CLINICAL TRIALS:
8 THINGS TO CONSIDER WHEN CHOOSING A
CLINICAL RESEARCH PARTNER
A NUTRASOURCE DIAGNOSTICS WHITEPAPER
Authored by: Joshua Baisley, H.B.Sc
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SELECTING A PARTNER FOR CLINICAL RESEARCH
The term “partnership” has become a trendy marketing tool used by contract research organizations (CROs) rather than being truly collaborative relationships between the Sponsor and CRO. Previously, Sponsors and CROs
engaged on a function-by-function or project-by-project basis which placed emphasis on a single sale with little
focus on customer service and retention.
A true partnership provides a means to extend expertise in a cost effective manner, improve efficiencies and accelerate time-to-market while focusing on the relationship, customer retention and the customers values.
Partnerships are committed relationships that offer the benefit of the CRO team having insight into the Sponsor’s
product development plans, pipeline and strategy. This allows the CRO to plan and respond to Sponsor needs
accordingly. Furthermore, the CRO may be able to advise the Sponsor on product development strategies, GAP
analysis and suggest solutions for mitigating regulatory risk and hurdles.
Concept to Claim Pathway
RESEARCH &
DEVELOPMENT
REGULATORY
STRATEGY
CLINICAL
RESEARCH
PRODUCT
TESTING
HEALTH & MARKETING
CLAIMS
When investing in a true partnership with a CRO, communication and trust are key to forming cohesive project
teams. It takes effort from both parties to create a true partnership and allowances must be made to learn each
company’s strengths and weaknesses.
Both the Sponsor and CRO should be involved in strategic planning and be accountable for risks. The CRO and
Sponsor should discuss realistic timelines, milestone goals and an effort should be made early on to identify and
circumvent potential issues.
Once the relationship is established, communication is key to maintaining the relationship. Each Sponsor may
have their own preference for communication; to some it may be regular updates by e-mail and others via teleconference or face-to-face meetings. The CRO should be flexible and accommodate their partner’s needs in this
respect, and expectations regarding communications and timing of project updates should be defined.
“
Partnerships offer unique advantages such as reduced cost, alignment of goals
for product success, strategic planning and risk mitigation.”
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1. Transparency, Honesty, Accountability and Trust
Transparency, honesty,
accountability and trust
are the foundation to a
successful partnership.
Clinical trials are pivotal studies in a product’s life cycle. While efforts are
made in advance to mitigate risk, not all trials will run without problems.
The CRO you choose should be honest and open about issues experienced, whether it be differences in opinion regarding study design, difficulties with recruitment, or change of staff during the course of a clinical
trial.
A CRO that values its customers will value their input and opinion. The
CRO should be forthcoming and bring the Sponsor on board, making
them fully aware of the issue, and propose solutions to not only address
the issue but also prevent it from occurring again in the future. Transparency, owning up to mistakes and being accountable when problems arise,
are core values that you should look for when partnering with a CRO.
The Sponsor should have discussion surrounding how a CRO handles unanticipated problems. This includes,
but is not limited to, recruitment issues, regulatory hurdles, unforeseen safety issues and equivocal or unfavorable
results. How will adverse events be handled and who is responsible for tracking serious adverse events (SAEs).
Who is responsible for regulatory reporting of SAEs? Is there documentation for the transfer of regulatory responsibility?
In the case of unfavorable results, some Sponsors may wish to report the results “as is” while others may suggest
additional statistics that may require a change order. In any case it may be appropriate to hold a teleconference or
meeting prior to moving forward with finalizing a report to discuss these or other options.
The risk for failure can be mitigated through pilot studies and dose finding studies. The CRO may advise on
options such as these when bidding on studies and partnering with Sponsors. The CRO may also suggest that a
clinical development strategy be initiated prior to undertaking clinical research. This speaks to the importance
a CRO places on protecting the sponsors best interests. An added service such as this can save time and money
downstream, reducing the risk of project failure during pivotal large studies.
2. Location
The industry is global, yet many Sponsors are focused on local marketing due to lack of resources or experience
and as a result may choose a CRO due to proximity to their office. With today’s technology, location of a CRO
should not be a primary consideration, though a Sponsor should do their due diligence in interviewing the CRO
either through an on-site visit or via other means of qualification.
