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This
document was downloaded and archived from http://www.seas.upenn.edu:8080/~kfoster/reinvent.htm
on June 12, 2001. |
OVERVIEW
"Today, Americans don't have to worry about safety or
effectiveness when they buy [drugs and medical devices]--
from cough syrups to the latest antibiotics or pacemakers.
The Food and Drug Administration has made American
drugs and medical devices the envy of the world and in
demand all over the world. And we are going to stick with
the standards we have--the highest in the world. But strong
standards need not mean business as usual in every area."
President Clinton -- March 16, 1995
Introduction
Reforming the Federal government's regulatory processes, while
maintaining critical public health and safety standards, has been and
will continue to be a top priority for the Clinton Administration.
Consistent with this commitment, President Clinton and Vice
President Gore asked Health and Human Services Secretary Donna
Shalala to help them carefully examine the regulatory requirements
of the Food and Drug Administration (FDA).
As part of the Vice President's reinventing government initiative,
FDA has been reviewing its regulatory processes to determine which
requirements could be reduced or eliminated without lowering
health and safety standards. This report contains recommendations
resulting from the initial phase of the review of drug and medical
device regulation.
Background
FDA is the Agency within the Department of Health and Human
Services charged with ensuring that drugs, vaccines, and medical
devices are safe and effective and that foods meet basic safety
standards. In carrying out these and other responsibilities, FDA
annually oversees more than $1 trillion worth of products, which
account for 25 cents of every dollar spent by American consumers.
FDA was created in 1906 to protect Americans from unsafe foods and
drugs. In 1976, FDA's responsibilities were expanded to include
additional authority over medical devices. During this
Administration, FDA has taken significant initial steps to streamline
the regulatory process. These recent initiatives, building on earlier
reforms to ensure access for patients to new drugs and to accelerate
approval of treatments for life-threatening illnesses, have resulted in
new products being brought to market sooner; but more can be done.
A Record of Accomplishment
FDA's recent regulatory improvements include:
Shortening Review Times for New Drugs and Devices
1) FDA now uses expert review panels to expedite the review of
certain biotechnology products. (For example, a joint committee of
FDA experts oversaw the licensing in record time of the drug
interferon beta 1b to treat certain patients with multiple sclerosis.)
2) Under the Prescription Drug User Fee Act of 1992, drugs are
now reviewed more quickly. This law authorizes FDA to charge user
fees for drug applications, and to use these additional resources for
the reviews of new drugs, vaccines, and biotechnology products.
Already, review times for new chemical drugs have dropped from an
average of 30 months in 1992 to 20 months in 1994.(1) By 1997, FDA
will be getting these products to market in a year or less, as fast as
or faster than anywhere else in the world, with no sacrifice in review
quality.
3) Medical devices are benefiting from a number of new processes
that speed up their review; for example, devices that provide
significant medical advances are now given priority review.
4) Animal drugs are now reviewed in a more efficient manner,
resulting in a record number of 38 new drugs approved in 1994.
Eliminating Unnecessary Regulatory Burdens
1) FDA exempted 148 categories of low-risk medical devices from
premarket review in December 1994, relieving manufacturers from
submitting applications to the Agency and waiting for their approval.
2) FDA has helped to assure safe and high-quality mammography
by using existing private sector standards to certify mammography
facilities, which are mostly small businesses. Utilizing these
standards allowed FDA to implement the requirements of the 1992
law quickly and with minimum burden on accredited and certified
facilities.
3) FDA has begun a joint program with the Customs Service to
automate the entry of imported products into the United States. The
program allows an importer to notify FDA by computer of import
entries and receive prompt permission for the products to enter this
country.
4) FDA has issued a proposed regulation to permit regulated
companies to use electronic records and signatures in place of paper.
This will save industry substantial costs by simplifying record-
keeping and speeding the filing of applications and other regulatory
documents.
As noted in the President's State of the Union address and his recent
announcement highlighting some of the recommendations in this
report, the Administration is committed to promoting results and not
rules. The reforms this report advocates will reduce paperwork,
eliminate unnecessary regulation, and thus get products to market
more quickly. In so doing, they will strengthen the economy and
maintain the health and safety of Americans.
Principles for Reforming FDA Regulation in Carrying out this Review
In carrying out its regulatory review, the Agency carefully
considered the financial burdens that its requirements impose on
industry and consumers. It looked for ways to eliminate these
burdens so that its regulatory systems would not be a bar to bringing
beneficial new products to market. In reforming its procedures and
requirements, FDA followed these principles:
* Using performance standards, rather than command
and control regulations, whenever possible;
* Expediting product review without sacrificing the
health and safety of the public;
* Eliminating unnecessary requirements that may
have been appropriate once but are not now necessary to public
health; and
* Utilizing modern automated technology as a tool in
streamlining internal Agency management and as an aid to industry
in meeting its regulatory requirements.
Regulatory Reform Recommendations
FDA is proposing a number of reforms that reinvent how FDA
regulates. The reforms included in this report are estimated to save
the drug and device industries $500 million per year in unnecessary
regulatory costs. These reforms will also let FDA better target its
resources toward expediting market access of new products:
* Reducing or eliminating many of the FDA
requirements for companies to get approval for changes in their
manufacturing facilities or processes for manufacturing drugs,
biotechnology drugs, and other biologics;
* Allowing manufacturers of biological drugs to get
licenses for pilot facilities instead of making them build full-
scale plants. Manufacturers will still have to show they can meet
safety, purity, and potency standards;
* Permitting greater flexibility in the appearance of
distributors' names on biological product containers, package labels,
and labeling;
* Eliminating outdated requirements for insulin and
antibiotics and allowing a private standard-setting body to establish
testing and quality standards (thus eliminating nearly 700 pages of
Federal regulations);
* Excluding drug and biologic manufacturers from
requirements for most environmental assessments, which currently
cost tens of thousands of dollars each time a new product is
developed yet provide no real benefit to the environment;
* Exempting nearly 125 additional categories of low-risk
medical devices from premarket review;
* Eliminating the "Reference List" by clarifying that
market clearances of devices will not be withheld unless FDA finds a
reasonable relationship between the nature of current violations and
the application under review;
* Developing a pilot program for review of low-risk
medical devices by outside review organizations to determine if such
a system could be developed permanently;
* Speeding the marketing of medical devices by seeking
authority to charge industry user fees for device reviews, and
committing FDA to meet certain strict performance goals;
* Expanding opportunities to export drugs and
medical devices to industrialized countries;
* Issuing a public statement clarifying how FDA
determines the effectiveness of new drugs and devices and that
a single, multi-center study may support approval of a drug;
* Harmonizing FDA's drug and device testing
requirements with those of other countries, thus expediting
worldwide marketing of new products by reducing duplicative
testing;
* Expanding and standardizing the use of new
information technologies for reviewing new products and speeding
up import entries.
