The purpose of a clinical trial is to
assess reliably the benefits and harms of an intervention. In this
book, we have focused on good clinical trial design, conduct,
monitoring, and analysis principles. For many clinical trials,
including those involving new drugs, devices, or biologics, or new
indications for existing interventions, there are national and
local regulations that must be followed in order to conduct
clinical research, including the types of trials we have discussed.
Furthermore, in order for an industry sponsor to market a medical
product, regulatory agency approval is required in the U.S. and
much of the rest of the world. The primary goal of this chapter is
not to summarize all of the regulations relating to medical
products; that is beyond the scope of this book. Rather, it is to
focus on those laws, regulations and policies that bear on the
design, conduct, and reporting of clinical trials. Even then, it
will be highly selective, limited to those aspects that we think
are most relevant and we will concentrate on U.S. laws, policies
and regulations.
In the U.S., the Food and Drug
Administration is the agency that reviews products for marketing
and use to prevent disease, diagnose disease or treat individuals
or animals, regardless whether the product was developed by
industry or other research institutions. The FDA is a large
organization composed of seven Centers: Center for Drug Evaluation
& Research (CDER), Center for Devices & Radiological Health
(CDRH), Center for Biologics Evaluation and Research (CBER), Center
for Food Safety and Applied Nutrition, Center for Toxicological
Research, Center for Veterinary Medicine and Center for Tobacco
Products [1]. (See
Fig. 22.1.) Most of these Centers have divisions that
reflect disease types such as cardiovascular and renal diseases, or
types of interventions such as cardiovascular devices or surgical
devices. While each Center abides by the laws under which it was
created and follows the regulations written to describe its
standards and procedures, there are important differences in the
kinds of study designs (control groups, end points, blinding, etc.)
that reflect the specific disease area or product type.
Fig.
22.1
FDA organizational chart 2013
In Europe, the European Medicines
Agency (EMA) has regulations that apply to those countries under
its purview [2]. The development of
the International Conference on Harmonisation (ICH) guidance
documents [3] was aimed to make
clinical trial standards more comparable internationally. But
regulatory agency rules and guidelines still differ among
countries, and these differences may contribute to different
approval decisions [4]. Regulations
and guidelines in Europe have changed over time [5]. Importantly, rules of conduct differ in the
various countries in which a multinational trial might be
conducted. Even within a country with a common standard,
differences in judgment in applying those standards may exist.
Thus, another purpose of this chapter is to provide links and other
sites to which investigators can go for fuller and more current
information and assistance.
The differences can be challenging for
a new investigator to navigate. Nevertheless, investigators must
become knowledgeable if they want to develop a successful clinical
trial program.
Fundamental Point
When designing and conducting a clinical
trial, investigators must know and follow national, state, and
institutional regulations that are designed to protect research
integrity and participant safety.
Background
Overview
Research under the Code of Federal
Regulations is defined as “a systematic investigation, including
research development, testing and evaluation, designed to develop
or contribute to generalizable knowledge” [6]. Clearly, clinical trials fall into that
definition.
Clinical research regulations (or
rules) and guidelines in the U.S. are created at the federal level
by the Department of Health and Human Services, the Office of Human
Research Protection and the Food and Drug Administration (FDA) and
include several guidance documents [6–9]. In addition
there are local requirements from universities and other research
institutions, in response to some of the federal guidelines.
Clinical researchers must be familiar and be in compliance with
these regulations and guidances. Finally, the FDA requires
investigators and trial sponsors to register all trials with
ClinicalTrials.gov [10], providing
basic information about the design of the trial within 21 days
after the first participant is enrolled, and within 1 year after
trial completion to submit the overall results to the same web site
[11], as discussed below.
Other chapters in the book cover
regulatory issues as they concern topics discussed in those
chapters (Table 22.1). Chapter 1 discusses clinical trial phases.
Chapter 2 contains discussions of trials in
emergency settings and studies that enroll vulnerable populations,
which have special regulatory requirements, as well as requirements
for Institutional Review Boards that are mandated in the Code of
Federal Regulations [6], sometimes
referred to as the Common Rule. These will not be repeated here.
Noninferiority trials, the use of adaptive designs, and cross-over
trials, all of which might involve input from regulatory agencies,
are discussed in Chap. 5. In this chapter, we will focus on
pretrial requirements, trial conduct, and posttrial requirements.
