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150 Cobert’s Manual of Drug Safety and Pharmacovigilance
Investigator-Initiated
Research
Investigator-Initiated Research (IIR) includes Investi-
gator-Initiated Trials (IITs) and Investigator-Initiated
Studies (IISs), also called Investigator-Sponsored Trials
(ISTs). These usually arise from new ideas thought up
by researchers in the academic world or occasionally
suggested by the pharmaceutical company. New uses
or ways of administering drugs are frequently proposed
by academic researchers to pharmaceutical companies.
Many companies actually have physicians, PhDs, or
pharmacologists on staff (often called “medical liai-
sons”), who travel to academic medical centers and seek
out such clever new uses. Such trials are usually done
at single centers. Sometimes, the investigator will come
up with the idea and approach the company (sponsor
or patent holder) for assistance with either a grant or
product supply (especially if the product is costly).
These types of studies are instrumental in the sci-
entific development of a drug, and are also a source of
safety data, therefore, making these types of studies an
important component of the pharmacovigilance and
safety system for any given product.
The advantages of IIR are that new ideas are found
and explored, costs are usually relatively low, and the
studies can often be done fairly quickly. The disadvan-
tage is that many details that should be determined
before the trials are not addressed (e.g., effective dose
and safety in this population). IIR that fails usually ends
that idea. Thus, if too low a dose is chosen, one might
never know that a higher dose would produce positive
results. Funding is usually from the pharmaceutical
company in the form of a grant-in-aid, drug supply,
protocol, or case report form support. It is important
to understand the roles and responsibilities of the com-
pany versus investigator.
The legal bases which support the inclusion of IITs/
ISTs in a pharmacovigilance system stem from US FDA
21 CFR 312.32 (c) (1) “Findings from Other Studies”,
which states that the sponsor must report any findings
from epidemiological studies, pooled analysis of mul-
tiple studies, or clinical studies... whether or not con-
ducted under an IND, and whether or not conducted by
the sponsor, that suggest a significant risk in humans
exposed to the drug. This regulation necessitates a
robust communication channel between Investiga-
tors conducting their own research and the sponsor/
manufacturer of the products.
Once an Investigator determines he/she will con-
duct research on a given product, there is typically a
contract or agreement signed by both parties which out-
lines each party’s role in the IIR, including the respon-
sibility of reporting safety information to the agencies
and within the two parties. This contract or agreement
is typically called a Safety Data Exchange Agreement, or
SDEA, and can be a part of the primary Master Service
Agreement, or a separate document that is legally bind-
ing and subject to review during audits and inspections.
In these cases, the legal sponsor of the study is not the
pharmaceutical company but rather the investigator. It
is he or she who opens the IND with the FDA or the
equivalent in other countries (often with the help of
the pharmaceutical company by giving the investiga-
tor permission to reference a company IND). The usual
safety provisions are followed: Good Clinical Practices,
investigational review boards, and SAE reporting to the
health agency by the investigator. Note that FDA IND
regulatory rules requires the investigator/sponsor to
handle safety reporting to the FDA, IRB, etc., as if he/
she were a typical sponsor, such as a pharmaceutical
company. Most pharmaceutical companies also require
the investigator to report SAEs to the company (in addi-
tion to the health authority) so that the company main-
tains a full safety database for all uses of a product.
The contract/agreement between the investigator
and the company must be perfectly clear regarding
safety responsibilities among the parties concerned.
This includes a mechanism for adaptation to new reg-
ulatory or partner requirements. The company should
not engage in monitoring the data, i.e., checking source
documents, because this could be construed as assum-
ing the responsibilities of a sponsor. It is less clear from
FDA regulations whether the pharmaceutical company
should also submit the cases if the company receives
them from the IIR investigator, who is required to sub-
mit them directly to FDA. These trials would technically
be phase I if a new indication, formulation, or delivery
is being studied. If not, they would most probably be
Clinical Trial Phases and Investigator-Initiated Trials 151
considered phase IV trials. Not all studies require an
IND (if the use of the drug is fully covered within the
approved labeling). Such studies usually have to be reg-
istered with the appropriate health authority and clin-
ical trial database (e.g., clinicaltrials.gov in the US and
EudraCT in the EU).