Partnering with a CRO with global experience has certain advantages as expertise can be passed on to the Sponsor
considering product entry into multiple or foreign markets. Furthermore, costs may be lower in some jurisdictions while the data will still be accepted by regulatory bodies in other markets.
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SELECTING A PARTNER FOR CLINICAL RESEARCH
KEY QUESTIONS FOR
CRO
Who is responsible for filing the clinical trial applications?
How many has he/she filed?
What types of products have been filed?
For example, the populations in Canada and the U.S. are demographically
similar. Canada is an ICH country, thus data will be accepted by the U.S. regulatory body (FDA) as well as other countries that recognize ICH guidelines
and those that have mutual recognition agreements (MRAs) with Canada. It
is vital that the CRO has an understanding of the jurisdiction that the Sponsor wants to market entry so that the clinical trial(s) can be designed appropriately to support label claims that can be made in the country or countries
of interest.
In Canada, phase I (first in man, bioavailability studies, etc.) to phase III studies (large efficacy studies) on health products must be submitted to Health
Canada for review and authorization as well as an ethics board. In the US, an
Investigational New Drug (IND) may or may not need to be filed depending
on trial design and health product being studied. Typically, Health Canada
has a 4- to 6-week turnaround time for clinical trial applications (from submission to notification of decision), but depending on trial design can be as
short as 1 to 2 weeks. The speed of turnaround largely depends on the familiarity of staff with respect to filing regulatory applications and more specifically clinical trial applications.
While the clinical trial application process in Canada does add a small percentage of time to the overall timeline, it offers an advantage over only requiring an ethics review. Ethics review boards (IRB/REB) review the protocol and supporting trial documents to ensure the conduct of the study is
ethical and places priority on subject safety. Health Canada reviews ethical
and safety aspects as well as the scientific rigor of the trial and often provides
insight into their current regulatory thinking, trial design and inclusion/exclusion criteria. This affords a second level of scientific and regulatory scrutiny to the trial design adding benefit when substantiating claims with your
clinical data.
As Health Canada regulates natural health products, performing a study in
such a regulated environment provides another level of quality to the study
not found in other jurisdictions such as the United States. A submission made for a clinical trial application in
Canada can be cross referenced to a product license application, which can expedite the preparation of documents
and the approval process within Canada. There are mechanisms in place to protect the confidential nature of the
information contained in a clinical trial application.
There also exists the option to subcontract an independent firm to only submit the clinical trial application, or IND,
for the specific jurisdiction; however, the disadvantage of this is that the firm may not have working knowledge of
clinical trial execution and should changes be required by the regulatory body, may not know what issues to nego-
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tiate with the health authority and which to accept and revise within the
protocol. Therefore, when considering a CRO it is best to choose one with
extensive history in filing clinical trial applications, and/or INDs, as well as
experience managing and executing clinical trials. Ask the CRO who files
the applications. How many has he/she filed? What types of products have
been filed? The latter question is essential as different product types have
differing requirements and there are nuances with certain ingredients and
health product types.
3. Therapeutic Expertise and Project Management
KEY QUESTIONS FOR CRO
Does the CRO assign a
project manager?
How many projects is he/
she currently managing?
What is his/her experience?
CROs often promote various indications that they have studied. Equally
important, and perhaps not always considered, is the CRO’s capabilities
and ability to manage trials. Experience in therapeutic indications offer
familiarity of the indication under study, and knowledge of common measures. However, much of this is dictated by current standard of care and
regulatory acceptance of endpoints, making regulatory knowledge and experience of utmost importance when considering a partner who will be
involved in or lead protocol design.
Who may be on the team
assigned to my project and
what experience do they
have?
When a Sponsor is considering to partner with a CRO for a project(s), it is crucial for the Sponsor to ask who will be on the study
team and what experience they have with respect to the indication. A CRO may have conducted several trials in a particular
indication, but current staff have not been involved in these studies. Further, some CROs may promote their “A” team but when
the trial is started will select a “B” or “C” team if the Sponsor is
not considered an “A” client, then it is essential to be aware of the
expertise of the team that will be assigned to your project.