Table
22.1
List of regulatory issues discussed in
other chapters
|
Pages
|
||
|
Chapter 1
|
Trial Phases
|
4–10
|
|
Chapter 2
|
Ethics Committees
|
25, 28–29, 31–34, 36, 39
|
|
Informed Consent
|
34–37, Table 2.2
|
|
|
Trials in Emergency Settings
|
36
|
|
|
Trials in Vulnerable Populations
|
37
|
|
|
Chapter 3
|
Use of Surrogate Outcomes
|
62–65
|
|
Chapter 5
|
Cross-Over Trials
|
102–103
|
|
Noninferiority Trials
|
109–113
|
|
|
Adaptive Designs
|
114–115
|
|
|
Chapter 7
|
Blinding of Nonpharmacologic Trials
|
154
|
|
Chapter 9
|
Pharmacogenetic Markers
|
206
|
|
Chapter 11
|
Audits
|
248–250
|
|
Chapter 12
|
Assessment of Harm
|
256
|
|
Boxed Warnings and Drug Approval
Withdrawal
|
258
|
|
|
Classification of Adverse Events
|
260
|
|
|
Reporting Adverse Events
|
266
|
|
|
Recommendations for Assessing and Reporting
Harm
|
273
|
|
|
Chapter 13
|
Health Related Quality of
Life/Patient-Reported Outcomes
|
279
|
|
Chapter 16
|
Data Monitoring Committees
|
345–350, 367
|
|
Chapter 19
|
Data Cleanup and Verification
|
469
|
|
Storage of Data and Materials
|
470–471
|
|
|
Chapter 20
|
Data Sharing
|
493–494
|
|
Chapter 21
|
Globalization of Trials
|
511–514
|
|
Site Investigator Responsibilities
|
510, Table 21.1
|
History
Regulation of drugs, devices, and
other medical products has a long history [12, 13]. In
many countries, including the U.S., various laws and amendments
require that new products (i.e., those not yet marketed) such as
drugs, biologics or devices be proven safe and effective before
they are approved for marketing. As medical practice and our
understanding of how interventions work improves, and as a result
of several egregious events [14],
these regulations have evolved over the years. Following the Pure
Food and Drug Act of 1906, a key event in the U.S. was the passage
of the Food, Drug, and Cosmetic Act of 1938 [15]. Among other things, this act required that
new drugs be shown safe and authorized standards of quality. In
1962, the Kefauver-Harris Drug Amendments required that the
effectiveness of products be shown before marketing [16]. They said that the required “substantial
evidence” of effectiveness could be demonstrated only on the basis
of “adequate and well-controlled trials.” The “s” at the end of
“trials” is important as it implies that more than one trial is
needed. The Medical Device Amendment in 1976 provided guidance on
how devices were classified for regulation and approval
[17]. The Safe Medical Device Act
(1990) further expanded the role of the FDA [18].
In recent years, there have been rules
that allow for making drugs available as rapidly as possible,
including four approaches: fast
track, breakthrough therapy, accelerated approval, and
priority review
[19]. Fast track is aimed at expediting
review of drugs filling unmet clinical needs for serious
conditions. Breakthrough
therapy is a process for drugs that have early evidence of
improvement over available treatments for serious conditions.
Accelerated approval is for
unmet clinical needs for serious conditions using surrogate
endpoints with a requirement for further studies. The priority review designation provides
for an FDA goal of regulatory action within 6 months (compared to
10 months under standard review), based on anticipated significant
improvements in safety and/or efficacy for serious
conditions.
Regulatory Requirements
Table 22.2 lists key actions and
responsibilities required of investigators (both lead and other)
conducting trials that fall under the purview of the FDA.
Table
22.2
Actions and responsibilities of
investigators conducting clinical trials under auspices of
FDA
|
Trial
|
Site
|
|
|---|---|---|
|
Leadership
|
Investigators
|
|
|
Pretrial
|
||
|
Ethics Training
|
||
|
Principles of Research
|
x
|
x
|
|
IRB Requirements
|
x
|
x
|
|
Informed Consent Process
|
x
|
x
|
|
Knowledge of Basic Regulations
|
||
|
45 CFR 46 (Common Rule)
|
x
|
x
|
|
21 CFR 50 (FDA Regulations)
|
x
|
x
|
|
45 CFR 160 (Privacy Act)
|
x
|
x
|
|
IND or IDE Completion
|
||
|
Pre-clinical materials and
references
|
x
|
|
|
Final protocol (allowing FDA up to 30
days for review)
|
x
|
|
|
Information Showing Competence of
Investigator(s)
|
x
|
x
|
|
Information Showing Adequacy of
Facilities
|
x
|
x
|
|
Registration with
ClinicalTrials.gov
|
x
|
|
|
IRB Approval
|
x
|
x
|
|
Conduct
|
||
|
Site Monitoring
|
x
|
|
|
Data Monitoring
|
x
|
|
|
Other Quality Assurance Activities
|
x
|
|
|
Reporting to IRB(s) and FDA
|
||
|
Protocol Modifications
|
x
|
|
|
Investigator Changes
|
x
|
|
|
Safety Reports
|
||
|
Serious Adverse Events
|
x
|
x
|
|
Routine
|
x
|
|
|
Posttrial
|
||
|
Submission of data and documents to FDA
(if seeking product approval)
|
||
|
Protocol
|
x
|
|
|
Completed Case Report Forms
|
x
|
|
|
SAE Reports
|
x
|
|
|
Product Accountability
|
x
|
|
|
Presentation to Advisory Committee
|
x
|
|
|
Possible Conduct of Post-Approval
Studies
|
x
|
x
|
|
Publication of Trial Results
|
x
|
x
|
|
Timely Submission of Data to
ClinicalTrials.gov
|
x
|
|
Although the principal investigator
(PI) is traditionally considered to be the individual designated as
being responsible for the clinical trial, from a regulatory
perspective, it is the sponsor who has primary responsibility. “The
sponsor may be an individual or pharmaceutical company,
governmental agency, academic institution, private organization, or
other organization. The sponsor does not actually conduct the
investigation unless the sponsor is a sponsor-investigator”
[20]. Thus, being PI on a grant
that funds the clinical trial is not the same as being a sponsor.
The sponsor is responsible for seeing that all of the
documentation, approvals, and reporting requirements, including
under the purview of the IRB, are fulfilled. The same individual
often serves in both capacities, but they need not be the same. As
listed at the end of this chapter, many guidance documents are
available on the web to help familiarize investigators beyond the
level of detail presented here. The National Institutes of Health
and many universities require clinical researchers to take courses
or workshops (often online) on research ethics and regulations, and
many research institutions provide them. See Chap. 2 for specific resources.
