there is uncertainty as to the relation of
the surrogate endpoint to clinical benefit, or of the observed clinical benefit
to ultimate outcome. Postmarketing studies would usually be studies already
underway. When required to be conducted, such studies must also be adequate and
well-controlled. The applicant shall carry out any such studies with due
diligence.
§ 314.520 Approval with restrictions to assure safe use.
(a) If FDA