December 4, 2019
Medical Product Innovation and Regulation: Benefits and Risks
Prior to being marketed in the United States, medical
products are reviewed for safety and effectiveness, among
other things, by the Food and Drug Administration (FDA).
Medical products regulated by FDA include prescription
drugs, medical devices, and biologics. When evaluating a
product, FDA weighs the potential benefits of a medical
product against the potential for certain harms associated
with the use of that same product. It is in this context that
Congress and FDA have established both premarket and
postmarket requirements for medical products, as well as
expedited development and review pathways for certain
medical products for serious diseases with few available
treatment options. In establishing these expedited pathways,
Congress and FDA have acknowledged an implicit tradeoff between reducing time to marketing and a potentially
less complete safety profile upon approval.
History of Medical Product Regulation
The Biologics Control Act of 1902 (P.L. 57-244) was the
first attempt to regulate a pharmaceutical product at the
national level. It was also the first premarket approval
statute, in contrast to a retrospective postmarket product
evaluation. The act focused on the manufacturing process
and required that manufacturing facilities be inspected
before a federal license was issued to market the biologic.
The regulation of drugs began with the Pure Food and
Drugs Act of 1906 (P.L. 59-384). The 1906 law did not
involve premarket control over new drugs to ensure safety
and did not include inspections or any other regulation of
manufacturing facilities. Rather, the law focused on the
drug label, which could not be false or misleading, and
required that the presence and amount of certain dangerous
ingredients (e.g., alcohol, cocaine) be listed. In addition, it
defined “adulterated” with reference to the U.S.
Pharmacopoeia and National Formulary standards for
purity, quality, and strength. It prohibited the introduction
into interstate commerce of misbranded or adulterated
drugs and food.
In 1938, Congress replaced the Pure Food and Drugs Act
with the Federal Food, Drug, and Cosmetic Act (FFDCA).
The FFDCA required that drug manufacturers submit, prior
to marketing, a new drug application (NDA) demonstrating,
among other things, that the product was safe. In addition,
the FFDCA expanded the prohibition of the introduction
into interstate commerce of misbranded or adulterated
products to include therapeutic devices and cosmetics. The
FFDCA also included some controls over manufacturing
establishments, including an authority to inspect such
facilities. In 1962, Congress passed the Kefauver-Harris
Drug Amendments to the FFDCA (P.L. 87-781), which
required that manufacturers provide “substantial evidence”
of drug effectiveness, in addition to safety.
The Medical Device Amendments of 1976 (MDA, P.L. 94295) was the first major legislation enacted to address the
premarket review of medical devices, and it included a
number of postmarket requirements as well (e.g., current
good manufacturing practices, or CGMPs). The MDA
established a risk-based method for classifying and
regulating medical devices, and established two premarket
regulatory pathways: premarket approval (PMA) and
premarket notification (510(k)).
Speeding Access to Medical Products
Over the years, Congress and FDA have made
modifications to the established standard premarket review
pathways in an attempt to improve access to medical
products that would meet a compelling unmet need. The
aim of congressional reforms to FDA’s review process has
primarily been to speed medical product entry to market.
These changes are often described as benefiting patients by
allowing an innovative drug or device to be more rapidly
available in a potentially dire situation for the patient. On
the other hand, the less fully regulators explore the safety
and effectiveness of medical products before marketing
relative to standard review, the higher the odds of
unidentified adverse events. The appropriate balance
between this risk of unidentified adverse effects and having
faster access to beneficial new drugs and devices—and
therefore the ideal degree of scrutiny of their safety and
effectiveness prior to their marketing—is and will continue
to be a matter of debate.
Broadly, in an effort to improve access to medical products
for serious or life-threatening diseases with limited
treatment options, FDA and Congress have established
mechanisms to (1) expand access to drugs and devices that
are still under investigation, and (2) expedite the actual
premarket development and review processes for new
products coming onto the market. As used in the following
sections, the term drugs generally includes biologics.
Investigational Medical Products
In general, a drug or device may be provided to patients
only if FDA has cleared or approved its marketing
application or authorized its use in a clinical trial under an
investigational new drug (IND) or investigational device
exemption (IDE) application. In certain circumstances,
patients may be able to obtain access to investigational
drugs and devices outside this framework through expanded
access (compassionate use) programs. In 1987, FDA issued
a rule creating procedures through which patients could
request permission from FDA to obtain an investigational
drug outside a clinical trial (treatment IND program; 52
Federal Register 19466). This pathway was codified in the
FDA Modernization Act of 1997 (FDAMA, P.L. 105-115)
and expanded to include investigational devices. In the
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Medical Product Innovation and Regulation: Benefits and Risks
early 1990s, FDA issued additional policies to allow access
to HIV/AIDS drugs for patients unable to enroll in a clinical
trial (e.g., parallel track). In 2018, the Right to Try Act
(P.L. 115-176) created a pathway for patients to obtain
access to investigational drugs without FDA permission.