The U.S. Health Insurance Portability
and Accountability Act (HIPAA), passed in 1996, includes the
Privacy Rule that protects the privacy of individually identifiable
health information [21]. The HIPAA
Privacy Rule gives conditions under which protected health
information (PHI) may be used or shared with individuals or what is
referred to as covered entities for conducting medical research.
Protected health information refers to patient names, date of birth
or other identifying dates, telephone numbers, email addresses,
Social Security numbers, medical record numbers, photographs or any
other identifying information. The HIPAA establishes conditions
under which PHI data collected for research may be used or
disclosed for research purposes, including who may obtain such
information. Trial participants must be informed of uses and any
disclosures of their medical information and disclosure of PHI data
requires the permission of the individual or special approval
procedures. If clinical trial data are shared outside of the trial
that collected the data, they must be de-identified [22]. These HIPAA requirements can bring
challenges in carrying out clinical trials. The investigator is
responsible for doing this correctly. Often, these issues can be
addressed in the informed consent process if anticipated.
Trial Phases
Clinical trial phases are discussed in
Chap. 1. It should be noted that
traditionally it was the drug trials that were divided into phases
I, II, III, and IV [23].
Guidelines for early phase studies for biologics have also been
developed [24]. These take into
account the special needs of development and testing of cellular
and gene therapy products and other biologics.
Before marketing of a new product or
for a new indication of an already approved product, late phase
trials are typically conducted. Sometimes, though, new products or
new indications may be approved on the basis of trials that do not
use clinical outcomes but rather an intermediate outcome as a
surrogate endpoint With devices, the situation is even more
variable, as modifications of approved devices (through the 510 (k)
process [25]) may not require any
clinical trials when a suitable combination of preclinical data
(i.e., bench testing, animal model, and computational modeling) can
be demonstrated to show substantial equivalence to the predicate
device.
Pretrial Requirements
What kinds of trials do and do not
require regulatory agency approval? Trials that involve new drugs,
devices, and biologics that are not marketed require approval prior
to conduct. Interventions that are already approved for the
indication that is being studied in the trial do not generally need
to be submitted for FDA regulatory review. For example, a drug may
have been approved on the basis of a surrogate outcome, but an
investigator now wants to evaluate it using a clinical outcome.
Though, if the trial is to test a new indication or to evaluate the
intervention administered in a different way or using a different
dose, regulatory agency approval would typically be required
[26, 27]. If new information is to be generated with
the intent of including that information in the drug label or in
advertising, an Investigational New Drug Application (IND) is
needed [28]. Non-drug and
non-device trials, where the intervention might consist of
training, education, or surgical procedures do not, as a rule,
require prior approval by the FDA, although other countries may
require national regulatory approval even for these trials.
The FDA and the EMA websites include
current clinical trials guidance documents, as well as forms that
need to be completed for trials of drugs or biologics and devices
[2, 9]. All investigators considering conducting
clinical trials that might fall under FDA or EMA guidance should
consult these materials before designing the trial. The version of
the ICH document E6 (Good Clinical Practice: Consolidated Guidance)
[29] that was amended in June,
2014 contains considerable information concerning the design and
conduct of clinical trials and is generally consistent with the
fundamental principles outlined in this book. While this document
was created with a focus on all phases of pharmaceutical trials,
and it has features that are overly complex for many large, simple
or pragmatic trials, it does allow for some flexibility
[30].
In advance, it is often useful and
recommended to meet with staff of regulatory agencies to discuss
the planned protocol and the proposed data to be collected,
especially for phase III studies. This is especially true in an
area where scientific knowledge is rapidly changing or if other
than a standard design and outcomes are being considered. For
example, if any of the adaptive designs will be used (see Chap.
5), it may be advisable to solicit
advice from the FDA. Similarly, if the outcomes that will be used
are not ones that are generally accepted for the condition being
studied, discussions with regulatory agency staff are essential.
The FDA may agree that some of the proposed data collection is not
necessary for their approval process and offers an opportunity for
some reduction in effort and cost. Additionally, studies in
children or other vulnerable populations, and trials in emergency
settings have special regulations and requirements of which
investigators need to be aware.
The draft protocol and the statistical
analysis plan along with the data monitoring charter and the
monitoring plan, if appropriate, should be submitted to agencies
before the trial begins. For complicated Bayesian or adaptive
designs the actual computer code may be requested by a regulatory
agency to independently assess accuracy.
Conduct
Protocol amendments for a trial being
conducted under an Investigative New Drug (IND) application should
be submitted prior to implementation. Also, after initiation of the
trial, investigators and/or sponsors must report adverse events to
the regulatory agencies. Generally, this is as an annual report.
However, serious adverse events, particularly those that are
unexpected or life-threatening, need to be reported in a more
prompt manner. For FDA definitions of serious, life-threatening,
and unexpected, and what actions need to be taken, see Chap.
12. As a rule, those that are
unexpected (e.g., not related to the condition being studied nor in
the drug investigator brochure or the package insert) need to be
submitted in a timely way as safety reports. Historically,
investigators reported to the trial sponsor any and all adverse
events they discovered with the trial participant, and in turn
these reports were sent to the FDA and other regulatory agencies as
well as to all investigators in the trial worldwide, who in turn,
sent them to their ethics committees. This resulted in a flood of
individual adverse event reports that by themselves were largely
uninterpretable. It has been recognized that this extensive adverse
event reporting is not only unhelpful, but can be harmful to trial
quality, since it diverts limited resources from aspects of trial
conduct that are more important for quality.