Additional proposals for reforming the regulation of drugs and
medical devices are being developed and will be announced later.
They will accompany recommendations related to the regulation of
foods and veterinary products.
FDA'S PROPOSALS FOR REFORM
DRUGS
New drugs must be approved by FDA prior to marketing. Under the
provisions of the Federal Food, Drug, and Cosmetic Act, they are
tested first in animals, then in humans, and the data are submitted to
FDA scientists for review via a New Drug Application. Biologics
include vaccines and blood products, and drugs made using
biotechnology. They are licensed under a different legal authority
from drugs, and are therefore subject to somewhat different
requirements. Before marketing a new biological product, the
sponsor must submit for FDA's approval a Product License
Application, which presents safety and efficacy data. The facility
making the product must submit an Establishment License
Application demonstrating that the product can be accurately and
safely manufactured.
Although full marketing of drugs must await FDA review and
approval, in recent years the Agency has established ways for
patients to gain early access to treatments for life-threatening
diseases.
FDA also approves such changes as substituting different ingredients
by reviewing a "supplement" to the original application for approval.
This section of the report describes reforms in the regulation of
biologics and drugs. The reforms include: permitting biologics
manufacturers to demonstrate their capability to make the product
without first building a full-scale production plant; changing biologics
labeling requirements to remove an impediment to flexible
manufacturing, packaging, and distribution arrangements; allowing
manufacturing changes for both drugs and biologics to be made with
less FDA prior approval; eliminating certain manufacturing
requirements concerning antibiotics and insulin; and eliminating
most environmental impact assessments for both biologics and drugs.
Drugs and Biologics: Eliminating Many Requirements
For FDA Approval of Manufacturing Changes
Background: FDA regulations governing drugs and biologics require
applicants to obtain FDA approval before implementing many
manufacturing changes for those products. To obtain approval,
manufacturers submit "supplemental" applications to FDA, of which
the Agency receives several thousand each year. These changes
range from the addition or subtraction of an ingredient, to the use of
a different production facility or different equipment within the
same facility, to changes in packaging. Manufacturers must often
wait six to twelve months to receive FDA approval, during which
time the manufacturers are prevented from making changes to the
product or production facility that they believe are more efficient or
otherwise necessary.
Proposal and Justification: FDA will reduce the number of
changes that require pre-approval. Described below are the
procedures for implementing this new policy for drugs and biologics.
DRUGS
FDA's Center for Drug Evaluation and Research (CDER), the Agency
component responsible for oversight of human drug products, is
developing a guidance document for drugs in tablet and capsule form
(other than those for controlled release). This document, designed to
ease pre-approval requirements for certain manufacturing changes,
would distinguish changes that are unlikely to have any detectable
impact on a drug product's quality and performance from those that
could have a significant impact. Examples of changes unlikely to have
an impact include the deletion of a color from a product or changes
from non-automated or non-mechanical equipment to automated or
mechanical equipment for moving ingredients. The proposed FDA
guidance would ease the pre-approval requirements for these and
other manufacturing changes when the proposed manufacturing
change does not affect the drug's quality or performance.
In all instances in which prior approval would no longer be required,
FDA would still receive notification of the manufacturing changes
from the drug manufacturer, either when the change takes effect or
through annual reports on the drug application.
BIOLOGICS
The Agency will create a reporting process tailored to the severity
and complexity of the change. Less stringent reporting requirements
will apply when the changes do not pose demonstrable effects on
product purity, potency, or safety -- or when changes are readily
amenable to on-site scrutiny during routine inspection of the
production facility. FDA will classify its oversight of manufacturing
changes for biologics as follows:
Category I: Changes where no supplement submission will be
required. The sponsor will generate and retain all relevant data
defining (and validating, if necessary) changes being made. The firm
may voluntarily notify the Agency of the changes and dates of
implementation.
Examples: Changes in the supplier of components (such as stoppers,
vials, seals) that meet established specifications; changes which
tighten existing specifications to provide greater assurance of
product purity and potency; relocation of equipment in appropriate
areas within approved facilities.
Category II: Changes for which the sponsor submits a standard
supplement; unless the Agency objects, the sponsor can automatically
implement the change in 30 days.
Examples: Expansion of existing manufacturing support systems
(such as heating, ventilation, and air conditioning); modification of an
approved manufacturing area which does not adversely affect safety,
purity, or potency of product (such as adding new interior partitions
or walls to increase control over the environment or replacing or
adding new surfaces to enhance cleaning); replacement of equipment
with that of similar but not identical design and operating principle
that does not change the manufacturing process.
Category III: Changes requiring Agency approval prior to
implementation.
Examples: Change in processing conditions (such as process time,
process temperature, or filtration process); change in dosage form
(such as a change from a liquid to a powder); extension of dating
period; use of a previously unapproved manufacturing area or
facility.
Impact: These changes will benefit industry by: (1) saving resources
that would have been spent on preparing supplemental applications;
(2) permitting changes to occur without waiting for prior FDA
approval; and (3) encouraging certain manufacturing improvements.
Under the new procedures, the manufacturing site changes described
above for drugs could be carried out--and the new site could begin
operating--in a matter of weeks, and with significant cost savings.
And the new policy will permit a drug manufacturer to change
automated equipment without prior FDA approval, an improvement
that will make newer facilities and equipment available to
manufacturers much more quickly. Similar changes for biologics
manufacturers will speed their ability to make changes in production
facilities or make other manufacturing improvements.
