Medical Product Innovation and Regulation: Benefits and Risks
December 4, 2019
Medical Product Innovation and Regulation: Benefits and Risks
Prior to being marketed in the United States, medical
The Medical Device Amendments of 1976 (MDA, P.L. 94-
products are reviewed for safety and effectiveness, among
295) was the first major legislation enacted to address the
other things, by the Food and Drug Administration (FDA).
premarket review of medical devices, and it included a
Medical products regulated by FDA include prescription
number of postmarket requirements as well (e.g., current
drugs, medical devices, and biologics. When evaluating a
good manufacturing practices, or CGMPs). The MDA
product, FDA weighs the potential benefits of a medical
established a risk-based method for classifying and
product against the potential for certain harms associated
regulating medical devices, and established two premarket
with the use of that same product. It is in this context that
regulatory pathways: premarket approval (PMA) and
Congress and FDA have established both premarket and
premarket notification (510(k)).
postmarket requirements for medical products, as well as
expedited development and review pathways for certain
Speeding Access to Medical Products
medical products for serious diseases with few available
Over the years, Congress and FDA have made
treatment options. In establishing these expedited pathways,
modifications to the established standard premarket review
Congress and FDA have acknowledged an implicit trade-
pathways in an attempt to improve access to medical
off between reducing time to marketing and a potentially
products that would meet a compelling unmet need. The
less complete safety profile upon approval.
aim of congressional reforms to FDA’s review process has
primarily been to speed medical product entry to market.
History of Medical Product Regulation
These changes are often described as benefiting patients by
The Biologics Control Act of 1902 (P.L. 57-244) was the
allowing an innovative drug or device to be more rapidly
first attempt to regulate a pharmaceutical product at the
available in a potentially dire situation for the patient. On
national level. It was also the first premarket approval
the other hand, the less fully regulators explore the safety
statute, in contrast to a retrospective postmarket product
and effectiveness of medical products before marketing
evaluation. The act focused on the manufacturing process
relative to standard review, the higher the odds of
and required that manufacturing facilities be inspected
unidentified adverse events. The appropriate balance
before a federal license was issued to market the biologic.
between this risk of unidentified adverse effects and having
faster access to beneficial new drugs and devices—and
The regulation of drugs began with the Pure Food and
therefore the ideal degree of scrutiny of their safety and
Drugs Act of 1906 (P.L. 59-384). The 1906 law did not
effectiveness prior to their marketing—is and will continue
involve premarket control over new drugs to ensure safety
to be a matter of debate.
and did not include inspections or any other regulation of
manufacturing facilities. Rather, the law focused on the
Broadly, in an effort to improve access to medical products
drug label, which could not be false or misleading, and
for serious or life-threatening diseases with limited
required that the presence and amount of certain dangerous
treatment options, FDA and Congress have established
ingredients (e.g., alcohol, cocaine) be listed. In addition, it
mechanisms to (1) expand access to drugs and devices that
defined “adulterated” with reference to the U.S.
are still under investigation, and (2) expedite the actual
Pharmacopoeia and National Formulary standards for
premarket development and review processes for new
purity, quality, and strength. It prohibited the introduction
products coming onto the market. As used in the following
into interstate commerce of misbranded or adulterated
sections, the term drugs generally includes biologics.
drugs and food.
Investigational Medical Products
In 1938, Congress replaced the Pure Food and Drugs Act
In general, a drug or device may be provided to patients
with the Federal Food, Drug, and Cosmetic Act (FFDCA).
only if FDA has cleared or approved its marketing
The FFDCA required that drug manufacturers submit, prior
application or authorized its use in a clinical trial under an
to marketing, a new drug application (NDA) demonstrating,
investigational new drug (IND) or investigational device
among other things, that the product was safe. In addition,
exemption (IDE) application. In certain circumstances,
the FFDCA expanded the prohibition of the introduction
patients may be able to obtain access to investigational
into interstate commerce of misbranded or adulterated
drugs and devices outside this framework through expanded
products to include therapeutic devices and cosmetics. The
access (compassionate use) programs. In 1987, FDA issued
FFDCA also included some controls over manufacturing
a rule creating procedures through which patients could
establishments, including an authority to inspect such
request permission from FDA to obtain an investigational
facilities. In 1962, Congress passed the Kefauver-Harris
drug outside a clinical trial (treatment IND program; 52
Drug Amendments to the FFDCA (P.L. 87-781), which
Federal Register 19466). This pathway was codified in the
required that manufacturers provide “substantial evidence”
FDA Modernization Act of 1997 (FDAMA, P.L. 105-115)
of drug effectiveness, in addition to safety.