As a result, in 2011 the FDA issued a
new Investigative New Drug (IND) Rule for drugs that tried to
reduce the number of adverse event reports that were not
informative [31]. In the revision,
the sponsor of the trial is to review the investigator reported
events and determine if these events are Serious Unexpected
Suspected Adverse Reactions (SUSARs) before they are reported to
the FDA. Serious adverse events (SAEs), defined as events that are
fatal, life threatening, require hospitalization, or result in
permanent injury, must be reported in a more expedited fashion
(e.g., less than 15 days from identification). Unexpected refers to
events that are not listed in the Investigator Brochure or the
package insert or other relevant documents regarding the product. A
suspected adverse reaction is an event that has a reasonable
probability of being caused by the intervention and is otherwise
uncommon in the treated population. An event may be a SUSAR if it
is: 1) a single occurrence of an uncommon serious adverse event
that very rarely occurs spontaneously (e.g., Stevens-Johnson
syndrome), 2) one or more occurrences of event that does not
commonly occur (e.g., tendon rupture), or 3) an aggregate analysis
of a specific event in a clinical trial observed more frequently on
drug than control [31].
Implementing this new IND rule has been challenging because
sponsors have been reluctant to unblind even small numbers of
participants with these SAEs while the FDA has said that the needed
assessment will generally require unblinding of certain parties
within the sponsor organization in a way that will not damage the
study integrity [32]. Those
parties who are unblinded should not be those involved in the
conduct of the trial and they should not be investigators.
It may not be necessary to collect
adverse events that are non-serious and that do not result in
discontinuation of study drug after data have been collected on a
certain number of participants(e.g., 2,000 to 5,000). Whether to
collect all adverse events for a non-approved drug needs to be
negotiated with the FDA before the trial begins. Serious but
expected adverse events (related to the drug and/or expected in the
course of the disease) may be collected on the case report form,
and reported to the FDA in a systematic way, again with prior
agreement of the agency.
A certain amount of quality assurance
by the study sponsor is essential (see Chap. 11). Obviously, those that ensure
proper assignment to intervention and control (including the
randomization process), appropriate intervention, and outcome
assessment are important, as are those that guarantee ethical
standards (e.g., informed consent). Ongoing measurement, feedback,
and improvement of these parameters are necessary during the
conduct of the trial. Corrective action can be taken so as to
prevent continuation of data collection problems and poor
application of the protocol. Source data verification of all
variables, and using this information simply at the end of the
trial for documentation, is usually not helpful because the trial
is over and it is too late to take corrective action. However,
regulatory agencies reserve the authority to check on data that
have been collected, including by means of visits to clinic sites.
Investigators should be prepared for such visits, particularly at
the end of trials that are viewed as yielding practice-changing
outcomes. These visits may also review documentation of informed
consent and study drug reconciliation, accounting for the amount of
drug received and the amount dispensed according to the protocol.
Standards for computerized data systems and record retention are
included in guidance documents [33]. It should be emphasized that site visits
may be of three sorts; routine, structured, and for cause. See
Chap. 11 for a discussion of the kinds of
audits.
Often, however, the effort spent on
quality assurance is beyond what is needed for important aspects of
trial quality and required by regulatory agencies [34–37]. Having
unbiased assessment of key primary outcomes without an unusually
large percentage of missing data will do far more to promote good
quality clinical research than spending time and resources ensuring
that secondary and tertiary measures are perfectly performed.
Additionally, site visits to clinics for data verification are
often unnecessary, as most key monitoring can be done centrally.
There may be other reasons for site visits, though. For example,
they help to assure appropriate training of research personnel and
adequate understanding of the protocol and the informed consent
process. Regulatory agencies have given mixed messages regarding
the kinds and amount of essential quality assurance. Therefore,
many clinical trial sponsors, especially those from pharmaceutical
and device companies, have typically engaged in exhaustive quality
assurance. Yet the results of many trials conducted by others
(e.g., the National Institutes of Health) have been accepted by
regulatory agencies despite less extensive quality assurance.
Central and “risk based” monitoring is within the FDA guidelines
[38] and should be actively
discussed with the agency in early phase meetings to determine if
appropriate.
The U.S. law requires that clinical
trials conducted in emergency settings, when informed consent is
unobtainable, have a data monitoring committee [39, 40]. With
that one exception, data monitoring committees are not required by
law. FDA guidelines, however, discuss the importance of an
independent data monitoring committee when the trial outcomes
entail mortality or major morbidity, when there are major risks to
the participants, or when having such a committee will “help assure
the scientific validity of the trial” [40]. There is considerable emphasis on the
independence of the committee members and on keeping the trial
sponsor uninformed of interim data by intervention assignment. The
European Medicines Agency has issued similar guidelines
[41]. The International Conference
on Harmonisation (ICH) [42] and
the World Health Organization [43]
also provide guidelines that are generally consistent with those of
the FDA. For a fuller discussion of regulatory guidelines and data
monitoring committees, see Chap. 16, and Ellenberg, Fleming, DeMets
[44].
Interventions: Drugs
The classic structure of clinical
trials, with its phases, placebo control, and blinding, derive from
trials of drugs. Most regulatory agencies require that new drugs or
drugs being tested in new settings or for new indications undergo
the kind of clinical trials described in this book. Obviously,
depending on the situation, the comparison may be another drug
already proven to be beneficial or accepted as standard therapy,
rather than placebo (unless the placebo is on top of standard
therapy), and the trial could be designed either as a superiority
study or as a noninferiority trial. In some circumstances (see
Chap. 5), crossover or other special
designs might be used.