Project management is a crucial factor in the success of a clinical trial. During the interview or selection process of a CRO, the
Sponsor should ask how their project will be managed. The project manager is usually the primary contact between
the CRO and the Sponsor during a clinical trial and will provide the Sponsor with status updates. The CRO must
also have a quality assurance (QA) department. The QA department is responsible for the CRO’s quality management system including but not limited to ensuring that the CRO has Standard Operating Procedures (SOPs),
auditing the system and ensuring processes are in place for qualifying sites if the study is to be conducted off-site.
4. Scientific and Regulatory Competence
Clinical trial design should be questioned by the Sponsor if the CRO is preparing the protocol, specifically the
design (open-label vs. blinded; parallel vs. crossover; pilot vs. full-scale), choice of populations, endpoints, timing,
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KEY QUESTIONS FOR CRO
What do you base your
study designs on?
How much regulatory
experience does the CRO
have?
Does the CRO actively
engage with regulatory
authorities?
how does the design relate to standard of care, and how would regulatory
bodies weigh in from a market standpoint. The CRO should be able to justify their decisions with respect to clinical trial design.
Clinical trial design and execution cannot live in isolation of regulatory
compliance. The end goal for clinical research is to support the marketing of health products, either new products, reformulated products or new
claims. Each jurisdiction must abide by local and industry regulations, and
accordingly, protocol design must meet regulatory requirements where the
trial will be marketed. Clinical trial design can significantly impact what
the Sponsor can claim about the product’s effect.
Often, trial designs are based on scientific literature, incorporating the latest tests or endpoints in line with current scientific thinking. Unfortunately regulatory bodies often do not accept new tests and endpoints, thus a
balance is required in clinical trial design to ensure that data will support a
Has the CRO worked
regulatory filing, and additional innovative scientific endpoints may be powith products that have
successfully obtained health sitioned as supportive information until such time that they are recognized
by regulators.
claims?
When a CRO is providing assistance or leading protocol design, it is necessary to be cognisant of their understanding of regulations and their limitations. Ask the CRO about their experience with the health authorities
which you intended on filing with (e.g., Health Canada, FDA, EMEA, etc.).
Do they actively engage with regulators? How do they keep abreast of current regulatory thinking? Does your CRO understand regulations pertaining to clinical trials as well as market authorization or post-market support? Has the CRO worked with products that have been accepted with health claims in a regulated environment,
and were the claims considered novel and/or aggressive? Will the CRO partner with you and support you during
the regulatory approval process when you move the product forward to market?
Were the claims novel or
aggressive?
5. Request a Meeting with the CRO
When a Sponsor receives quotes from multiple CROs it is often difficult to compare the proposals as each CRO will provide the budgets
in varying degrees of detail. Most CROs will provide a proposal that
briefly outlines key aspects of the study with budgets for main tasks
to be completed, while others may provide detailed line items and a
detailed protocol synopsis.
There are reasons why CROs differ in the manner that proposals are
presented, often it is to prevent study designs from being provided to
other CROs by the sponsor. Differences in price between CROs may be
due to additional time points or endpoints for scientific or regulatory
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rigor, differing sample sizes, or level of quality including safeguards and expertise. It is essential to note that proposals provide estimated costs for the trial based on assumptions.
CROs should be open to feedback on the proposals and adjustments to design. Sponsors interested in receiving
greater detail should request a meeting (face-to-face or teleconference) to discuss the protocol and budgetary
items. A face-to-face meeting is a great way to develop a deeper personal relationship and evaluate the CRO’s capabilities, offering a platform to discuss the impact of study design changes on both regulatory cost and risk.
While proposed budgets are certainly a factor in choosing a CRO, it is usually not the single determining factor.
The Sponsor should consider all the services offered by the CRO and whether they may be of benefit to the project(s) under consideration as well as potential future product lifecycle work.
6. Outsourcing
It is important for you, the Sponsor, to be aware of what services will be
provided “in-house” and what services will be outsourced when partnering with a CRO. The CRO should be transparent regarding all subcontractors planned to be used during the trials. Some CROs have an
in-house clinic site and staff which may or may not include internal monitors, others have a network of sites and employ clinical research associates (monitors) to audit the sites they manage, or may provide a combination of both depending on trial design.