FDA will also benefit from these changes. The Agency estimates that
this reform will eliminate its current review of more than 800
supplemental applications for drugs and 500 for biologics annually(2).
Implementation and Timeline: For drugs, by the end of the year
FDA will issue guidance for most products sold in tablet form that
will describe how these requirements will be relaxed. By the end of
1996, FDA will develop a similar guidance document for other dosage
forms, including controlled release drugs, liquids, and semi-solids.
For biologics, FDA will immediately issue a guidance document to
implement the new three-category plan. The document will identify
the types of changes in manufacturing procedures and
establishments that may be carried out without prior approval. It
will clarify which changes will not require a supplement at all.
Within nine months, in a second step, FDA will propose amending its
regulations to further reduce the instances requiring its approval
before products may be marketed. Likewise, the Agency will review
its policy on lot release of some biologics (i.e., a procedure whereby
the Agency approves each batch of biologics prior to distribution), to
determine how those burdens can be minimized as well.
New Policy to Permit Use of Small-Scale and Pilot Facilities
During Development of Biologics
Background: Lack of clarity about establishment licensure
requirements has led some biologics manufacturers to make major
capital investments in full-scale manufacturing facilities before
initiating the large clinical trials necessary to demonstrate the safety
and efficacy of their products. Such investments can result in
significant financial losses if the product is not ultimately brought to
market.
Proposal and Justification: FDA will specifically state that
manufacturers may use pilot and small-scale facilities to
demonstrate safety and effectiveness and to support
approval. Under this reform, companies may immediately submit
applications for clinical studies or approval of products manufactured
in small-scale or pilot facilities.
Although the manufacture of biologics warrants a high degree of
quality control and regulatory oversight, FDA believes that licensure
of pilot and small-scale facilities provides industry with the
flexibility it needs without diminishing public health protection. As a
result, FDA will issue product and establishment licenses on the basis
of demonstrated safety, purity, and potency of the product
manufactured in the pilot or small-scale facility. Moving to a full-
scale facility will require only a supplement to the manufacturer's
product/establishment license applications.
Impact: Of 1,500 active and pending investigational new drug
applications (INDs) (the manufacturer's application to begin testing a
drug product in humans) for biologics, 100 to 500 current applicants
need to decide whether to construct new facilities. Under this reform,
a significant number of these companies may choose not to construct
a new full-scale manufacturing facility. Instead, they may decide to
use a pilot or small-scale facility, with potentially great cost savings.
It has been estimated to cost $25 million to construct a biologics
manufacturing facility, and about $15 million a year to operate it.
Implementation and Timeline: Companies may apply
immediately for licensure of small-scale and pilot facilities and their
applications will be considered. FDA will issue a guidance document
to clarify its policy on licensing small-scale and pilot facilities within
the next three months.
Revision of Labeling Requirements for Biological Products
Background: Companies that develop a product sometimes find it
advantageous to have their product manufactured by another
company. Many small start-up companies, such as many
biotechnology firms, prefer this option because they do not always
have the manufacturing capabilities necessary to produce
commercial quantities of a drug. However, FDA's current labeling
regulations are a disincentive to such arrangements: The
manufacturer's name must be displayed on the label more
prominently than that of the developer (which can be listed only as a
selling agent or distributor).
Proposal and Justification: FDA will allow the distributors'
and selling agents' names to be displayed prominently on
biological product containers, package labels, and labeling.
This change will provide the biological products industry with the
flexibility that it wants, and, at the same time, maintain current label
information on product manufacture and origin.
Impact: The change in labeling requirements will allow prominent
display of the name of the distributor or selling agent, thereby
removing an impediment to flexible manufacturing, packaging and
distribution arrangements.
Implementation and Timeline: FDA will publish a proposal to
revise its biologics labeling regulations within six months.
Antibiotic and Insulin Standards and Insulin Certification
Background: Section 506 of the Federal Food, Drug, and Cosmetic
Act requires FDA to certify individual batches of drugs containing
insulin as meeting the standards of identity, strength, quality, and
purity that are described by FDA regulations.
Section 507 of the Act imposes similar requirements for antibiotic
drugs. The regulatory specifications for antibiotic drug products
occupy almost 700 pages in the Code of Federal Regulations.
Antibiotics and insulin are subject to more stringent requirements
than those applied to other drug products. For example, section 505
of the Act, which applies to most human drugs, does not require FDA
to certify individual batches of drug products or to issue product
specifications prescribed in regulations. Moreover, in some cases, the
insulin and antibiotic regulations known as "monographs" are
outdated, reflect old technology or methodology, prescribe standards
for products that are no longer marketed, or conflict with the
standards found in the United States Pharmacopeia (USP). The USP, a
compendium of standards of strength, quality, and purity for drug
products, is published by the United States Pharmacopeial
Convention, a private entity. Because the FDA can change its
standards for insulin and antibiotic products only by regulation, the
USP standards are often more up to date. The existence of conflicting
standards can be confusing to the industry and to FDA staff who
must determine whether a particular product meets the correct
specifications.
Proposal and Justification: FDA proposes to support the
repeal of the certification requirement for insulin. Congress
enacted this statutory requirement decades ago, when insulin
products were new and manufacturing and testing technology was
rudimentary. Since then, the Agency and industry alike have become
much more sophisticated and experienced with insulin
manufacturing, so that certifying each batch of insulin is no longer
necessary. Moreover, only two firms currently market insulin in the
United States, and in the past 8 years FDA has found no failures in
more than 500 batches of insulin that it has tested for certification
purposes.
FDA also proposes to support the repeal of the statutory
requirements for the FDA monographs that are now issued for
insulin and antibiotics. In the 1940's, when Congress enacted those
sections of the Federal Food, Drug, and Cosmetic Act, detailed
regulations setting forth standards and tests were thought to be
necessary to ensure the quality and the safety of these products. At
that time, Congress also expressly recognized, at least with respect to
antibiotics, that a time would come when manufacturing technology
would overcome the need for such detailed regulation and that the
manufacturing controls used for chemically synthesized drugs would
suffice for antibiotics as well.