Approval of drugs generally falls into
the responsibility of the FDA’s Center for Drug Evaluation and
Research, better known as CDER. (This is somewhat of an
oversimplification since some biologics can be viewed as drugs but
are reviewed by the Center for Biologics Evaluation and Research.)
Within CDER, there are many Divisions to handle drugs for different
disease entities. Divisions may use external advisory committees to
assist them in their evaluations. Criteria provided in the FDA and
ICH guidelines are applied in the approval process for level of
evidence.
Prior to initiating the evaluation of
a new drug in humans, an Investigational New Drug (IND) application
must be submitted [26]. One basis
for this requirement is the federal law that requires such
submission before a drug can be transported across state lines for
research purposes. During early phase pre-clinical development,
sponsor and investigators are attempting to establish some evidence
of favorable drug activity and that it is reasonably safe to
administer to humans for initial testing [23]. This generally means that the molecule has
been screened for pharmacologic activity and toxicity in animal
models. As the drug development progresses under the IND through
the various phases, typically including two phase III trials,
sponsors will submit all of their data as part of a New Drug
Application (NDA) for approval for sale and marketing in the
U.S.
Safety standards are not different for
expedited review, accelerated approval or regular approval, but the
efficacy requirements are different, as accelerated approval is
based on an intermediate marker used as a surrogate outcome, with
requirements for further studies using clinical outcomes.
Post-market safety issues after approval of a drug that may later
turn out to be not beneficial, or even harmful, can arise with any
of the approval strategies. In 2012, the FDA approved the use of
ponatinib for chronic myeloid leukemia, under an accelerated
approval pathway, on the basis of hematologic and cytogentic
reponses as the primary outcome [45]. Subsequently, increases in cardiovascular,
cerebrovascular, and peripheral vascular thromboses were observed.
This led the FDA to at first suspend, and then allow limited
marketing of the drug. The FDA approved bedaquiline for
drug-resistant tuberculosis on an accelerated basis for a serious
unmet need using results from a trial showing greater conversion of
sputum culture from positive to negative [46, 47]. This
was done despite more deaths in the bedaquiline group than the
placebo group (10 out of 79 vs. 2 out of 81), in part because of
the urgent need for effective anti-tuberculosis drugs. A drug that
seemed to clear sputum seems unlikely to increase death from
tuberculosis and renders the patient noncontagious. The fact that
many of the deaths did not seem to be drug related and occurred
long after the patients were off treatment were also determining
factors in the accelerated approval [48]. However, as with any accelerated approval
based on a surrogate, the FDA required that a confirmatory trial be
conducted.
Interventions: Devices
Approval of devices in the U.S. has
usually not required the same kind of evidence as approval of drugs
since regulations for device approval were developed separately and
at different times [17,
18]. In many cases the mechanism
of action and performance of a device can be adequately assessed
without a large clinical trial. Examples might be diagnostic
coronary catheters or electrocardiographic machines where proper
preclinical bench testing is what is needed to assess adequate
performance. On the other hand, with the burgeoning importance of
device technology, well designed and performed clinical trials to
assess safety and effectiveness may be needed to properly assess
devices. Recent examples include drug-eluting stents and
percutaneous aortic valve devices. Device review and approval falls
under the FDA’s Center for Device and Radiological Health (or
CDRH). Similar to CDER, CDRH has internal divisions based on
disease or device type (e.g., cardiovascular devices or surgical
devices) and also use external independent advisory committees to
assist in the review and approval process.
Medical device development often has
important differences from drug development. Drugs do not often
change over time but devices are continually being changed
(improved or modified) based on bench or clinical performance. With
complex devices the performance of a device, and subsequent
clinical results, may be operator dependent, which is not typically
the case for drugs. Device development may be led by visualization
of the performance of the device that is clearer than predicting
the action and effects of a drug. FDA device laws and regulations
traditionally required only one trial where drugs typically require
a minimum of two trials although there is now some flexibility in
that due to the 1997 FDA modernization act [49].
Unlike drug regulation which utilizes
a reasonable uniform pathway for regulation, devices are classified
into one of three categories or classes that affect the standards
for approval and the approval process [50]. These classes are based on the level of
control necessary to establish safety and effectiveness. Class I
devices have minimal risk and are defined as those not intended to
support or maintain life and may not present any risk (e.g.,
surgical gloves). Class II devices have moderate risk and are
designed to perform as indicated without causing harm or injury
(e.g., infusion pumps, diagnostic catheters, guidewires). Class III
devices are high risk and generally support or sustain human life
or present a potential for an unreasonable risk of illness or
injury (e.g., pacemakers, defibrillators, heart valves). These
devices require FDA approval of a premarket approval application
(PMA) Due to the complexity of these devices, extensive preclinical
and clinical testing are often required prior to approval, making
this application process in many ways similar to the standard drug
approval process [51]. A 510 (k)
premarket notification [52] allows
the FDA to evaluate whether the proposed device is essentially
equivalent to a predicate device already cleared via a 510 (k).
This might be the case for a modified model of the original
predicate or a competitor’s “equivalent” model. An investigative
device exemption (IDE) is much like an IND for drugs in that it
gives the manufacturer permission to conduct trials on the device,
usually in preparation for a PMA submission [53, 54].
