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350 Cobert’s Manual of Drug Safety and Pharmacovigilance
In countries with limited Regulations, they usually
consider a reference country (EU, USA …) for label-
ing content; both SmPC and PIL are then copied/pasted
from those of the reference country.
Comments
The pharmacovigilance worker in a company or health
agency should be sure to receive updated labeling by the
group in charge of preparing these documents. Though
obvious, this is not always routine. Groups other than
those that deal with pharmacovigilance usually prepare
labeling, and preparers may not always remember to
distribute new labeling to drug safety and other groups
that need it.
For pharmacovigilance professionals, knowl-
edge of the labeling for the drugs for which they are
responsible is absolutely necessary. For drugs
with many AEs, it is generally a good idea to prepare
a separate table as a reference, listing the AEs, to aid
when determining expectedness. These AEs may, in
fact, appear in multiple sections and at varying levels
of specificity. They should be harvested and grouped
appropriately so that a ready reference (known as a
“cheat sheet”) can be consulted when evaluating and
coding AEs. It may be useful to list the corresponding
MedDRA terms and level (verbatim, preferred term,
lower-level term). Some computer safety databases are
able to mechanize the specific MedDRA terms that are
considered labeled/listed, obviating the need for such
“cheat sheets”. All such cheat sheets should be con-
trolled and validated.
Many drugs have multiple labeling documents if
there are different preparations (e.g., different label-
ing for intravenous and oral preparations of the same
active ingredient). The AEs in the two labels may differ
because some will be route-specific (e.g., injection site
reactions or those related to a first-pass effect after oral
intake).
Some companies are working on QR code solu-
tions for labeling. A QR code (abbreviated from Quick
Response Code) is the trademark for a type of matrix
barcode (or two-dimensional barcode) first designed
for the automotive industry in Japan. A barcode is a
machine-readable optical label that contains informa-
tion about the item to which it is attached. The goal is
to allow one to scan a QR code on a drug package with
a smart phone or other device after which the package
leaflet/labeling immediately appears (in your native
language) on your cell-phone screen. Such a solution
would ensure that each patient has the up-to-date drug
label. The QR code option for labeling is not likely to be
required in the short term but some health authorities
are investigating whether such a mechanism should be
made mandatory in addition to the current word-rich
printed process.
The UK MHRA is one of the health agencies that
performs many PV inspections. Their inspections are
well known to be thorough and detailed. Each year they
publish the most frequent findings identified during
routine periodic and special “for cause” inspections.
Note that the information for 2021 occurred during
the height of the Covid pandemic and lockdowns.
Fewer inspections were done and it is not clear that one
can ascribe the drop in critical and major findings to
improvement in labeling.
In 2014, the most frequent critical findings were
due to labeling update (42% of critical findings). This
percentage decreased to 17% in 2017 (20% in 2021 —
the limited number of critical findings over the past
years does not permit meaningful interpretation). The
previous figure shows the importance and attention the
UK health authorities give to the labeling update pro-
cess as well as any commitments (e.g., content, format,
MHRA PV
Inspections
Critical findings Major findings
Labeling
update
number
Total
number Percentage
Labeling
update
number
Total
number Percentage
2014 8 19 42% 21 192 11%
2021 1 5 20% 5 59 8%
Product Labeling 351
timelines) that the company might promise to the health
agency. This concern is shared by all health authorities
and companies must scrupulously handle label updates
and commitments made to each agency (https://www.
gov.uk/government/statistics/pharmacovigilance-in-
spection-metrics-2009-to-present).
Frequently Asked Questions
Q: It seems rather duplicative and wasteful
to have each country handle the labels sepa-
rately. In general, wouldn’t the safety profile
be the same worldwide? Wouldn’t one label be
sufficient for a marketed drug?
A: In theory, both questions should be answered with a
“yes”. However, labeling is quite complicated, and each
health authority wants to reserve its right to review and
change the labeling. The CCSI is the common world-
wide label, and this concept seems to work well and
could reasonably be extended to full official labeling.
That said, there are situations in which a drug might
work differently in one group or region. Thus, regional
differences requiring different labels may be justified in
some cases. Nonetheless, all differences and sub-groups
could still be listed in one single global label. One, two,
or perhaps three countries at most could be responsible
for a drug and its labeling, safety profile, and updates.
This probably is feasible but, given the geopolitical sit-
uation in the world, is unlikely to come about anytime
soon.