FDA also supports the repeal of the statutory provisions which
provide for the certification of antibiotic drugs. The ability to control
antibiotic drug quality is also well-established. For example, a GAO
study published in 1981 reported that from 1977 through 1980, less
than one percent of all antibiotic products did not comply with
monograph standards. FDA therefore concludes that the additional
controls are no longer necessary to ensure the safety and efficacy of
antibiotic drug products.
The Agency therefore proposes to regulate the approval of new
insulin and antibiotic drug products, and generic antibiotic drug
products, much as it does for other human drug products. Concerning
tests and methods of assay, the USP will maintain the standards for
insulin and antibiotics in the same way that it maintains such
standards for other drugs.
Impact: Under this reform, insulin manufacturers would no longer
be required to submit applications and samples to obtain batch
certification. And because the insulin industry is subject to
certification fees under section 506 of the Act, the change would
eliminate those fees.
Eliminating the statutory requirement for FDA to issue antibiotic
monographs that set forth product standards, tests, and methods of
assay for particular drugs would benefit antibiotic drug product
manufacturers. This change would eliminate the confusion created by
actual and potential differences between FDA regulatory standards
and the USP.
Eliminating the regulations specifying insulin and antibiotic drug
standards and tests will remove nearly 700 pages from the Code of
Federal Regulations.
Implementation and Timeline: The Administration will promptly
propose legislation to repeal section 506 of the Act (which pertains to
insulin) and to repeal section 507 of the Act (which pertains to
antibiotic drug products). FDA would seek to have both insulin and
antibiotic drug products regulated under section 505 of the Act.
Environmental Assessments for Human Drugs
Background: The National Environmental Policy Act (NEPA)
requires all federal agencies, including the FDA, to assess the
environmental impact of their actions which may significantly affect
the quality of the human environment. A drug cannot be approved
unless the manufacturer has submitted an acceptable Environmental
Assessment (EA). On the basis of FDA analysis of the EA, the Agency
can either issue a "finding of no significant impact" (FONSI), or decide
that a full environmental impact statement (EIS) must be prepared.
Preparation of an EA is usually quite expensive; yet, in virtually
every case, FDA issues a FONSI.
Each year, the pharmaceutical industry submits approximately 50 to
60 full EAs and about 50 abbreviated EAs to CDER. Pharmaceutical
firms also send 20 to 25 EAs annually to the Center for Biologics
Evaluation and Research (CBER), some in abbreviated form. It can
take up to 6 months to review an EA, obtain additional information
from the firm to correct any deficiencies, and issue a FONSI.
And yet, in recent years, FDA has identified only one product, Taxol,
as presenting any potentially significant environmental concerns. In
the case of Taxol, the environmental impact was due to harvesting of
Pacific yew trees, an endangered species. In Taxol's case, CDER
incorporated by reference the EIS prepared by the U.S. Forest Service
to address the resource question; the manufacturing process and use
were addressed through the routine EA and were found to have no
significant impact.
Proposal and Justification: FDA proposes to increase the
number of categorical exclusions from the EA and EIS
requirements.
FDA proposes to reduce the number of EAs required to be submitted
by industry and, consequently, the number of FONSIs prepared by
the Agency under NEPA by increasing the number of categorical
exclusions based upon little or no impact on the environment from
the use of the drug. Based upon its experience to date in reviewing
environmental assessments, FDA believes that nearly all product
approvals will qualify for categorical exclusion. For example,
virtually all drug approvals would result in only minute releases of
the drug into the environment as a result of human use and such
releases would not be environmentally significant. FDA procedures
will provide for extraordinary circumstances in which a normally
excluded action may have a significant environmental impact--
circumstances that would require at least an EA. Taxol is an example
of such an extraordinary circumstance.
Impact: These changes will substantially benefit industry and will
improve regulatory efficiency without having any adverse impact on
public health or the environment. Industry would save from $40,000
to $150,000 on each EA.
Implementation and Timeline: These changes will be
implemented by amending FDA regulations, in consultation with the
President's Council on Environmental Quality (CEQ), to increase the
number of categorically excluded actions for which an EA or EIS is
not required. New regulations will be proposed in consultation with
CEQ in six to nine months. Policy guidelines clarifying current
procedures will be published sooner.
Medical Devices
There are three classes of medical devices. Class I devices, such as
tongue depressors, are subject only to general regulatory controls
and receive little Agency oversight. Class II devices, such as infant
incubators, are subject to special controls, such as performance
standards, to ensure their safe and effective use. Class III devices,
such as implantable pacemakers, are generally life-sustaining or life-
supporting, are implanted in the body, or present potential
unreasonable risk of illness or injury.
New devices enter the market in one of two ways: (1) through a
premarket notification process, known as a "510(k)" because it is
authorized under section 510(k) of the Federal Food, Drug, and
Cosmetic Act; and (2) through a more extensive premarket approval
application (PMA).
Under the 510(k) process, FDA must determine whether a device is
"substantially equivalent" to a device that is already legally
marketed. A manufacturer using the premarket notification process
informs FDA about the device and why any changes in its device can
be made safely. (Some low-risk devices have been exempted from
premarket notification.) If FDA finds the device to be "substantially
equivalent," the manufacturer may market the device and must then
comply with good manufacturing practice (GMP) requirements to
ensure that the device is properly made. More than 90 percent of all
devices enter the market under the premarket notification process.
The more extensive premarket approval application is targeted
toward Class III devices.
The reforms below are: additional exemptions from premarket
notification; elimination of the current reference list program, which
links GMP inspections to new device approvals, and its replacement
by a process that focuses on serious GMP problems and how they
may be applicable to individual premarket notification actions; a
pilot program for external review of new devices; and, a user fee
program to speed device approvals.
Medical Device Exemptions from Premarket Notification
Background: Currently, the Federal Food, Drug, and Cosmetic Act
requires that manufacturers of most medical devices submit
information to FDA and receive FDA clearance before putting a
device on the market, even if the device has an extremely low risk.
Review of low-risk devices is not necessary to protect the public
health, places an unnecessary regulatory burden on device
manufacturers, and delays introduction of new devices.