A PMA device is considered safe when,
based on valid scientific evidence, the probable benefits outweigh
the probable risks as long as the device is used according to
conditions for which it was intended. A device is considered
effective if the benefits are clinically significant. As with
drugs, there are no perfect intermediate outcomes to be used as
surrogates for clinical outcomes in trials of devices, but CDRH
must often rely on them. Moreover, many important PMA devices are
chronic implants where significant device failures may occur after
the intermediate time point assessed in a usual FDA device approval
trial. As a result, CDRH relies heavily on a “total product life
cycle” regulatory strategy where post market approval studies are
an important and necessary part of device assessment.
All the principles of good clinical
trial development and conduct discussed in this text are relevant
for planning an appropriate device development strategy. It is
therefore often the case that when assessing new types of medical
device technologies, a randomized clinical trial will be required
for demonstration of safety and effectiveness. However, when
considering the often small to moderate iterations that occur over
time for a particular device and/or the maturation in basic device
design that often occurs for a given device area, it may be
reasonable to consider other trial designs (i.e. nonrandomized) as
being appropriate for demonstration of safety and effectiveness.
The usual cautions apply to the use of nonrandomized designs.
Reference to the FDA CDRH guidance document on Clinical Trial
Design of Device Trials as well as consultation is therefore
recommended [55].
Given that many devices are no longer
totally or predominantly external, but may be implanted and remain
in the body for some years (e.g., pacemakers, defibrillators,
stents), concerns about adverse events occurring long after the
device implantation also need to be considered. The optimal system
for medical device development and regulatory approval remains
controversial. Unlike the U.S., the European System of Regulation
does not require demonstration of clinical effectiveness for high
risk devices prior to approval. On the other hand Dhruva
[56] and Redberg [57] using a drug-centric series of metrics
suggested that there were possibly major problems associated with
the current U.S. device approval system. Dhruva et al.
[56] assessed what kinds of
studies were conducted to support approval of 78 high-risk cardiac
devices. Of the 123 studies, only 33 were randomized clinical
trials. Only about half of the primary outcomes were compared with
controls and almost a third of these were retrospective. Almost 90%
of the primary outcomes were surrogate measures such as lesion
revascularization or lead implant success.
Redberg [57] has suggested that lack of sham controls is
often a major weakness of device clinical studies. The placebo
effect can be so great that seemingly large benefits may not
reflect a true intervention effect. She cites the apparent benefit
for treating hypertension from radiofrequency ablation of renal
artery nerves. Only when an FDA required trial using sham treatment
for the control group was conducted, was lack of benefit (versus
the blinded control) observed [58]. A similar situation occurred with laser
transmyocardial revascularization, in which open-label trials of
using lasers to create myocardial channels resulted in substantial
improvement in angina. When a sham-controlled trial was conducted,
the sham procedure was equally effective [59]. Much earlier, devices such as intermittent
positive pressure breathing (IPPB) for patients with advanced
chronic obstructive pulmonary disease were in wide spread use
before a clinical trial with a control group demonstrated no
clinical benefit [60]. Their use
was based on the ability of the device to deliver a treatment deep
into the lungs using the pressure gradient.
Objections to requiring conduct of
clinical trials with control arms and clinically important outcomes
include the fact that many devices have frequent modifications so
that a formal clinical trial for each modification would not be
feasible. In addition, many device manufacturers are small
companies that do not have the human and financial resources to
conduct large trials. Requiring a late phase trial for every device
and every modification would not be feasible for them or even for
large companies.
Rome et al. [61] looked at FDA approval of cardiac
implantable electronic devices originally and as supplements. The
authors found that from 1979 to 2012, the FDA approved 77 original
devices with an average of 2.6 supplements per device that involved
design or other major modifications. For those approved supplements
that involved major design changes from 2010 to 2012, less than a
quarter (15 of 64) provided clinical data.
Yet randomized clinical trials of
devices compared to best standard of care, using objective and
clinically meaningful outcomes, are feasible. The Comparison of
Medical Therapy, Pacing, and Defibrillation in Heart Failure
(COMPANION) trial [62] compared a
pacemaker alone and a combination of pacemaker and defibrillator
against best standard of care in a New York Heart Association class
III or IV heart failure population. The primary outcome was
all-cause mortality plus all cause hospitalization. Over 1,500
patients were randomized in a 2:2:1 ratio. For the primary outcome,
the two intervention arms were statistically and clinically
superior to standard of care (approximately 20% relative reductions
in events). For the secondary outcome of all cause mortality and
cardiovascular hospitalization, approximately 30% reductions were
observed in each device arm. The pacemaker-defibrillator arm had a
43% relative reduction and the pacemaker alone arm a 24% reduction
in mortality, both being highly significant statistically.
Despite the argument that increasing
clinical trial requirements for new or improved devices would
discourage and lessen investment in device development and
innovation, we think that many medical devices could and should be
evaluated according to the fundamentals presented in the previous
chapters.
Interventions: Biologics
From a legal and regulatory
perspective, biologics products, which replicate natural substances
in human bodies such as enzymes, antibodies, or hormones, are
generally similar to other drugs. Some, such as vaccines and blood
products, are regulated by the Center for Biologics Evaluation and
Research (CBER), whereas others, such as anti-TNF agents, are
regulated by CDER. Although they are regulated under different
acts, the standard requiring that biologic agents be “safe, pure,
and potent” is considered to be equivalent to other drugs being
“safe and effective” [63].
However, there are some differences (Siegel J, personal
communication). First, most biologics are immunogenic.
Immunogenicity affects pharmacokinetics, safety, and efficacy.