Q: Since the health agency in each country
has the ultimate approval authority for all
labels, it seems then that they would have the
responsibility for label updates. What is the
actual responsibility of the pharmaceutical
company?
A: In theory, we could consider each health authority to
be independent and responsible for the content of the
label, as they actually approve the document. In real-
ity though, the scientific and medical data are handled
primarily by the pharma companies. It is the companies
that receive most ADRs and source data on their drugs.
The companies prepare ICSRs and aggregate reports
(PSURs/PBRERs) and submit them to the agencies with
this data. If, by chance, the health agency is the first one
to receive new and important information, the agency
will often immediately contact the company and send
them the data so that both the agency and company can
review to it and put in place any changes necessary.
Many health agencies are small and do not have the
capacity to review all data on all drugs approved in their
country. So it is generally accepted that the responsibil-
ity lies with the companies. Most lawyers would agree
with this!
More generally, we can describe four different rea-
sons to support the view that labeling is largely pharma-
ceutical company’s responsibility:
Scientific and medical: it is the company’s
responsibility to include any important and up to
date information in the labels to help patients and
healthcare professionals to be fully aware of the
information for safe prescribing and use.
Ethical: As drugs are products used to treat or pre-
vent diseases/symptoms, it would not be ethical to
hide needed information.
Regulatory: The product information documents
are heavily regulated and each company must fully
comply with all regulations in all the countries
where their drugs are authorized.
Legal: Media attention on major drug safety issues
can produce or magnify the legal risks and conse-
quences of incomplete or inaccurate labeling. This
can lead to lawsuits against companies.
In the US, there is the concept of the “learned
intermediary”. This doctrine states that a manufac-
turer (e.g., the pharma company) has fulfilled its duty
of care by providing the prescriber (e.g., the physician)
of all needed information (“material risks”). It is then
the prescriber who informs the patient of risks. This
is a complex legal doctrine. Certainly, consult with an
attorney knowledgeable in this area for more definitive
information.
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CHAPTER
353
32
Business Partners
and Exchange of
Safety Data
D
evelopment costs for a new
chemical entity from creation
to marketing can cost from $160
million up to $4.5 billion based on
2021 data (https://link.springer.com/
article/10.1007/s40273-021-01065-y).
In addition, patents are now being
challenged and generics are prolifer-
ating. Many new products, particularly
biologics and oncology products are
developed by small, start-up compa-
nies who do not have the capacity to do
the full development.
One response to these phenomena
includes the development and market-
ing of a product by multiple partner
companies; small companies can also
sell their products to big pharma at
the end of phase I, II or III. The cost for
development of a new chemical entity
from creation to marketing can be in the
billions and require an endless number
of legal arrangements between other
manufacturers, packers, co-developers,
licensees, and even other marketing
authorization holders depending on
the region. The variety of entities are
often referred to as a lump of “business
partners” and are an important and
critical part of the pharmacovigilance
system when considering the safety
data that can be known and researched
by each entity.
354 Cobert’s Manual of Drug Safety and Pharmacovigilance
Therefore, when discussing sources of
safety data, we must consider the vari-
ety of different business partners and
entities that have access to important
safety data and develop a process for
the exchange of that data to remain
compliant with regulations and ensure
up-to-date information regarding a
product at any given time. The activity
of organizing the proper arrangements
and exchange of safety data in a timely
manner for even a small to mid-size
pharmaceutical company can often be
a full-time job and requires direct and
well managed cross-functional engage-
ment with areas such as Legal, Qual-
ity, Finance, Marketing, and Clinical
Development. It is extremely import-
ant to establish and maintain efficient
communication between and among
all relevant functions, particularly
when two or more business entities are
partners.
Introduction
A common method used by companies to share costs
and reduce risks is partnerships. The goal is to speed
up development and use the additive or synergistic
strengths of each partner. Co-development may be lim-
ited to two partners, but combinations of three or more
partners are common, especially when expanding into
areas (e.g., Japan, China) where language, laws, and
customs are often a challenge for US and European
companies or small start-ups. The current trend in the
pharmaceutical world is for co-development and co-
promotion/marketing of products as expenses skyrocket
and simultaneous rather than sequential international
development occurs. We are seeing large, small, and
midsized companies creating contractual arrangements
with one or multiple other pharmaceutical companies,
contract research organizations (CROs), and other ven-
dors to handle development, sales, marketing, safety
handling, regulatory matters, phone centers, manu-
facturing, and just about every other possible function
except senior management. These contracts may be
short-term or long-term and involve companies all over
the world. There are many possible combinations; some
partners are chosen for expertise in a particular country
or region or technical discipline.