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
Accountability Office (GAO) report found that from
to HIV/AIDS drugs for patients unable to enroll in a clinical
October 2006 through December 2014, of the 216 NMEs
trial (e.g., parallel track). In 2018, the Right to Try Act
approved (excluding new biologics), 51% used at least one
(P.L. 115-176) created a pathway for patients to obtain
expedited program. The most common product category for
access to investigational drugs without FDA permission.
drugs that used at least one expedited program was
oncology. Some also have expressed concern with the
Expedited Development and Review Programs
terminology used to describe these programs; for example,
In 1988, FDA issued an interim rule establishing what is
the term “breakthrough drug” may be misinterpreted by
now called fast track designation to “expedite the
patients and physicians to mean that the “FDA designated
development, evaluation, and marketing of new therapies”
breakthrough drug” is somehow more effective than other
by allowing, for certain serious and life-threatening
drugs when this has not been proven to be the case.
conditions, FDA review to begin before clinical trials are
completed (53 Federal Register 41516). In 1992, FDA
Other commentators, however, have characterized the
issued a rule creating an accelerated approval pathway,
current drug development and review processes as slow and
allowing for the use of surrogate endpoints (e.g., biomarker
requiring companies to invest in costly and time-intensive
test) to predict the likely success of a new treatment, rather
clinical testing. These commentators have generally
than clinical endpoints (e.g., heart attack or death), with the
supported further expediting drug development and review.
requirement that postmarketing studies be completed to
demonstrate actual benefit (57 Federal Register 53942).
Postmarket Surveillance
FDA has several systems to monitor drug and device safety
Mechanisms to expedite drug development and review also
following approval or clearance. Drug manufacturers must
have been established through legislation. For example,
report all serious and unexpected adverse events to FDA
actual and perceived delays in the review of NDAs prior to
within 15 days of becoming aware of them, and all other
marketing resulted in continued pressure from industry and
adverse events in other mandated periodic reports to the
patient groups on Congress and FDA for a faster drug
agency. The reports are made publicly available through the
review process. Toward this end, the Prescription Drug
FDA Adverse Event Reporting System (FAERS). Medical
User Fee Act of 1992 (PDUFA, P.L. 102-571) gave FDA
device manufacturers must report device-related deaths,
the authority to collect fees from the brand pharmaceutical
serious injuries, and malfunctions to FDA within 30 days of
industry and to use the revenue to support the drug review
becoming aware of them. These reports are made publicly
process by hiring additional personnel to evaluate NDAs.
available in the Manufacturer and User Facility Device
Medical device user fees were added 10 years later by the
Experience (MAUDE) database or Alternative Summary
Medical Device User Fee and Modernization Act of 2002
Reporting (ASR) data files that were made publicly
(MDUFMA, P.L. 107-250). In 2012, the FDA Safety and
available when the ASR program ended in June 2019.
Innovation Act (FDASIA, P.L. 112-144) authorized FDA to
However, these passive surveillance systems have several
collect fees to support the review process of generic drugs
limitations. As such, FDA also conducts active postmarket
and biosimilar biological products. The five-year
surveillance. For drugs, this occurs through FDA’s Sentinel
reauthorization cycle of FDA’s user fees has served as a
System, which uses electronic health records and other data
legislative vehicle for modifying FDA regulatory
sources to obtain information about a drug. For devices,
authorities. For example, Congress codified the fast track
FDA is in the process of developing the National
designation in FDAMA. FDASIA made changes to the fast
Evaluation System for health Technology (NEST). The goal
track designation, codified accelerated approval, and
of NEST is to synthesize real-world evidence from multiple
created the breakthrough therapy designation, another
sources to inform medical device safety and effectiveness,
expedited drug development and review pathway. FDA user
and is intended to serve a similar purpose to the Sentinel
fees are currently authorized through FY2022.
System. However, NEST is not without its limitations (e.g.,
it does not link to electronic health records), and FDA’s
More recently, the 21st Century Cures Act (P.L. 114-255)
timeline for a full rollout of NEST is not clear.
established a new breakthrough device category allowing
FDA to expedite development and prioritize review of
In addition, while premarket studies are designed to identify
devices that (1) provide more effective diagnosis or
safety issues, they may not identify all long-term or rare
treatment of a life-threatening or irreversibly debilitating
adverse events. As such, FDA may require a drug or device
condition, and (2) represent breakthrough technologies for
sponsor to conduct postmarket studies. These studies may
which no approved alternatives exist, offer significant
be particularly useful when one of the expedited pathways
advantages over existing alternatives, or are in the best
is used because it allows for the marketing and benefits of
interest of patients. The Cures Act included additional
the product to be realized sooner, while at the same time
provisions intended to streamline medical product approval.
allowing for a fuller safety profile to be developed. Several
GAO reports have identified some weaknesses in FDA’s
Some commentators have expressed concern with the
oversight of postmarketing safety studies and their timely
increasing reliance on expedited programs. According to
completion.
FDA, 73% of novel drug approvals—new molecular
entities (NMEs) and new therapeutic biologics—in 2018
Agata Dabrowska, Analyst in Health Policy
were designated in at least one expedited program. In 2017,
Amanda K. Sarata, Specialist in Health Policy
61% were (FDA’s 2017 and 2018 New Drug Therapy
Victoria R. Green, Analyst in Health Policy
Approvals reports). A December 2015 Government
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Medical Product Innovation and Regulation: Benefits and Risks
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