FDA currently regulates about 1,700 types of medical devices. Of
these, 441 categories of low-risk devices (such as stethoscopes,
hernia supports, and surgical microscopes) have already been
exempted from the requirement of premarket notification, including
148 exempted in December 1994.
Proposal and Justification: FDA will exempt up to an
additional 125 medical device categories from premarket
notification requirements. As a result, about 570 categories,
or one-third of all categories of devices, will be exempt
from premarket notification requirements.
Public health will not be compromised by the exemption of these
devices from premarket review. These devices will reach the market
sooner and will remain subject to good manufacturing practice
requirements, which include regular factory inspections, record
keeping and device problem reporting. (Of course, continuation of an
exemption is dependent upon a safe marketing history, and
exemptions can be revoked if safety problems are later identified; a
review of whether these exemptions should be continued, or others
added, will be conducted in two years.)
Impact: The device industry will no longer have to prepare and
submit--and the Agency will not have to process and review--510(k)
premarket notification submissions for the exempted device
categories. FDA receives about 700 submissions each year for devices
in these 125 categories and will be able to redirect the resources for
the review of these products to more complex products.
Implementation and Timeline: FDA device advisory panel chairs
are now reviewing the proposed exemptions. The majority of the
device categories are currently in Class II and, under the law, must
be reclassified to Class I before being exempted from FDA review. By
June 1995, FDA will propose to reclassify these devices from Class II
to Class I and to exempt them from premarket notification
requirements.
Elimination of the Reference List
Problem: Under a program known as the "Reference List," FDA
tracks medical device manufacturers found by FDA field inspections
to have serious GMP violations. GMP violations are flaws in the
manufacturing process that have the potential to affect the safety or
efficacy of the product. If a firm is on the list, FDA may defer
authorization for the firm to market a new product under section
510(k) of the FD&C Act.
The basis for placing a firm on the list has been an inspectional
finding of serious GMP problems. In issuing the manufacturer a
warning letter about its GMP violations, FDA has advised the
manufacturer that the Agency may not give marketing clearance to
pending applications until the violations are corrected. A company is
removed from the list only after FDA has re-inspected the firm and
found that all serious GMP violations have been corrected. This
process can take up to 6 months.
Industry has criticized the list as not needed to protect the public
health. Industry views the list as a "blacklist" because it feels that
the Agency does not make clear which firms are placed on the
Reference List or when they are removed from it. Moreover, because
it takes time to re-inspect after violations are found, manufacturers
may be delayed in marketing their products.
Proposal and Justification: FDA will eliminate the Reference
List and instead focus attention on the appropriate linkage
between serious GMP deficiencies and individual pending
510(k) applications. FDA will also clarify that market clearances
of Class I and II devices will not be deferred unless FDA finds a
reasonable relationship between the nature of the current GMP
violations and the application under review. A reasonable
relationship will be found only if there are GMP violations that are
directly related to the product under review or if there are systemic
violations that are generally applicable. FDA will not defer 510(k)
applications if no such reasonable relationship is found.
Second, if market clearance of a 510(k) is deferred because
of GMP violations, FDA will either reinspect the firm within
60 days after being notified that corrective actions have
been taken, or clear the 510(k) application without a
reinspection.
Finally, FDA will prepare clear written policies and
procedures so that companies will know if they have an
outstanding GMP violation, will understand when their
510(k) applications may be held up due to GMP violations,
and will know the procedures to follow to correct the
problems and obtain marketing clearance.
Impact: The proposed changes benefit industry by providing
assurance that no market clearance will be deferred unless a clear
linkage between GMP violations and the device under review is
found. In addition, by clarifying FDA's procedures, any industry fear
of indiscriminate delay in the clearance of a 510(k) application will
be eliminated. Finally, the fixed time frame for reinspection benefits
manufacturers by removing uncertainty about when they will be
able to market their products after they correct GMP violations.
Implementation and Timeline: The Agency will implement these
new policies and procedures by publication of a notice in the Federal
Register by May 1995. FDA will immediately review all deferred
applications to determine if the GMP violations are reasonably
related to the pending applications. Firms with GMP violations
unrelated to the pending applications will have their applications
cleared unless there are other problems.
Medical Device External Review Pilot Program
Background: Almost all medical devices enter the market by an
application process in which the manufacturer demonstrates that the
device is "substantially equivalent" to a device already marketed.
The device industry contends that this process inhibits innovation
and competitiveness because, due to limited resources, FDA takes too
long to review these applications. (A comprehensive assessment of
FDA's device review resource needs, conducted by FDA and audited
by the device industry, documented an annual shortfall of about $24
million and more than 200 staff positions.)
Industry recommends that FDA adopt an approach similar to that
used in the European Community, in which device firms have their
device applications reviewed by a third-party scientific organization
accredited by the government. Under this approach, a manufacturer
pays a third-party organization for its review, the third-party
organization notifies the government of the results of its review, the
device is marketed without government review, and the government
monitors the device after it is on the market for subsequent safety
problems. This concept has not been tried in the United States, so its
applicability in this country is unknown.
Proposal and Justification: FDA proposes to create a pilot
program for external reviews of devices. This pilot program
will contain several key elements of the European model to test
whether that model is appropriate for the United States. The
program will have the following elements:
* At least ten categories of devices, comprising at least
100-400 device applications annually, will be identified for eligibility
in the program;
* Those categories of devices will have a low to moderate
risk profile, clear standards for market clearance, and no
requirement for clinical data as part of their application (e.g.,
applications which principally raise engineering issues);
* The outside reviewers will be accredited by FDA as
capable of assessing the design, performance, and safety of devices;
* The accredited review organization will be responsible
for conducting the entire review of the device application, producing
a written review document, and making a recommendation to FDA.
The review will be checked by FDA, and the final decision will be
made by FDA and communicated to the company;
* The program will be funded by the manufacturer's
payment to the reviewer for its services. Participation by
manufacturers will be voluntary; and
* The accredited reviewing organization will be expected to
demonstrate independence from device manufacturers for whom it
will be doing reviews and adherence to conflict of interest standards.
Impact: The pilot program will allow FDA and the device industry to
determine the feasibility of third-party reviews of devices. It will
answer questions such as whether private groups can conduct a
thorough, rapid review; whether such groups exist or will need to be
created; whether safeguards against improper influence of non-
government reviewers can be established; and how much groups will
charge for these services.