Whenever two or more companies join forces for
whatever reason, a written contract must be developed
between or among them. Normally, these contracts are
developed by the “business development” or the “licens-
ing group” with input from the legal department and
other groups on a “need-to-know” basis. Often, they are
developed under great secrecy (for competitive reasons),
and others in the company are not informed of the sit-
uation until the last minute, when their input and/or
approval is requested, often with a minimal amount of
lead time. (“The CEO wants to sign this contract tomor-
row morning. Please approve your section now.”)
The safety group (unless involved in due dili-
gence) may be one of those groups learning about the
agreement at the last minute and asked to review a
document with a minimal or even non-existent safety
section. Sometimes when the safety section is present,
it is incorrect and would not keep the company in com-
pliance with regulations in countries where the partners
are working or help protect the company from litigation
and other pitfalls. This can be a problem if the CEO
wants to sign the agreement immediately (see above).
When such a situation occurs, the immediate acute
step is to ask that the safety section, if inadequate, be
removed and replaced with one or both of the following:
1. A “generic” or “one-size-fits-all” safety section
(see below).
2. A statement that a safety section is needed and will
be developed by the safety groups of the respec-
tive signatory companies to cover safety data
issues within, say, 90 days. It will be appended
to the agreement or will act as a stand-alone
Business Partners and Exchange of Safety Data 355
agreement (whichever the lawyers prefer). This
time frame may need to be shortened if the sales
or studies start in a shorter time. Often, however,
studies or sales will not begin for several months,
giving all parties sufficient time to develop a safety
section. One advantage of a stand-alone pharma-
covigilance agreement is that it can ordinarily be
modified relatively easily if (when) regulations/
requirements change during the course of the
contract. The parties would then not need to open
and renegotiate the entire contract. Sales or devel-
opment of a drug should not be started by a part-
ner unless a safety section is in place.
Why a Written Safety
Exchange Agreement
is Needed
Why does a company need a Safety Data Exchange Agree-
ment (SDEA) or Pharmacovigilance Agreement (PVA)?
Primarily, it is required by law (e.g., FDA: 21CFR314.80(b);
EU: See Good Vigilance Practice, modules I and II). Sec-
ondly, these agreements help facilitate the successful and
timely exchange of data regarding a product, thus further
increasing compliance with safety reporting obligations.
Thirdly, if these agreements are tracked and executed
properly, it will assess with the overall oversight of the
Pharmacovigilance System for any given product, thereby
increasing visibility to the EU QPPV via the PSMF and
other key safety stakeholders globally.
One may come across individuals in a company that
see this activity as a burden of task and an unimportant
hindering activity, which can lead to non-compliance
and a disruption of the exchange of data. And it adds to
the overhead of the partnership! Therefore, it is critical
to ensure the applicable functional areas are all trained
on the legal basis for these requirements to receive suc-
cessful buy-in and cooperation.
There are other reasons to have safety agreements
in place:
To give guidance and instructions to all involved par-
ties regarding their responsibilities for drug safety;
To ensure that all parties receive the safety docu-
ments they need to remain in full compliance with
all regulatory and legal requirements in their juris-
dictions of sale or study;
To ensure that adequate signaling is done periodi-
cally and that a benefit-to-risk analysis incorporates
as complete a database as possible;
To produce the best product labeling possible to
enhance proper product use and to protect the pub-
lic health;
To have the contract and PV data ready for a corpo-
rate audit or health authority inspection; and
To have data available for litigation should that sit-
uation arise.
A general principle to keep in mind during
exchanges with the other partner(s) is to try to avoid,
as far as possible, duplication of work. Quite often, this
is challenging as the other partner refuses any com-
promise and wants to stick to its internal rules and
SOPs. Nevertheless, accepting duplicate tasks means
that very often additional prospective periodic quality
controls to ensure consistency must be put in place
to ensure compliance and data reconciliation to avoid
conflicts because of non-compliance/discrepancies/
divergences. Duplication also adds to cost. The best
option is to share risks and responsibilities in an equi-
table way based on the skills of each company. For
example, a partnership between a big pharma and a
small startup company may be worked out such that
there is one single safety database under the control
of the big pharma with access (either full or limited)
by the smaller company. The smaller company may be
given other duties (e.g., case follow-up by the small
company in its territories).