Expedited Development and Review Programs
In 1988, FDA issued an interim rule establishing what is
now called fast track designation to “expedite the
development, evaluation, and marketing of new therapies”
by allowing, for certain serious and life-threatening
conditions, FDA review to begin before clinical trials are
completed (53 Federal Register 41516). In 1992, FDA
issued a rule creating an accelerated approval pathway,
allowing for the use of surrogate endpoints (e.g., biomarker
test) to predict the likely success of a new treatment, rather
than clinical endpoints (e.g., heart attack or death), with the
requirement that postmarketing studies be completed to
demonstrate actual benefit (57 Federal Register 53942).
Mechanisms to expedite drug development and review also
have been established through legislation. For example,
actual and perceived delays in the review of NDAs prior to
marketing resulted in continued pressure from industry and
patient groups on Congress and FDA for a faster drug
review process. Toward this end, the Prescription Drug
User Fee Act of 1992 (PDUFA, P.L. 102-571) gave FDA
the authority to collect fees from the brand pharmaceutical
industry and to use the revenue to support the drug review
process by hiring additional personnel to evaluate NDAs.
Medical device user fees were added 10 years later by the
Medical Device User Fee and Modernization Act of 2002
(MDUFMA, P.L. 107-250). In 2012, the FDA Safety and
Innovation Act (FDASIA, P.L. 112-144) authorized FDA to
collect fees to support the review process of generic drugs
and biosimilar biological products. The five-year
reauthorization cycle of FDA’s user fees has served as a
legislative vehicle for modifying FDA regulatory
authorities. For example, Congress codified the fast track
designation in FDAMA. FDASIA made changes to the fast
track designation, codified accelerated approval, and
created the breakthrough therapy designation, another
expedited drug development and review pathway. FDA user
fees are currently authorized through FY2022.
More recently, the 21st Century Cures Act (P.L. 114-255)
established a new breakthrough device category allowing
FDA to expedite development and prioritize review of
devices that (1) provide more effective diagnosis or
treatment of a life-threatening or irreversibly debilitating
condition, and (2) represent breakthrough technologies for
which no approved alternatives exist, offer significant
advantages over existing alternatives, or are in the best
interest of patients. The Cures Act included additional
provisions intended to streamline medical product approval.
Some commentators have expressed concern with the
increasing reliance on expedited programs. According to
FDA, 73% of novel drug approvals—new molecular
entities (NMEs) and new therapeutic biologics—in 2018
were designated in at least one expedited program. In 2017,
61% were (FDA’s 2017 and 2018 New Drug Therapy
Approvals reports). A December 2015 Government
Accountability Office (GAO) report found that from
October 2006 through December 2014, of the 216 NMEs
approved (excluding new biologics), 51% used at least one
expedited program. The most common product category for
drugs that used at least one expedited program was
oncology. Some also have expressed concern with the
terminology used to describe these programs; for example,
the term “breakthrough drug” may be misinterpreted by
patients and physicians to mean that the “FDA designated
breakthrough drug” is somehow more effective than other
drugs when this has not been proven to be the case.
Other commentators, however, have characterized the
current drug development and review processes as slow and
requiring companies to invest in costly and time-intensive
clinical testing. These commentators have generally
supported further expediting drug development and review.
Postmarket Surveillance
FDA has several systems to monitor drug and device safety
following approval or clearance. Drug manufacturers must
report all serious and unexpected adverse events to FDA
within 15 days of becoming aware of them, and all other
adverse events in other mandated periodic reports to the
agency. The reports are made publicly available through the
FDA Adverse Event Reporting System (FAERS). Medical
device manufacturers must report device-related deaths,
serious injuries, and malfunctions to FDA within 30 days of
becoming aware of them. These reports are made publicly
available in the Manufacturer and User Facility Device
Experience (MAUDE) database or Alternative Summary
Reporting (ASR) data files that were made publicly
available when the ASR program ended in June 2019.
However, these passive surveillance systems have several
limitations. As such, FDA also conducts active postmarket
surveillance. For drugs, this occurs through FDA’s Sentinel
System, which uses electronic health records and other data
sources to obtain information about a drug. For devices,
FDA is in the process of developing the National
Evaluation System for health Technology (NEST). The goal
of NEST is to synthesize real-world evidence from multiple
sources to inform medical device safety and effectiveness,
and is intended to serve a similar purpose to the Sentinel
System. However, NEST is not without its limitations (e.g.,
it does not link to electronic health records), and FDA’s
timeline for a full rollout of NEST is not clear.
In addition, while premarket studies are designed to identify
safety issues, they may not identify all long-term or rare
adverse events. As such, FDA may require a drug or device
sponsor to conduct postmarket studies. These studies may
be particularly useful when one of the expedited pathways
is used because it allows for the marketing and benefits of
the product to be realized sooner, while at the same time
allowing for a fuller safety profile to be developed. Several
GAO reports have identified some weaknesses in FDA’s
oversight of postmarketing safety studies and their timely
completion.
Agata Dabrowska, Analyst in Health Policy
Amanda K. Sarata, Specialist in Health Policy
Victoria R. Green, Analyst in Health Policy
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Medical Product Innovation and Regulation: Benefits and Risks
IF11379
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