In earlier years, disputes occurred over ownership
of data and the publication (or rather lack of publica-
tion) of negative results. These are resolved, in general,
with both parties retaining “ownership” of data and
with the right to publish retained by the investigator
regardless of the results.
Ultimately, how a company decides to handle the
oversight of such studies is up to the company, but
these studies are subject to regulatory scrutiny and
should be tightly controlled and understood by both the
Investigator/owner of the IND as well as the product
manufacturer.
Other Study-Related Issues
Study phases are often hazier than the “official” schema
described above. Phase I studies that go beyond the ini-
tial dose finding and escalation studies are often done
throughout the phases over several years. If a drug does
not go beyond phase II because of lack of efficacy (i.e.,
the company “kills” it), there is little point in doing
drug, food, or alcohol interaction studies. Thus, these
are usually not performed early in the course of devel-
opment. Likewise, it is not common for the initial stud-
ies to use a formulation that is eventually approved for
marketing.
Some companies have been known to try to speed
up development (and lower costs) by doing somewhat
larger phase II trials that, should they succeed, are sub-
mitted to the health agencies as combined phase II and
III trials for approval. For critical drugs, this may be
advantageous as long as it does not compromise the
safety and efficacy evaluations. In general, the more
patients who are studied, the more comfortable one
is with the safety profile of the drug. Smaller safety
databases obtained in phases I–III may require larger
post-marketing safety study commitments to obtain
additional information to adequately evaluate the ben-
efit/risk profile as larger numbers of disparate patients
use the drug. Obviously, the sponsor should discuss any
proposed alterations of the classic drug development
with the health authorities.
Phase I studies are created and supervised in most
pharmaceutical companies by a dedicated phase I group
(e.g., the pharmacokinetics/pharmacodynamics group)
usually run by pharmacologists (PhDs, PharmDs),
nurses, and physicians. The actual study is often out-
sourced to CROs or academic centers (clinical research
units), where the patient enrollment and dosing occur.
This permits close observation and continuous moni-
toring of participants.
Phases II and III are usually run by “high power”
clinical or medical research groups within the company
led by physicians (often sub-specialists such as cardiol-
ogists, oncologists, etc.). These studies are complex and
have large infrastructures supporting them in biostatis-
tics, study-site monitoring, in-house data monitoring,
clinical research, regulatory affairs, safety monitors,
quality control, quality assurance, coordination of cen-
tral laboratory services, independent data monitoring
committees for individual protocol oversight, a Safety
Assessment Committee for development program over-
sight across all protocols, and so on. Many companies,
particularly smaller ones, also outsource the trials (or
parts of the trials) to one or more CROs and other ven-
dors. These studies are rigorously done and are likely
to be audited by the health authority before marketing
approval. A co-development or co-marketing arrange-
ment will increase complexity and increase require-
ments for well-organized logistical arrangements. The
team must agree on SOPs and training, coding conven-
tions, record-keeping responsibilities, and a governance
structure. These agreements must be reviewed period-
ically if changes occur in either party or new parties
enter. These studies may run into tens of millions of
dollars and require complex organization, project man-
agement, and information technology support.
Phase IV studies may be done by the phase II and III
group or by a separate post-marketing group. If phase
IV studies are done in the clinical research department,
the rigor of the earlier phases usually carries over to
these phase IV studies. If the phase IV studies are done
152 Cobert’s Manual of Drug Safety and Pharmacovigilance
by the marketing department in isolation from the clin-
ical research group, these studies may be somewhat
more variable in quality and rigor. Some companies
now have separate Safety/Epidemiology/Risk Manage-
ment departments that handle PMCs and PMRs, e.g.,
post-marketing clinical and epidemiologic trials (but
not the marketing studies). Many of these are now out-
sourced to CROs or firms specializing in “late phase”
trials.
Some company executives have argued that small
phase IV marketing studies or IIR programs are danger-
ous because they might discover some safety “problem”
and might fail to show efficacy, thus doubly hurting the
drug. Safety officers often argue just the reverse: these
studies may uncover a previously unknown safety issue
that represents good product stewardship, i.e., the new
finding can be added to the product labeling to better
inform prescribers and patients. It is arguably better for
a company to discover a potential issue first, so that the
company has strong and useful input into the situation.