Telling the Safety
Department about a New
Contract or Arrangement
The safety department should be informed of any
agreement being negotiated early in the process so it
can review the document and determine what is needed
concerning safety. It is usually prudent to perform a due
356 Cobert’s Manual of Drug Safety and Pharmacovigilance
diligence evaluation of the pharmacovigilance functions
of the parties to the contract as early in negotiation as
prudent (the due diligence process must also investigate
past PV activities to ensure no safety signal has been
missed for the concerned product(s)). This approach
should be included in company standard operating pro-
cedures (SOPs) that address the negotiation of agree-
ments with other parties where drug products (either
finished products or components) are involved. Agree-
ments for non-product-related items do not need to be
included (e.g., raw chemical products, supplying vend-
ing machines, or ordering furniture).
Many types of arrangements must have safety
agreements. They include but are not limited to agree-
ments on licensing-in or licensing-out; manufacturing;
co-marketing; co-development, including pre-clinical
or clinical development; advertising; clinical study
research; consultants; contract sales forces; distribu-
tion; disease management programs; patient support
programs; promotion and co-promotion; speakers
bureau consultants; master vendors; other vendors; and
other services. These contracts should cover all possi-
ble permutations: prescription drugs, over-the-counter
drugs, drugs that are prescription in one country and
over the counter in another, biologics, vaccines; blood
products, devices, nutraceuticals, cosmetics, foods, and
combination products (a device with a drug in it, such
as a prefilled syringe, a drug-impregnated gauze pad, or
two drugs in one tablet, etc.)
The Generic, Boilerplate, or
Template Agreement
Even before any agreement is on the table, the drug
safety and the legal groups (at least) should develop a
“boilerplate”, “generic”, or template agreement approved
by management and general enough to be inserted into
almost any type of contract anywhere in the world,
either in the body of the contract or as an appendix,
until a customized agreement is made to replace it. An
appendix is usually preferred, as it is easier to change
without opening renegotiation of the commercial
aspects when pharmacovigilance regulations change.
Multiple regional versions and languages might be nec-
essary. The agreement should, at the very least, specify
the following:
1. Exchange between the parties of all serious
adverse events (SAEs) from clinical trials, spon-
taneous reporting, solicited reporting, litera-
ture, special arrangements (e.g., named patient
or compassionate use or patient support initia-
tives), Internet and social media safety reports
and reports from health authorities.
Cases should be exchanged as E2B files (or on
either MedWatch/CIOMS I forms) within a spec-
ified time frame from first receipt by anyone in
the companies or their agents. Coding conven-
tions, e.g., MedDRA
®
, should be exchanged and
agreed. Reports should be exchanged in sufficient
time to meet expedited reporting rules (usually
15 calendar days) so that exchange should, in
general, be no later than 3–5 calendar days.
Deaths and life-threatening SAEs from tri-
als should be exchanged in time to meet 7-day
reporting requirements (e.g., 2–3 calendar days)
for deaths and life-threatening events. If this is
too difficult to distinguish from other SAEs, then
all SAEs should be exchanged in 5 or so calendar
days.
2. All regulatory submissions (Periodic Safety
Update Reports [PSURs/PBRERs], NDA Periodic
Reports, Annual Reports, and their local equiva-
lents) should be exchanged between the parties
within a specified time (e.g., 1 week) after sub-
mission to the health authorities by the responsi-
ble partner. If one party wishes to review the doc-
ument before submission, then this must be spec-
ified, and time allotted to perform the review. If
separate parties will be performing different, but
related functions, e.g., party A handles case pro-
cessing and party B is responsible for aggregate
reports, this should be clearly defined, including
a dispute resolution process.
3. In case of Health Authority questions, details
must be provided on whether the other partner
must be informed only or involved in the draft-
ing of the response (before decision for an option,
Business Partners and Exchange of Safety Data 357
estimate the potential number of questions to be
managed and therefore, the workload).
4. A formal and detailed safety agreement will be
completed by the two (or more) drug safety
groups within, say, about three months of the
signing of the business contract, if deemed
necessary.
The above generic agreement should suffice in
almost all cases until the formal safety document is
created. Sometimes it may suffice as is. Additions, of
course, may be added to the generic agreement if the
specific case warrants it and if there is sufficient time to
get agreement internally and from the other contractual
partner(s). This could include exchange of commu-
nications with the health authorities, including safety
reviews of PSURs/PBRERs, literature searches, and a
data dump (e.g., a paper printout or an electronic file of
all AEs in the safety database) from the partner holding
the safety database.