Immunogenic toxicity can be very prominent for some biologics and
very serious. Second, biologics have high specificity and are much
less likely to have off-target effects than other drugs. Toxicity,
therefore, may be more predictable. Off-target effects (e.g., on
liver, cardiac rhythm, bone marrow) are less common, although still
may occur. Third, biologics usually do not compete with other drugs
for clearance so interactions tend to be less common. Biologics,
though, can induce liver enzyme production, and can have
interactions related to their pharmacodynamics, rather than their
metabolism. Fourth, manufacturing biologics in a consistent manner
is more difficult than with other drugs, as is characterizing them.
Thus, investigators in phase III trials have a strong incentive to
use the same commercial process that would be used after approval
in preparing the biologic materials to minimize the challenge of
showing that the commercial material is comparable to the clinical
trial material.
Finally, it has been argued that
producing generic versions is far more difficult. Many think that
because it is far more difficult to demonstrate that two biologic
products are identical, the term “biosimilar” is preferable to
generic [64–66]. This has implications for how much clinical
data is required for each, presumably comparable, product. Generic
drugs, by definition, have the same active pharmaceutical
ingredient as the reference product. As a result, they can be
developed by referencing data from an approved product without
clinical testing other than bioavailability. Due to limitations in
the ability to manufacture and characterize biologics, one cannot
ensure that two products are the same, and, even if they were, one
cannot know that. Therefore, biologic generics are not technically
possible at present. Due to this broadly accepted fact, unlike for
small molecules, there is no law or regulatory pathway to have a
generic biologic in U.S., in EU, or much of the rest of the world.
As one cannot have abbreviated development pathways based upon the
same approved product indication (as for generics), abbreviated
pathways were created (part of the Affordable Care Act in the U.S.)
allowing the referencing of an approved product where a high degree
of similarity has been shown, i.e. biosimilars pathways. But
similarity as opposed to sameness leaves more potential for
clinically meaningful differences, so biosimilars pathways envision
that usually some amount of clinical testing will be required to
rule out such differences.
Post-trial Requirements
At the end of the clinical trial,
regulatory agencies will expect a complete submission of the data
in a format that is acceptable to the agency [67, 68]. The
ICH document E6 [29] lists the
documents that are considered important for the regulatory agencies
to have on file, although this list is designed for what is needed
for approval of new drugs and may not be applicable to pragmatic
trials. These documents include the protocol and any amendments,
informed consent materials, sponsor-investigator financial and
other arrangements, ethics review committee approval, master
randomization list, enrollment logs, source documents, completed
case report forms, serious adverse event reports, investigator
brochures and any updates, and product accountability.
The following discussion refers
primarily to U.S. FDA requirements. However, similar requirements
exist in other countries. Sponsors and/or investigators may face
three regulatory issues. First, if the trial shows efficacy of an
intervention and regulatory approval is sought, documentation in
support of the efficacy claim has to be submitted to the FDA,
generally through the sponsor or the manufacturer. Second, if the
regulatory agency decides to bring the case to a public FDA
Advisory Committee meeting for recommendations, the investigators
may be called upon to present the trial findings to and answer
questions by the committee. Third, FDA approval for marketing of
the intervention in the U.S. may require additional post-marketing
clinical investigations.
In January of 2015, the Institute of
Medicine (IOM) released a report on “Sharing Clinical Trial Data:
Maximizing Benefits, Minimizing Risk” which calls for sharing of
patient level de-identified data after study results have been
published or after trials have been submitted for regulatory review
[69]. While these are currently
recommendations by the IOM, they are likely to also be adopted by
many sponsors of clinical trials.
Documents for FDA submission
Many regulatory provisions govern the
types of documents that need to be submitted in connection with a
clinical trial that shows efficacy of an intervention and supports
a marketing application. The documents discussed below are not an
exhaustive list of those that must be submitted. In addition, from
a scientific standpoint, the extent of documentation necessary
depends on the particular study, the types of data involved, and
the other evidence available to support the effectiveness claim.
The FDA guidance on Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products [70] provides some general considerations on the
documentation of the quality of evidence supporting an
effectiveness claim. It notes that when submitting the requisite
quantity of data to support approval of a new product or new use of
an approved product, regulations state that sponsors must also
document that the studies were adequately designed and well
conducted. To demonstrate that a trial supporting an effectiveness
claim is adequate and well-controlled, extensive documentation of
trial planning, protocols, conduct, and data handling is usually
submitted to the FDA, and detailed participant records are
available at the clinical sites. Providing written standard
operating procedures and statistical analysis plans (as well as the
charter for a data monitoring committee, if one was used), and the
interim reports the committee reviewed along with minutes of those
meetings are also part of the documentation. Documentation tends to
be very extensive for sponsors and investigators.
Advisory Committee Meeting
Advisory committees, which are
convened when the FDA desires external advice around a drug or
device approval, provide independent advice to the FDA on a range
of issues, including those relating to a specific drug, device or
biological product [71]. FDA
regulations and guidelines concerning advisory committees do not
address what is expected from clinical investigators in the
preparation for advisory committee meetings since most of that
responsibility rests with the trial sponsor. It is possible that in
practice a sponsor-applicant may seek assistance from the trial
investigators when preparing these background materials. This
assistance could include oral presentations of the trial results or
an overall summary of the product’s benefits and harms at the
advisory committee meeting as well as written summaries of the
trial design, conduct, and results. The summary information often
includes, among other items, clinical pharmacology and dosing
evaluations, clinical efficacy data, and clinical safety
data.
Post-approval Issues and Postmarketing Investigations
Postmarketing clinical investigations
are subject to many statutory and regulatory requirements if they
have the potential or intent to support a product label change.