Clinical trial registries have been set up by health
authorities and governments (clinicaltrials.gov in the
US and EudraCT in the EU), as well as by pharmaceu-
tical companies and others in which all or almost all
research trials are now posted, in detail, on a website. It
has been felt by some that this will raise the standards
for all trials and allow for easier data comparisons. That
is not yet clear. Several things have happened, though.
Patients, disease support groups, and patient advo-
cates are now more easily able to find and track studies
involving their disease by simply searching through the
databases. There is also an industry that mines various
databases for information on patient and investigator
availability, enrollment, completion dates, and so forth.
IIR programs have traditionally posed problems. IIR
is usually encouraged by companies that have roving
medical liaisons. They visit academic medical centers
to provide medical information and seek out new trials.
These visiting medical liaisons may or may not be trained
in classic clinical research methodology. They may also
do “in-service” teaching or training on the company’s
new products. Thus, this role combines a medical and
a marketing function. In well-structured pharmaceuti-
cal companies, protocols submitted by academics are
reviewed by the clinical research department, the stat-
isticians, and the pharmacovigilance group to ensure
good quality. A formal contract requiring completion,
a final report within a finite period (e.g., 1 year), and
SAE reporting must be done under good clinical prac-
tices. Pharmacovigilance departments in companies
usually submit the SAEs to their own MAs, NDAs, and
INDs, as the case may be, even if the investigator has
said he or she has also done so. In less well-structured
companies, the medical marketing group may be less
well-connected to the other research groups and details
may slip. Specifics of the contract (agreement) should
be audited for compliance.
Other types of outreach programs (sometimes in
combination with registries) are also used by compa-
nies for various reasons:
To help patients finish the course of therapy when
they are already taking the drug;
As part of a REMS/RMP as an ETASU (an “element
to assure safe use of the drug”);
To help sell the drug: In particular, for chronic
therapy diseases such as cancer, hepatitis, and
hypertension, companies have found that it is
good medicine and good marketing to encourage
patients to stay on their therapy to the end (until
the cancer is in remission or cured, the viral titers
drop, etc.). This means continued sales of the drug
as well as successful patient treatment. The usual
reasons for stopping therapy are AEs, dosing prob-
lems, or convenience reasons. Sometimes it is cost.
Outreach programs that use nurses or pharmacists
to contact patients every week or month on how
to handle AEs and other issues are now common.
These are a type of a Customer Engagement Pro-
gram and must be linked to (or at least known
to) the safety department because they are often
a source of safety information. When the program
is well-executed, the patient’s physician is kept
informed of issues and progress. The outreach
team is able to work with the patient to get the
patient over rough patches in the treatment regi-
men. AE data must be collected by the company,
kept in the safety database, and reported to the
health authority as required.
Clinical Trial Phases and Investigator-Initiated Trials 153
Frequently Asked Questions
Q: Does the company have to collect all AEs
from all trials?
A: Basically yes. The sponsor has a responsibility to
fully understand the safety profile of the product, and
in order to do so, you need all of the data available.
Second, it is legally required in most instances (US FDA
21 CFR 312.32(c)(1) and 312.32(c)(1)(ii) support this
requirement). In practice, only SAEs must be collected
from clinical trials in real time by the sponsor, i.e., the
sponsor’s drug safety group. The data must be evalu-
ated and reported to the authorities either in 7 or 15
calendar days or periodically in annual reports. Tighter
timelines may be required by SOPs or in certain con-
tracts. Non-serious AEs and some SAEs (e.g., expected
SAEs that the sponsor and health authority agree will
be reported only at the end of the study) do not get
reported until the final study report.
Q: What if the clinical trial data is in multiple
databases? How can I collect all the data from
various sources?
A: In many pharmaceutical companies, two or more
databases contain safety information. There is the drug
safety database maintained by the drug safety group for
expedited and periodic regulatory reporting and the
clinical research database for marketing authorization
and NDA submissions. Furthermore, if you have mul-
tiple studies ongoing with different CROs, your data
could end up in a variety of places that needs to be
consolidated into a single system. The safety database
contains all SAEs (as well as all serious and non-serious
post-marketing AEs) but not non-serious clinical trial
AEs. This database is dynamic and always up to date.