Developing a Safety
Agreement with the Safety
Department
As soon as the type of contract is determined and the
safety department is brought into the discussions, the
area of involvement should be ascertained: geographic
territories (e.g., United States or European Union only,
United States and the European Union, Canada, Japan,
UK etc.), regulatory and marketing status indications
(MA/NDA approved, in clinical trials only), labeling,
etc. This allows the tailoring of the specific agreement
to ensure that all needs are met.
At this point the safety and regulatory departments
will be able to determine what is needed. If the drug
has never been marketed, for example, there will not
be an issue of existing post-marketing spontaneous
SAE reports, and this may not need to be included
in the agreement (though a clause indicating that the
agreement will be revised, say, two months before
a marketing request is submitted anywhere in the
world. In the EU, the post-authorization PV system
must be in place at the time the MAA is submitted). If
more than one partner is involved, this also allows the
signatories to determine various responsibilities and
negotiate any new or altered requirements; if possible,
it would then make sense to develop one single PV
agreement applicable to all partners rather than sep-
arate agreements. This may not always be doable,
however.
Again, there is usually no “one-size-fits-all” safety
arrangement that can simply be dropped into a con-
tract to take care of everything. Each agreement must
be negotiated individually. Usually, face-to-face contacts
between the two (or more) safety departments facilitate
the successful preparation of a safety agreement.
As always, contrary to the saying, business is per-
sonal, and it is always easier to develop a successful
working relationship of trust and confidence if personal
contact has been established rather than relying only on
e-mails, video conferences, and telephone calls. A meet-
ing should be set up at the earliest reasonable time after
preliminary negotiations are started to hammer out
the final document. The safety department needs to be
given sufficient authority to negotiate such an agree-
ment (pending, of course, final management and legal
approval on both sides).
The complexity of these agreements increases expo-
nentially if multiple companies, CROs, and territories
are involved. In such situations, it is usually worthwhile
for one of the companies or partners to take the lead
in safety matters. Some agreements, particularly for co-
development programs, provide for a joint safety com-
mittee that receives regular updates and provides a
platform for decision-making on important safety mat-
ters. When consensus cannot be reached within the
committee, the agreement should specify an escalation
process for timely resolution of the issue.
In the EU, the regulations require that Pharma-
covigilance Master Files (PSMFs) are cross-referenced
between companies. In addition, any link with other
PV organizations must be outlined in the PSMF and
a list of contractual agreements must be appended.
Some countries require local versions of the EU PSMF.
358 Cobert’s Manual of Drug Safety and Pharmacovigilance
Requirements must be deciphered, and responsibilities
agreed. Maintenance of these documents must be spec-
ified. See below.
Pharmacovigilance
Agreement Database
For companies that make many agreements worldwide,
it is imperative that a database containing the key points
of the safety agreements and the agreements themselves
be maintained. Multi-national companies may have
thousands of such agreements, in multiple countries,
in multiple languages, often with differing products,
durations, responsibilities, and territories. Even if the
contract is restricted to a non-English speaking terri-
tory and the local language is used in the agreement, an
English version should be available (and updated) for
audits and inspections (see below).
The agreements will become out of date rapidly
as new terms are made, new products launched, new
formulations made, new regulations are introduced,
and new partners (or distributors or sales forces, etc.)
brought in or terminated. These Pharmacovigilance
Agreements (PVAs) need to be revisited when regula-
tory requirements change. A database will help track
this. The database may start as a spreadsheet, but it
may be necessary to develop or purchase a database to
track and report on agreements. The purpose is to have
a repository of all PV versioned agreements but also to
have a tracking tool with reminders for key milestones/
commitments. As always, the database must have the
appropriate security, testing, validation, and change
control. Note that this is separate from the safety data
database, which contains SAEs and AEs, etc., and the
clinical trial database.
Historically, the legal and new business depart-
ments will not keep sufficiently detailed records to
ensure regulatory compliance regarding safety mat-
ters (a sad fact). Thus, it falls on the local drug safety
department to do its best to ensure that all revisions
to agreements are transmitted to the central (or des-
ignated) safety department. A dedicated person must
be designated as liaison and have the responsibility to
track and revise such agreements and changes to them.