They are often conducted under an IND and therefore may be subject
to the IND requirements. Postmarketing reporting of adverse events
and submissions of an annual report are also generally expected.
When the product has been approved on the basis of a clinical
trial, postmarketing clinical investigations may be required if there is new safety
information or there is need to verify clinical benefit.
Postmarketing clinical investigations can be requested, as agreed-upon in
postmarketing commitments, if needed to further evaluate efficacy
and safety in a product that has undergone traditional
approval.
Certain postmarketing clinical
investigations must be registered and have results submitted to
ClinicalTrials.gov in a timely fashion. There may be financial
penalties or fines for not complying with these requirements. For
drugs and biological products, the trial registration and results
submission would be required for any “applicable drug clinical
trial,” which, in general, means a controlled clinical
investigation, other than a phase I clinical investigation. Despite
the requirement to submit data to ClinicalTrials.gov, many trials
either had delays in publication or no publication [72]. One study [73] showed that industry-sponsored trials had a
much higher compliance in entering results into ClinicalTrials.gov
than non-industry trials, although in neither case did the majority
submit results within the mandated 1 year. Low rates of data
submission were also found by Jones et al. [74]. Another study suggested that the high data
submission rates to ClinicalTrials.gov were limited to late-phase
trials [75].
The generally low rates of data
submission are perhaps due to inadequate understanding of the
requirements by the investigators. It is important that all
investigators know that trials conducted under FDA regulations or
with funding from the National Institutes of Health need to have
the data submitted to ClinicalTrials.gov. A proposal in 2014 to
expand the number of trials funded by the NIH that are required to
have their data entered into ClinicalTrials.gov [76] should be noted.
For many years, regulatory agencies
have solicited reports of adverse events that have occurred in
clinical practice, after a drug or device has been approved and is
marketed. As discussed in Chap. 12, even large trials of long
duration may miss important adverse effects. Only after something
has been used in many different people for sometimes years will
some adverse effect be identified. Follow-up is even more important
for products that are approved and marketed without trials that
monitor important clinical outcomes. For example, for drugs
approved on the basis of surrogate outcomes, and when the trials
were therefore either too small or too short to obtain sufficient
numbers of clinical events, post-marketing reports become extremely
important. However, given the lack of a rigorous control group,
postmarketing reports can be misleading [77]. Pressures and incentives to approve
products more quickly, particularly for life-threatening conditions
for which there are few if any treatment options, has led to
regulatory changes for so-called “breakthrough drugs”
[19, 78, 79]. While
the law does not allow a different standard for use of intermediate
markers as surrogates with rare diseases than for other more common
diseases, still requiring a confirmatory clinical outcome trial,
the use of surrogates or biomarkers may be necessary with rare
diseases for which a sufficiently large trial with a clinical
outcome is difficult or even impossible [80, 81].
For products that have had accelerated
approval, whether drugs, devices, or biologics, the pre-approval
clinical information is far more limited than for products that
have undergone clinical outcome trials. Part of the accelerated
approval process calls for additional post-approval clinical
assessment, including adverse event monitoring [19]. Sometimes, actual clinical trials are
required after accelerated approval. As discussed in the section on
drug interventions, the FDA approved bedaquiline for a serious
unmet need using the first of a new class of drugs to treat
drug-resistant tuberculosis [47].
This was done on the basis of a phase IIb placebo-controlled trial
on an expedited approval path, with the requirement that a
confirmatory trial would be conducted, though not completed until
2022 [79]. Approval decisions are
often difficult and controversial. There are added complications
when expedited approval is used, involving the weighing of many
factors. As in the case with bedaquiline, advisory committees and
regulatory agencies need to use considerable judgment, balancing
early access to the benefits of important therapeutic early
interventions against possible longer term harms.
More rapid approval of drugs may lead
to identification of more adverse effects after marketing. Frank et
al. [82] noted an association
between a greater number of “boxed” warnings in drug labeling and
actual drug withdrawal for safety concerns and acceleration of FDA
drug approval. However, association does not demonstrate causation
and even if an association reflects causation, the balance between
any benefits from faster approval and the harms discovered later is
unknown.
An FDA web page on postmarketing
requirements and commitments may provide useful information
[83].
Key Links
It is essential that all investigators
conducting trials that are, or might be, subject to regulatory
approval, keep aware of current regulations and guidances. Key
links are shown here:
International Conference on Harmonisation
ICH Official Web Site: http://www.ich.org/
Efficacy Guidelines:
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
U.S. Food and Drug Administration
FDA Home Page: http://www.fda.gov/
FDA Guidances:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
Conducting Clinical Trials in Drugs:
http://www.fda.gov/drugs/developmentapprovalprocess/conductingclinicaltrials/default.htm
Conducting Clinical Trials in Devices:
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM373766.pdf
Conducting Clinical Trials in Gene
Therapy:
-
Early phase clinical trials.
-
Observing subjects for delayed adverse events. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm072957.htm
European Medicines Agency
EMA Home Page: http://maintenance.ema.europa.eu/
Clinical Trials in Human Medicines:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=WC0b01ac058060676f
Health Canada
Health Canada Home Page: http://www.hc-sc.gc.ca/index-eng.php
Guidance Document for Clinical Trials
Sponsors: clinical trial applications:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/ctdcta_ctddec-eng.php
Pharmaceuticals and Medical Devices Agency, Japan
Home Page: http://www.pmda.go.jp/english/
Ministerial Ordinance on Good Clinical
Practice for Drugs.
http://www.pmda.go.jp/english/service/pdf/ministerial/20130329No_28.pdf
Bioethics Resources
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