The clinical research database contains the (paper or
electronic) case report form information, including all
serious and non-serious AEs.
Sometimes data are not entered into the clinical
research database rapidly but rather only when paper
case report forms arrive in the research department,
perhaps monthly. In other cases, where electronic data
capture is used instead of paper CRFs, the data entry at
the site may be delayed or incomplete. Some companies
using electronic data capture (EDC) also require an
e-mail, fax, or direct download of EDC data into the
safety department’s database. Nonetheless, the use of
electronic case records should make data available more
rapidly than in paper-based studies.
Q: What are the challenges with having multi-
ple systems with the same data?
A: Having two databases produces various problems.
To get a full picture of the safety in the trial, one must
obtain the SAEs from the safety group (their database
is usually up to date) and the non-serious AEs from
the clinical research group’s database (which may not
be up to date). The data outputs must then be recon-
ciled (a problem if the two database outputs are not
compatible or normalized) to have a full dataset. In
addition, the SAEs in the two safety databases must
be reconciled if the same SAE safety data are collected
in two different places or in two different ways (e.g.,
EDC and e-mail/fax of the case to the sponsor’s drug
safety group).
For example, if a company has single case reports
(ICSRs) in one database, and aggregate reports in
another, these databases must be synchronized for cod-
ing conventions and other data points. This has been a
source of regulatory findings in inspections.
Signaling investigations should be done using all
serious and non-serious clinical trial data no matter
where they are stored or how they are obtained. This
may mean the creation of a “data warehouse” to allow
access to the data contained in both databases. It is likely
that, as EDC and health data standardization advance,
clinical trial safety data will be collected in one place
without the need for double collecting systems.
Modernizing clinical trial data collection will have
many implications:
Safety data (serious and non-serious AEs) would be
received in real time.
Electronic data entry would be done remotely at
each study site rather than centrally at the com-
pany or CRO. This takes the data entry out of the
direct control of the company or CRO and put into
the hands of employees (of variable skill levels and
154 Cobert’s Manual of Drug Safety and Pharmacovigilance
oversight) at each investigational site. Issues with
training, personnel turnover, and quality mainte-
nance at each site now become critical.
The company drug safety database may not be
linked electronically to the EDC database, and new
procedures would have to be developed to get the
safety data to the safety group for entry into the
safety database in an accurate and timely manner.
Source documents (e.g., laboratory tests, X-ray
reports) might not be sent to the company now
that studies are “paperless”. In fact, source doc-
uments may now be electronic, because the clas-
sic case report form no longer exists. Where paper
source documents exist, they may need to be
scanned and added to the EDC, clinical trial, or
safety databases.
Getting follow-up information, which continues to
be a challenge, will still remain difficult. One can envis-
age the day when the US, the EU, and other medical
systems are standardized and online. All data, including
study data and safety data, will be sent electronically
in real time and simultaneously to all needed data-
bases at the company, the health agencies, the hospital,
the insurance companies, and so on. Safety data will
be accurate and rapidly received everywhere they are
needed. Maybe. Some hope that AI will help smooth out
this situation in the future.
Q: Are phase IV study SAEs reportable as
clinical trial AEs (to the IND in the US) or as
post-marketing AEs (to the NDA in the US), or
as both?
A: If a study is done under an IND or a similar pre-
marketing situation, then the SAEs that meet reporting
criteria are reported to the IND. Note that FDA would
like only “informative” reports. Further, FDA is skep-
tical that causality can be attributed using reports of a
single subject. Thus, similar reports in the aggregate are
perceived to have greater value than single cases, partic-
ularly when background rates of the event are consid-
ered. Many companies believe that the NDA/MA takes
precedence over the IND and would report those SAEs
to the NDA/MA, also. This may vary from country to
country, so local rules and regulations must be checked.
SAEs from studies not done under an IND should be
reported to the NDA and in most jurisdictions treated
as post-marketing AEs.
Q: If multiple companies or investigators are
involved in a trial (whether it is an IIR or a for-
mal company sponsored trial), should there be
double (or even triple) reporting just to be sure
the cases are not missed?