Any new conditions (new INDs, NDAs, Marketing
Authorizations, new products, new regulations, new
PSUR/PBRER dates, etc.) must be transmitted to the
drug safety groups involved (e.g., the case processing
group, the aggregate reports group). In the European
Union, the EU QPPV is responsible for ensuring that
this occurs. Periodic reports of contracts in force, dates
of expiration (where they exist), and obligations should
be issued to the parties who need them.
Safety Agreement Contents
Ideally, all agreements should be in English or avail-
able in English, especially in companies that work or
sell across borders. This is not always the case. If not,
they should be translated into English for all parties
involved to be able to know and adhere to their obli-
gations. Translation software may be used realizing,
however, that the translation may contain errors and is
not certified. The contents should cover the following
sections:
Regulatory Status
A table by country with approval date, license holder,
companies marketing the product, and name (generic
and brand) should be included. A copy of the regulatory
table in a PSUR/PBRER is usually acceptable. It should
contain:
IND or equivalents;
MAs, NDAs/BLAs, or equivalents (in the European
Union, type of approval: central, mutual recogni-
tion, etc.);
REMS/RMPs in place;
Other: named patient/compassionate use, restric-
tions on use, etc.
Regulatory Responsibilities
The regulatory status of the products may not be the
same in each territory or country. It may be a marketed
Business Partners and Exchange of Safety Data 359
product in one and in clinical trials in the other. All
this must be tracked. It should be clarified what regu-
latory status and responsibilities are to be held by each
party and in what country (if multiple countries are
involved). Particular attention should be paid to assign-
ment of regulatory responsibilities in countries where
each contractual party has a regulatory office or physi-
cal presence. The actual names and contact information
for the responsible parties should be listed in an appen-
dix (allowing easy updating of changes in personnel,
phone numbers, e-mail, etc.).
It should be clarified who reports in each coun-
try, who makes contact with health authorities, who
answers questions (and if consultation with the other
party is obtained or not within X number of days, etc.),
and how REMS/RMPs or special conditions are han-
dled. A mechanism should be outlined for the obtaining
of any waivers or changes to routine procedures that
may be desired by the clinical teams, such as reporting
certain SAEs monthly or quarterly rather than as expe-
dited reports.
For the European Union, the EU Qualified Person
for Pharmacovigilance and contact information must
be clearly specified. If there are two (one in each com-
pany), duties must be agreed on in writing and the
competent authorities so notified. Nevertheless, de pend-
ing on the registration status and/or on the agreement
between partners, one single EU QPPV or several may
be nominated. The EU dictates that one pharmacovigi-
lance may have only one QPPV, so if possible, it is best
to have only one single EU QPPV. The same consider-
ation, including updates of name and contact informa-
tion, should be given to other territories that require a
person responsible for pharmacovigilance.
Regulatory Documents
The owner and maintainer of documents should be
specified for the Reference Safety Information (RSI),
e.g., Investigator Brochure, the SmPC/PIL, all other
labeling (CCSI), the Package Insert (PI), the prod-
uct monograph, the investigational and clinical core
safety documents, and protocols. Any consultation and
approval for each should be specified. The timing and
format of exchange should be spelled out for all doc-
uments. There should be an assurance that the latest
documents in force will be sent out to all parties auto-
matically on update or revision.
Health Authority Queries
and Requests
It should be stated clearly how health authority requests
and queries are to be handled. Usually, the company
in the country where the request is made must do the
physical answering (in the local language), but the
content of the response needs to be done by agreed-on
methods and must be consistent with the parties’ stance
elsewhere, particularly if it is a critical medical ques-
tion involving stopping of studies, drug withdrawal,
or labeling change. Case-specific questions of minor
import may usually be answered locally, but anything
more important should be resolved by the appropriate
groups in each company (usually through a joint oper-
ating committee).
A method of dispute resolution must be specified
so that senior management can make the final deter-
mination in the appropriate time frame. This usually
involves the regulatory and safety departments as well
as the clinical research groups in each company. Any
“pass through” situations (e.g., by a CRO to the spon-
sor) should be spelled out. The mechanism of answer-
ing questions and requirements from health agency
reviewers of aggregate reports should also be made clear,
particularly if questions are received from multiple
authorities for each DSUR, PSUR/PBRER, or PADER,
RMPs or REMS, etc. The agreement should specify who
should be notified (and how and the required time-
frame) of queries, requests, responses, and changes (if
any). A tracking mechanism should be in place so no
query “falls through the cracks.”
Regulatory Submissions
Who submits which documents in which countries
should be clearly noted. This includes individual