Implementation and Timeline: The pilot program will begin
early in the next fiscal year. The pilot program will operate for two
years, and during the second year FDA will evaluate its success and
potential for expansion and permanent continuation.
Device User Fees
Background: Even if the medical device external review pilot
program and other streamlining efforts detailed in this report are
successful in reducing resource demands upon FDA's device program,
the Agency will still lack sufficient resources to ensure timely review
of device applications. Each year, FDA receives approximately 40 to
60 Premarket Approval Applications (PMAs), 400 PMA supplements,
and 6,000 premarket notification actions for marketing devices
under section 510(k) of the Federal Food, Drug, and Cosmetic Act. In
fiscal year 1994, the average review times were about 2 years for
PMAs, 1 year for PMA supplements, and 215 days for premarket
notifications(3). Compare that to fiscal year 1990, when the average
review times were 10 months for PMAs, 6 months for PMA
supplements, and 100 days for premarket notifications. These
lengthy review times delay the introduction of devices to the market.
FDA can reduce these review times, without diminishing the public
health protections it provides, if it has adequate resources to review
applications.
Proposal and Justification: FDA proposes to authorize user
fees for applications. FDA will collect fees for reviewing PMAs,
PMA supplements and premarket notification actions -- 510(k)s --
and dedicate them to funding premarket review and related
activities. In addition, FDA will commit to specific performance goals.
FDA will agree to performance goals of (1) eliminating the backlog of
applications within 24 months; (2) completing a comprehensive,
substantive review for 90 percent of PMAs in 180 days; and (3)
taking a final action on 95 percent of 510(k)s in 90 days. These
performance goals were negotiated with the industry as part of
legislation proposed last year, and major segments of the device
industry supported them.
Impact: The proposed solution will address a major complaint about
federal premarket review times for devices. The device industry will
benefit from increasingly faster review and approval times, will be
able to market new and innovative products faster, and will become
more competitive in foreign markets. Consumers inside and outside
the United States will benefit from easier access to new and
improved products.
Implementation and Timeline: User fees will require statutory
changes to the Federal Food, Drug, and Cosmetic Act. The
Administration has proposed these changes in the budget for fiscal
year 1996. Device user fees would account for $23,740,000 of the
Agency's budget for the entire fiscal year, and the funds would
include associated start-up costs and the hiring of over 200 staff
people over the first two years.
Cross-Cutting
Several issues confronting FDA cut across product lines and affect
both the pharmaceutical and medical device industries. Two such
issues involve exports. One of them is the different mandatory
requirements that the Agency must follow in approving exports of
drugs and medical devices. The other export issue stems from the
varying standards for regulated health care products in the United
States and in many of its trading partners. FDA plans to ease some of
the current export restrictions. Also, the Agency will intensify its
efforts to bring into harmony international standards for health care
products, so that firms developing new products will have to deal
with only one set of requirements.
Another issue raised by both the drug and device industries is
whether FDA requires new products to be shown to be superior, as
opposed to equal, to products that are already on the market. An
upcoming policy statement will clarify the Agency position. FDA also
proposes to take steps to advance the development of an electronic
information system to support the review processes, and to
implement the second phase of an automated system for the
processing of imports.
Drug and Device Exports
Background: Drugs and medical devices not approved for sale in the
United States are now exported under different statutory
requirements.
Drugs may be exported only to the 21 developed countries listed in
the statute if, among other things, (1) the sponsor has an
investigational new drug (IND) exemption in effect that permits
testing in humans, and (2) the drug is approved in the importing
country.
Devices may be exported if FDA determines, based on information
supplied by the exporting company, that (1) export of the device
does not harm public health and safety, and (2) the device is
approved for importation by the importing country.
Manufacturers have contended that these requirements place them
at a competitive disadvantage and that FDA review of exportation to
foreign countries is both time-consuming and unnecessary.
Proposal and Justification: It is proposed to allow the
export of drugs to any of the countries listed in the statute
without an IND. In addition, the Administration proposes to work
with Congress on changes in the current law based on an examination
of whether to amend the present list of 21 countries, and whether to
adopt other changes.
FDA proposes two new criteria for allowing devices not
approved in the United States to be exported for marketing
abroad without prior FDA permission: (1) devices can be
exported to advanced industrialized countries (the list of which
would be determined in consultations with Congress) if the devices
conform to the importing country's laws; (2) devices can be exported
to countries not on the above-mentioned list if the exporter has an
Investigational Device Exemption (IDE) permitting testing on humans
in the United States, the importing country has given FDA a letter
providing blanket import approval for IDE-type devices, and the
device is in compliance with the importing country's laws.
This change from current procedures would significantly relax
restrictions on exports to industrialized countries, while leaving
intact existing protections for countries that are not industrialized.
Impact: For drugs, companies will be able to export their products
for marketing in the 21 developed countries listed in current law,
even if they do not have an IND in the United States.
For devices, exports to the most significant markets--industrialized
nations such as Japan and the European Community--will be exempt
from FDA's oversight. The U.S. industry will be spared the expense of
developing and submitting export requests to FDA and would not
need to await FDA review, which now averages 16 days but can take
as long as 150 days. Furthermore, a firm with an approved IDE will
be able to export the unapproved device to less developed countries
which have agreed to such importation, without going through FDA
review, currently averaging 10 days. The U.S. device industry
believes that these changes will encourage firms to remain in the
United States rather than moving their operations abroad. FDA could
redirect the resources used for the current export approval program
to more pressing public health matters.
Implementation and Timeline: Discussions with Congress on both
drug and device legislation could begin immediately. Permitting
devices with an IDE to be exported without further FDA clearance to
countries which have provided prior agreement can be accomplished
administratively by FDA, and proposed regulations will be issued
within 4 to 6 months.
Effectiveness of Drugs and Devices
Background: The pharmaceutical and medical device industries
have argued that FDA requires a new drug or Class III (highest risk)
device to be shown to be more effective for its intended use than
comparable therapies that are already approved for marketing.
Representatives of these industries believe FDA's requirements for
demonstrating efficacy present unreasonable difficulties in
developing new therapies and bringing them to market.