A: There is no logical reason for duplicate reporting in
general and most regulators discourage this. If more
than one company is involved, the protocol or other
formal written document should contain an agreed-
upon mechanism for a single company to handle safety
reporting. In such situations, both companies may keep
the AEs in their respective databases, but only one com-
pany should submit the cases to the regulatory author-
ities both as expedited and aggregate (annual) reports
(and the companies should audit each other for compli-
ance with the agreement).
In some situations, however, companies request
that the investigator involved in IIR send a copy of each
SAE ICSR to the company. The investigator, as the spon-
sor, must report such cases to the regulatory authority.
The company, in many cases, will also report the case to
the regulatory authority “just to be sure”, noting in the
transmission that this is an IIR and that the investigator
is the sponsor and should be submitting the case. Note
that in certain cases a duplicate report must be sent to
an IND and an NDA at FDA.
Q: Should AEs be reported from observational
or epidemiologic trials or registries?
A: This again may vary from country to country, but
in general, yes, if a case meets the four validity crite-
ria, then it should be submitted even if it is not from
a classic clinical trial. The FDA clarified this issue in
its IND reporting guidance by saying that such cases
must be reported. For large amounts of data (e.g., “data
dumps” from poison control centers), the sponsor may
wish to discuss with the agency how such large num-
bers of cases should be handled. The study protocol
should specify how these data should be identified and
handled and, in some instances, by agreement, will not
be reported.
Clinical Trial Phases and Investigator-Initiated Trials 155
Q: I thought most of the reporting require-
ments for clinical trial SAE cases have been
harmonized, so why does it seem so complex?
A: To a degree, there has been harmonization. Clinical
trial deaths and life-threatening SAEs that are unla-
beled and possibly related to the study drug are report-
able in 7- and 15 calendar days, respectively. However,
there are substantive differences between the way these
reports are handled for the US FDA and the rest of the
world. Outside the US, each individual SUSAR (sus-
pected unexpected serious adverse reaction) should be
expedited; causality is per either the investigator or the
sponsor. While the regulatory definition of “serious” is
consistent and there is a single, worldwide Investigator
Brochure for expectedness, determination of causality
for reporting to the US FDA is the responsibility of the
sponsor (only). Further, the term “SUSAR” is not rec-
ognized in US regulation, even though the concept is
the same. Across the globe there are many exceptions
or other requirements, local language requirements if
the case is a domestic case, non-expedited reporting if
the case is not domestic, and so forth. Some countries
want or require electronic reporting and others still take
or require paper reports (e.g., CIOMS I or MedWatch
forms). It is likely things will harmonize eventually,
but they are not yet at the level of harmonization for
post-marketing case reports. Note that there are dif-
ferent requirements for medical devices, combination
products, and, in some countries, there are different
requirements for over-the-counter products, neutraceu-
ticals, biologics, and herbals. Finally, a drug may be in
clinical trials and not yet approved for marketing in one
country, and approved and marketed in another coun-
try with different reporting requirements.
Note that the United States spells “harmonization”
with a “z” (pronounced “zee” in the United States and
“zed” elsewhere) and the UK and others as “harmonisa-
tion” with an “s”. So, we have not yet even harmonized
spelling and pronunciation!
Q: What if an Investigator performed the IIT
and did not inform the company?
A: This happens all the time. Unfortunately, some large
companies do not have a clear process for communicat-
ing with the MAH of the product. Therefor it is within
the best interest of the company to develop a process
to monitor Clinical Trial Listings (through ClinicalTri-
als.gov in the US for example) and conduct a regular
(suggest monthly) search for new trials involving their
products. Another suggestion would be to publicly state
your company policy on how to handle IITs and how
potential investigators can work collaboratively with
the manufacturer on developing their product for fur-
ther use. Making a company policy publicly available
may help with Investigators proactively including the
manufacturers in the beginning.