It is also imperative to be aware of the laboratory(s) being used for analysis of blood markers. Often safety tests will be performed by a local
or central laboratory while innovative endpoints may be analyzed by a
university or other contract laboratory. CROs may also have some laboratory capabilities in-house. It is essential that you ask questions about
in-house and subcontracted laboratory licensure. Are they licensed or
inspected by a regulatory body (e.g., Health Canada or the FDA)? Are
their certificates up to date? Will methods be verified or validated prior
to analyzing specimens collected in the clinical trial? Gathering answers
to these questions should provide a level of confidence regarding the
management of samples and analytic results.
KEY QUESTIONS FOR CRO
What activities will be
performed in-house and
which will be outsourced?
If monitors will be provided
for the study what
experience do they have?
How are vendors qualified?
What licenses or certificates
do the subcontractors have?
Are methods validated or
verified prior to analyzing
samples?
7. Data and Data Management
The data produced during a clinical trial is of utmost importance on several levels. Of paramount concern is the
protection and security of subject information and subject safety; in addition to these, importance is placed on
the integrity and accuracy data from which conclusions regarding the health product will be drawn from.
The integrity of data begins at the time of measurement, assessment or collection. The CRO should have access
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to the tools or equipment required to measure the endpoints of interest either in-house or through subcontracted
vendors. In-house equipment should be maintained, validated and calibrated to ensure that they are accurately
measuring (e.g., temperature monitoring devices are traceable and not expired, centrifuges, blood pressure devices and scales are routinely validated, etc.). Inquire with the CRO how they
ensure their equipment is functioning properly and when visiting the CRO
KEY QUESTIONS FOR CRO
ask to see equipment maintenance records and the equipment maintenance
schedule.
Does the CRO maintain and
validate equipment on a
scheduled basis?
What documentation
exists for traceability of
equipment validation?
What systems are employed
for data integrity?
Are systems 21 CFR Part 11
compliant?
Are databases tested and
validated?
Are standardized
dictionaries used for coding
adverse events?
Once the data is recorded either on paper source documents or electronic
source, the data is transferred or entered into case report forms (CRFs).
CROs have varying in-house capabilities with respect to data management.
CROs are embracing technology to efficiently manage subject data during
clinical trials. It is essential that a Sponsor understands the type of technology being used. In some cases a CRO may be using Microsoft Excel
spreadsheets while others modify Microsoft Access to create databases and
CRFs. FDA’s 21 CFR Part 11 has prompted many CROs to move toward 21
CFR Part 11 compliant software solutions to ensure that they are in compliance with regulations.
Software compliance may be of specific interest to Sponsors wishing to market their health product in the United States; however, its importance should
be considered by all Sponsors as such systems are secure and provide data
in a manner that provides a history of every entry and change made within
the database. This is of particular importance in ensuring the integrity of
the data. Thus a CRO using 21 CFR Part 11 databases and eCRFs should be
of primary consideration to a Sponsor.
Sponsors should ask what systems are utilized by the CRO for
data management and disaster
recovery to manage the data collected. What safeguards are in place to protect the integrity of the data?
Are data collection and storage systems compliant with regulations?
How are databases tested to ensure functionality and that all necessary
data points will be captured during data entry? What data review processes are in place? How is medical terminology coded for consistency
and ease of reporting (e.g., is a clinically validated terminology system
such as MedDRA (medical dictionary for regulatory activities) used to
code adverse events)?
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8. The Final Product: The Study Report
KEY QUESTIONS FOR CRO
The final product of a clinical trial is the final study report. CROs generally follow CONSORT and ICH format for reporting results to ensure
that the report is comprehensive and is written in a manner that will be
accepted by regulatory bodies.
Will the CRO work with me
to provide a final report that
meets my expectations?
What differs between CROs is the level of explanation of results. When
choosing to partner with a CRO, the expectations of the final report should
be discussed. Some Sponsors may want a report that simply states the results with no discussion, while some may want a report that discusses the
results and perhaps limitations as the scientific aspects may be of greater
importance to them. Whether a discussion of results in light of current
literature belongs in a final study report is often left up to the CRO’s discretion.