Proposal and Justification: FDA proposes to issue a public
statement to respond to this concern. The statement will make
the following points:
Under the Federal Food, Drug, and Cosmetic Act, new drugs and Class
III devices must be shown to be safe and effective for their intended
uses. In evaluating the safety of a new drug or Class III device, the
Agency weighs the demonstrated effectiveness of the product against
its risks to determine whether the benefits outweigh the risks. This
weighing process also takes into account information such as the
seriousness and outcome of the disease, the presence and adequacy
of existing treatments, and adverse reaction data.
In evaluating effectiveness, as with safety, FDA reviews new drugs
and Class III devices on their merits. The Agency does not require
new drugs and Class III devices to be more effective than therapies
for the same disease or condition that are already approved for
marketing. In general, both new drugs and Class III devices must be
shown to be effective through evidence consisting of well controlled
investigations that provide a basis on which it can be concluded that
the drug or Class III device will have the effect it is represented to
have.
For the majority of new drugs and Class III devices, i.e., new
products intended to treat less serious illness or provide relief from
symptoms, a showing of effectiveness is usually based on a clinical
trial comparing the product to a placebo. Such a showing does not
involve a comparison to any other product.
In certain circumstances, however, it may be important to consider
whether a new product is less effective than available alternative
therapies, when less effectiveness could present a danger to the
patient or to the public. For example, it is essential for public health
protection that a new therapy be as effective as alternatives that are
already approved for marketing when:
1. the disease to be treated is life-threatening or capable of
causing irreversible morbidity (e.g., stroke or heart attack); or
2. the disease to be treated is a contagious illness that poses
serious consequences to the health of others (e.g., sexually
transmitted disease).
It should be noted that new products are often developed for
particular subpopulations who either do not respond to or are not
able to tolerate an existing approved therapy. FDA will generally
approve for use in such a subpopulation a product that is shown to
have effectiveness in this group, regardless of whether the product
can be shown to be as effective in the broad target population as the
alternative therapy. This is because, in effect, there is no available
alternative therapy for the subpopulation. For example, a number of
patients cannot tolerate a widely used therapy for an AIDS-related
pneumonia. FDA approved the drug atovaquone for use in these
patients, even though it had been shown to be less effective than the
standard therapy when tested in a broad population.
Impact: Placing such a statement in the public record would clarify
for sponsors of drugs and Class III devices how FDA addresses and
evaluates effectiveness in the context of overall review for product
approvability. This clarification should be helpful to product sponsors
in the planning and development of new products.
Implementation and Timeline: Within the next 3 months, FDA
will publish a statement for comment in the Federal Register.
Additional Effectiveness Issue:
Industry representatives also argue that the Food, Drug, and
Cosmetic Act should not be read to require multiple clinical studies
when one pivotal study could suffice.
Clarification: FDA believes that a showing of effectiveness must be
replicated to constitute an adequate demonstration of effectiveness
for a new product. While a second study may well be needed to
replicate results demonstrated in a first study, in some instances it is
possible to replicate results within one large, well-designed multi-
center study. It should be emphasized that this approach can be
successful only when results are strong. A statistically marginal
result, even in a very large study, cannot provide convincing
evidence of replication.
The biotechnology drug Pulmozyme was recently approved to treat
cystic fibrosis on the basis of one multi-center study with features
that provided elements of replication. Similarly, the drug timolol was
approved to treat people after a heart attack following a
demonstration of improved survival in a single study. In that study,
the favorable effect was seen in patients at several levels of severity
at three different hospitals. A simple multi-center double-blind
placebo-controlled trial led to prompt approval of zidovudine for
AIDS in 1987 when it was found that 16 deaths had occurred in the
placebo group, as opposed to one death in the group receiving the
drug. FDA has also approved vaccines, including a vaccine for
hepatitis A, that have been studied for effectiveness in a single
controlled multi-center study.
Harmonization of Standards
Background: Nations have differing requirements for approval of
new drugs, biologics, medical devices, and animal drugs. This results
in multiple tests on animals and humans and different applications
for marketing approval. Nations also have differing standards for
manufacturing practices and regulatory inspections. There is a
substantial need to harmonize standards wherever possible, while
retaining the United States' high level of public health protection.
Proposal and Justification: Seek common international
standards. FDA will work with other countries, particularly the
European Community, Japan, and North American Free Trade
Agreement (NAFTA) partners, to harmonize product testing and
development standards with those of the United States. Work has
already begun on drug development and should be expanded to
other areas of FDA regulation.
In addition, where appropriate, FDA will adopt international
standards developed by multilateral or private-sector standards-
development bodies.
Impact: Increased harmonization offers clear benefits for U.S. public
health. It increases the safety and quality of imports into the United
States. It can also improve the safety and quality of products sold in
foreign countries and may help increase the availability of new
products.
Harmonization benefits industry by replacing many different
standards with one international standard that industry must meet.
In the long run, this brings cost savings to industry and enhanced
opportunities for export of U.S. goods, and may lessen the time
needed to bring new products to market.
Harmonization permits FDA to make more efficient use of its
resources, as other countries share the workload of developing new
standards. Harmonization also may save future FDA resources by
enabling cooperation with other countries in the assessment of new
products. (However, it should be noted that a sizable up-front
investment of FDA resources is needed to reach harmonization.)
Implementation and Timeline: FDA will build on and expand
efforts to achieve international harmonization by:
1. Launching work on new harmonization topics in the testing of
human drugs, biologics, and devices related to clinical trials,
biotechnology, medical terminology, and standards for the electronic
transfer of regulatory information. Harmonized standards will be
issued as guidelines for industry. Substantial progress on guideline
development is expected within 2 years.
2. Accelerating work on harmonizing drug Good Manufacturing
Practices, Good Laboratory Practices, and Good Clinical Practices
standards and inspections. A number of proposals for harmonized
guidelines should be completed within 2 years; however,
harmonization of inspections will probably take longer.
3. Beginning an initiative to harmonize registration requirements
for animal drugs. The first proposal for harmonized guidelines should
be completed within 3 years.