CHAPTER
157
13
Data Monitoring
Committees and
Investigational
Review Boards/Ethics
Committees
Data Monitoring
Committees
Over the years, in addition to Investigational Review
Boards (IRBs), the concept of a separate and additional
independent group to monitor the safety of clinical
trials has developed. This group or function is known
under several names, including Data Monitoring
Committee (DMC), Data Safety Monitoring Board
(DSMB), Data Safety Board, Clinical Trial Safety
Monitoring Committee/Board, and others. This was
codified as a draft guidance by the US Food and Drug
Administration (FDA) in 2001, updated in 2006 and
February 2024 and by the European Medicines Agency
in 2003, updated in 2005. (It must be read in conjunc-
tion with ICH Note for Guidance E3, E6, E9 but also
with Directive 2001/20/EC).
These committees are typically overseen by the
clinical development and regulatory teams, however
the safety and pharmacovigilance department should
have explicit insight into the charter and activities as
it relates to the safety evaluation of data and outcomes
that need reporting to agencies in either expedited
reports, interim analysis, or annual reports.
As stated in the FDA document: “A clinical trial
DMC is a group of individuals with pertinent expertise
that reviews on a regular basis accumulating data from
one or more ongoing clinical trials. The DMC advises
the sponsor regarding the continuing safety of trial sub-
jects and those yet to be recruited to the trial, as well
as the continuing validity and scientific merit of the
trial.” Usually, a DMC/DSMB focuses on a single pro-
tocol. The FDA has more recently introduced the con-
cept of a Safety Assessment Committee (SAC) charged
with monitoring an entire development program, i.e.,
all protocols.
The EMA definition is similar: “A group of indepen-
dent experts external to a study assessing the progress,
safety data and, if needed, critical efficacy endpoints of
a clinical study. In order to do so a DMC may review
unblinded study information (on a patient level or
treatment group level) during the conduct of the study.
Based on its review the DMC provides the sponsor with
158 Cobert’s Manual of Drug Safety and Pharmacovigilance
recommendations regarding study modification, con-
tinuation or termination.”
Even if some DMCs can be set up to assess both effi-
cacy and safety, the primary mandate is patient safety.
The sponsor or creator of the DMC can be the holder
of the IND or equivalent, a company or government
agency, or any individual or group to whom the spon-
sor delegates authority for decision-making, including
the study steering or executive committee, the contract
research organization (CRO), or the principal investiga-
tor. The presence of a DMC, however, is additive to the
safety precautions in the trial. All legal and regulatory
obligations in all jurisdictions must still be carried out
by the investigator (patient protection, AE reporting,
etc.) and sponsor (expedited reporting, signaling, etc.).
The DMC must be independent, meaning that no
member has any personal basis for preferring the trial
outcome to be in one or the other direction, and no
member has any ability to influence the trial conduct in
a role other than that of a DMC member.
The committees should contain at least three mem-
bers (usually those noted with an * below) and include
such expertise as follows:
1. *Clinical medicine (appropriate specialty)
physician
2. *Biostatistics
3. Biomedical ethics
4. Basic science/pharmacology
5. *Epidemiology/pharmacovigilance — drug safety
6. Clinical development and clinical trial methodology
7. Legal /regulatory
8. Patient advocate/community representative
These members should be on every committee.
Sometimes there are more than one from these areas.
The other members are not necessarily required. Some-
times ad hoc guests with expertise in these areas may
attend as needed. Patient advocates are usually not
included.
Ideally, there should be geographic representation,
especially in international trials, demographic repre-
sentation on the committee relevant to the trial (race,
gender, age), personalities amenable to consensus
development, reliability and time to attend meetings,
and prior DMC experience. The appointment to the
committee should be made by the sponsor, and, for
government-sponsored trials, members should be
acceptable to the health agency and the investigators.
Expenses and honoraria should be paid by the spon-
sor, and the members should be independent and free
of conflicts of interest. The DMC should not have any
representation from the industry sponsor, study inves-
tigators, or individuals who stand to gain or lose finan-
cially from the study outcome, such as major consul-
tants or investors in the sponsor or a competitor. A
DMC member should not have any planned author-
ship of publication(s) or of study results. A DMC may
cover more than one trial if the studies are very closely
related (note FDA’s requirement for a program-level
SAC).
A DMC is needed in general for the following:
FDA criteria:
Large, randomized multi-site studies that evaluate
treatments intended to prolong life or reduce risk
of a major adverse health outcome such as a cardio-
vascular event or recurrence of cancer;
Any controlled trial of any size that will compare
rates of mortality or major morbidity;
When DMC review is practical; and
When DMC review helps ensure the scientific valid-
ity of the trial.