Will the final report be
accepted by regulatory
authorities?
It may be advantageous for a Sponsor to have the results discussed in a
publication or dossier submitted to regulatory authorities rather than in
the final report depending on how the report will be used. This may also
be driven by the results of the study.
Who owns the data and
results?
Therefore, it is key for both parties to have an understanding of expectations in order to deliver a finished product that is satisfactory. Ask the potential partner how results are typically presented and what their flexibility
is around the reporting of the results. Would the CRO be open to having
a meeting (on-site or via teleconference) to present and review key results
prior to writing and issuing the final report? Your research partner should
be flexible in this regard. This will speak to the CRO’s focus on building
lasting customer relationships.
Is the CRO open to
discussing results prior to
issuing a final report?
Am I obligated to publish
the results of my trial in
a scientific or medical
journal?
Does the CRO offer
publication services if
I decide to publish the
results of the trial?
Another point to consider when selecting a partner for clinical research is who
owns the data/intellectual property. When working with CROs the data typically belongs solely to the Sponsor and the Sponsor can choose whether or not
results are published. In contrast, universities often reserve the right publish the
results in scientific or medical journals. It is pertinent that you ask your partner
what their policies are regarding publishing of results.
A sponsor may decide that they want to publish results once the results of the
trial are known. Ask if the CRO can accommodate such a request and if they are
able to prepare manuscripts and manage the publication.
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Summary
Choosing a CRO that has experience in product development strategy, product life cycle management, regulatory
filing, project management and clinical trial services is advantageous when forming a partnership. These capabilities are beneficial to the Sponsor as the ideal CRO should value your product, expectations and goals, and be able
to understand and manage risk, product positioning, health claim strategy and study design to support claims that
can be substantiated to regulatory bodies.
Nutrasource is uniquely positioned in the health product industry to partner with Sponsors in this manner and
looks to build and maintain symbiotic partnerships with our clients. Our team consists of experienced scientific
professionals with regulatory and clinical experience from the food, natural health product, pharmaceutical and
medical device industries.
Experienced in project management and clinical research, Nutrasource is able to offer clinical trials conducted
on-site, off-site or a combination thereof. The ability to combine in-house expertise on regulatory filing for health
claim substantiation with clinical trial design offers an unparalleled advantage within the natural health product
and food arena.
In 2013, Nutrasource expanded its capabilities through the acquisition of an analytical laboratory, Diteba, providing Nutrasource with the ability to offer product analytics (including end product release testing and stability
testing) and bioanalytic support in an FDA-inspected and Health Canada-licensed facility complementing Nutrasource’s clinical trials services.
For further information, please contact our customer service team by email ([email protected]) or phone
at 519-341-3367. We will be in touch within two business days.
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About the Author
Joshua Baisley, H.B.Sc
Associate Director of Clinical Trials, Joshua Baisley, is responsible for
the operational management of clinical research activities including;
preparation of clinical development strategies, regulatory and ethics
submissions, compliance with local and foreign regulations including
ICH guidelines, protocol design, preparation of consent forms and
investigator’s brochures, and overseeing NDI’s Clinical Trial Management System (CTMS) and Electronic Data Capture (EDC) systems
for clinical trials.
Joining the Nutrasource team in September 2013, Joshua brought
with him over 12 years of management level industry experience
including two years in biotech and over 9 years in the natural health
product/dietary supplement industry.
Mr. Baisley has extensive experience with Health Canada, having submitted over 10% of all natural health product (NHP) clinical trial applications that the NHPD has received in Canada, has been involved in more than 60
clinical trials and has co-authored 6 peer-reviewed scientific articles. Joshua is also an editor for a peer-reviewed
integrative medical journal.
His rapport with Health Canada has also earned him a place on a Health Canada Expert Working Group Committee where he represents NHP and clinical research industries. His clinical and regulatory experience includes
multiple product types including probiotics, prebiotics, herbs, extracts, vitamins, minerals, enzymes, homeopathics, combination products and pharmaceuticals in various health indications including osteoarthritis, diabetes, hypertension, hypercholesterolemia, weight management, oxidative stress, women’s health, men’s health,
gastrointestinal health, as well as healthy subject studies including bioavailability studies.
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