4. Initiating work towards more harmonization with our NAFTA
partners. Such harmonization efforts should become part of the work
plans of existing technical working groups formed under the
Canada/U.S. Free Trade Agreement.
Submission Management and Review Tracking (SMART) Program
Background: The current premarket review processes (preparation,
handling, and storage of information related to product applications)
are paper intensive with limited electronic means of accessing,
sharing, or archiving product-related information within the Agency.
Many applications consist of hundreds of volumes of detailed
scientific information. The regulated industry is similarly affected by
the need to generate an overwhelming amount of paper.
The Prescription Drug User Fee Act of 1992 (PDUFA) mandates
significant reductions in the time required to review new drug
applications. PDUFA funds the hiring of additional review staff to
accomplish these goals. However, one of the longer term objectives is
to improve the efficiency of the review process and to begin
addressing ways to improve regulated industry's data handling
efficiencies as well. FDA has begun to develop a comprehensive,
standardized information management system (SMART) to support
the review processes.
Proposal and Justification: FDA proposes to proceed with
the development of SMART by pursuing a series of
information systems pilot projects which will directly
support FDA's meeting the near-term PDUFA goals. The
Agency is already putting in place a system to identify, evaluate, and
prioritize these pilots. A longer term SMART strategic plan has been
developed that articulates how these pilots will serve as building
blocks toward integrated drug development/review information
management.
The pilots will focus on upgrading and interconnecting the hardware
and software on the reviewer's desk; establishing standards;
developing applications which will directly support the receipt,
review, tracking, and archiving of industry submissions; and provide
analytical tools to support the review process. This proposed
approach will provide the most immediate benefit to shortened
review times and will be funded with PDUFA fees.
Impact: The drug and biotechnology industries will continue to see
progress in meeting the PDUFA review time goals. Through
information systems design, the review processes will be clarified
and managed for greater consistency, better documentation, and
improved efficiencies. As standards are developed and implemented,
the regulated industry will achieve greater internal efficiencies in its
development and formatting of regulatory submissions and
significant savings on paper record generation, handling, storage, and
retrieval.
Implementation and Timeline: Over the next 12 to 24 months,
FDA's drug review programs will complete the upgrade of reviewer
hardware and software and networking capability, and develop and
implement a number of automated applications (e.g., electronic
Establishment Licensing Applications, electronic lot release testing,
gene therapy patient registry, pre-approval inspections, and other
pilots). The program offices will also begin selecting and
implementing electronic data interchange standards which are
acceptable to the regulated industry and to regulatory authorities in
Europe and Japan.
Operational and Administrative System for Import Support (OASIS)
Background: FDA is responsible for ensuring that the imported
products it regulates meet the same safety, efficacy, and quality
standards as products produced domestically. Importers must have
FDA clearance for each shipment before it can enter the United
States. The number of imported shipments of FDA-related products
has doubled in the 1990s to more than 2 million per year.
FDA's traditional process for clearing import shipments has required
that importers prepare and submit a prescribed form, with invoices
and any other documentation attached, for each shipment. FDA staff
reviews the documentation, decides whether to admit the shipment
in the country, and sends a paper response back to the importer. This
paper process often takes days to complete, and delays in clearing
shipments are a serious problem for importers. Reductions in
government resources and increasing workload make it clear that
FDA's traditional paper system for clearing imports must be
improved. Automation of the process is essential.
Proposal and Justification: FDA has begun developing a phased
information systems initiative to support automation of the import
clearance process. Phase I was implemented nationwide in 1994. It
operates in conjunction with the Customs Service, with which import
brokers are already on line.
The new FDA system enables the import broker to enter additional
FDA-specific data, which pass through a screening process that
recognizes what the product is, country of origin, producer, and
shipper. FDA has developed a set of decision criteria based on its
experience with import risks and surveillance-sampling techniques
to determine whether the shipment is admissible, or whether FDA
needs to look at it more closely.
Within minutes, the broker receives a return message, advising
either that FDA has cleared the shipment or that further examination
testing is needed. Shipments in which FDA has no further interest
can move immediately into commercial channels.
FDA will proceed with implementing Phase II of the
Operational and Administrative System for Import Support
(OASIS). Whereas Phase I automated the initial submission and
screening of import data from import brokers, Phase II will automate
FDA's internal handling of those import transactions requiring FDA
review beyond the initial screening. The Phase II system will
provide automated links between FDA laboratories and inspection
and compliance units.
FDA will achieve national uniformity in tracking and enforcement of
suspect products and a more rapid final response to brokers on
import disposition. In addition, full implementation of the OASIS
system will permit electronic links with other FDA data bases that
must be accessed during the import entry review process. For
example, FDA must confirm that an imported drug has an effective
NDA or an IND, that medical devices are approved and have been
properly registered, and that manufacturers of low-acid canned
foods have registered.
Impact: In February 1995, 67 percent of all shipments processed in
FDA's electronic system received final clearance within minutes.
Import brokers need not prepare and submit to FDA any paperwork
for these shipments that are cleared electronically. Importers' costs
for holding up shipments awaiting FDA clearance are reduced
markedly. Perishable shipments no longer risk spoilage from
clearance delays.
The American consumer is the major beneficiary. The freeing up of
FDA resources that would have been required to handle and review
the paperwork submitted by importers for all shipments allows the
Agency to focus its attention on those shipments that may not
conform to required standards. Implementation of the full OASIS
system will speed the clearance of the one-third of shipments that
require some form of FDA detailed review. FDA can target its
resources on those import shipments that are suspected of not
meeting quality requirements.
Implementation and Timeline: The full system will take several
more years to complete, assuming funding is available. FDA is
seeking user fees, to be paid by the importers, to fund full
development and implementation of the OASIS system.
References
1. The 1994 median review time for all new chemical drugs was
17.5 months; (the subset of drugs reviewed in 1994 under the user
fee program was reviewed in a median time of 13.5 months.
2. For biologics, approximately 25 percent of supplemental
applications (250 a year) will fall into Category I, 25 percent (250)
will fall into Category II, and 50 percent (500) will fall into Category
III.
3. However, premarket notifications, which have been the most
controversial, were down to a median time of 98 days as of January
1995.
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