EMA criteria:
In case of life-threatening diseases, usually the
implementation of a DMC is indicated from an eth-
ical point of view;
Certain patient populations (even if trial is in a
non-critical indication): pediatric and mentally dis-
abled patients;
Prior knowledge or strong suspicion that a treat-
ment under consideration has the potential to harm
patients (even though it will be eventually more
effective than other available treatments);
Pre-planned interim analyses for early stopping
(either for futility or for positive efficacy) or in
case of complex study designs in which a possible
Data Monitoring Committees and Investigational Review Boards/Ethics Committees 159
modification of the study design based on unblinded
interim data is intended. In such a situation, the use
of an independent DMC gives more credibility to
the process.
Some trials should almost always have a DMC:
1. If more than one investigational drug is being
used in a trial;
2. Trials where early stopping for efficacy is considered:
Treatment reduces mortality or major morbidity;
Treatment reduces toxicity, cost, or other
important secondary factors while maintaining
efficacy against mortality/major morbidity;
3. Trials raising special safety or ethical concerns:
Early AIDS vaccine trials;
Gene therapy trials;
Trials in especially vulnerable populations;
4. International and multi-center trials;
5. Phase III confirmatory trials;
6. Phase IIb proof-of-concept trials;
7. Trials where review by independent experts
would optimize patient safety and the scientific
integrity and credibility of the trial; and
8. Politically sensitive or highly “emotional” trials.
When a DMC is generally not needed:
1. Not required or recommended for most clinical
studies (FDA);
2. Trials at early stages of product development, for
example, phase I (FDA);
3. Trials addressing lesser outcomes, such as relief
of symptoms, unless the trial population is at ele-
vated risk of more severe outcomes (FDA);
4. A clinical study that can be performed in a short
time frame that does not allow for appropriate
preparation of information for a DMC or the
DMC process would delay the finalization of the
trial (EMA);
5. Clinical studies in non-critical indications where
patients are treated for a relatively short time and
the drugs under investigation are well character-
ized and known for not harming patients (EMA).
The DMC will have several functions during a
trial, including the rapid identification of any safety
problems; of logistical problems, such as inadequate
subject/patient accrual, undesirable distribution of
baseline characteristics, excess dropouts, or protocol
non-compliance; of the continued feasibility of the trial
as designed; and of whether the trial objectives have
been met and the trial terminated early. The commit-
tee must maintain full confidentiality, as they will usu-
ally receive unblinded data. Health agencies typically
expect that confidentiality of the interim data will be
maintained even if the DMC interacts with the spon-
sor or trial investigators to clarify issues relating to the
epidemiologic context, the conduct of the trial, poten-
tial impact on the trial of external data, or other topics,
such as scientific or medical progress that eclipses the
value of the trial.
To these ends, the DMC will review and approve the
study protocol, assess the study conduct, evaluate accu-
mulating data for both safety and efficacy, recommend
termination or continuation of the study, recommend
modifications of the study (including the informed
consent), and recommend additional safety or efficacy
analyses, if appropriate. Requests for additional anal-
yses will ordinarily focus on specific parameters and
results will only be distributed to DMC members on a
confidential basis.
There should be an internal procedure (SOP) that
discusses how each DMC is organized, the necessity for
a charter, and how they will receive and report informa-
tion. The SOP should be general enough to have appli-
cations to a variety of protocols and the charter should
be the more precise document that governs the DMC.
The DMC must have a written charter that is drafted
and approved by the sponsor and DMC members, ide-
ally before the first DMC meeting. The health agency
may in some cases also be involved in the drafting and
approval. The charter must include the schedule, for-
mat, and venue for meetings, including unscheduled
meetings if a safety problem occurs, the format for pre-
sentation of data, the specification of who will have
access to interim data and who may attend all or part
(closed sessions) of the DMC meetings, procedures for
assessing conflict of interest of potential DMC members,
the method and timing of providing interim reports to
the DMC from the sponsor or data-gathering group, the
definition of a quorum for decision-making, and details
on how the committee will communicate (webinars,