BEYOND
PROCUREMENT
TAKING A STRATEGICAPPROACH TO
COMPARATORDRUG SOURCINGIntroduction

3

Using a comparator instead of a placebo

4

The growing importance of comparators

4

Options for sourcing comparators

5

Seven common missteps in comparator sourcing

6

Anticipating challenges of comparator drugs

7

Case study: Supplying the EU from Asia

9

Getting it right: Five essential elementsof successful comparator sourcing

102

Introduction
The escalating volume and complexity of global
clinical trials have been accompanied by acorresponding increase in the demand for reference
medicinal products or so-called comparator drugs.
Active comparators are used in clinical trials asa means of establishing that drug candidates aresubstantially better than established treatments.
In the highly competitive biopharmaceutical industry,
demonstrating such differentiation is crucial for themarket success of new products and a prerequisite
for formulary listing, and, in some cases, forsuccessful licensure.

As the market for comparators grows, so do the challenges facing study
sponsors and the clinical supply chain industry. Among them: Securing large
volumes of comparator for multisite studies taking place in every corner of theworld, complying with evolving import requirements of markets where clinicalsites are poised to begin enrollment, addressing the special handling needsof temperature-sensitive biologics, and accommodating the higher costs
associated with the use of comparators instead of less costly placebos – allwhile taking the precautions necessary to prevent counterfeit product fromentering the supply chain.
Effectively overcoming these obstacles demands a strategic—rather than atactical, or procurement driven—approach to reference medicinal productsourcing. At a time when Good Manufacturing Practice (GMP) and Good
Clinical Practice (GCP) are more closely linked than ever before, an integrated
and strategic team approach is required for a successful clinical trial. Failure
to take such a strategic approach could have costly consequences down theroad, including the delay or halt of a clinical trial. It has been estimated thatbiopharmaceutical companies stand to lose between $600,000 and $8 million
for each day clinical trials delay the development and launch of a drug.1
Extensive global experience has enabled Fisher Clinical Services, by Thermo
Fisher Scientific to develop best practices in supply chain management,
including the creation of customized comparator sourcing plans for clinical
trials. This ebook discusses a strategic approach to comparator sourcing
and provides recommendations for biopharmaceutical companies that areplanning clinical trials involving comparators.

The key to a successful clinical trial
is an integrated and strategic teamapproach to comparator sourcing

1 Reprioritizing Investigator Meetings - Accelerating Clinical Trials through process improvement.

3

Using a comparator
instead of a placebo

The growing importanceof comparators

Placebo-controlled clinical trials have long been
considered the gold standard in biomedical research,
but for ethical reasons, not all clinical trials may use
a placebo as a control. Studies involving comparator
treatments are conducted when placebo-controlled
trials are considered unethical.

The value of showing superiority is the primary
driver behind the growing use of comparator drugs
in clinical trials.

When testing drugs for life-threatening diseases such as cancer,
it is unethical to deny patients established treatments. In these cases,
established treatment known as a comparator is given to a control groupof study subjects. In these trials, clinical investigators compare theperformance of the drug candidate or Investigational Medicinal Product(IMP) against that of the comparator or established treatment.
The objective is to determine which of the two treatments offers better
efficacy, tolerability or, preferably, both.2

In these resource-constrained times,
containing costs—through well-plannedsourcing, integrated efforts, andminimizing waste and overages—
is imperative.
2 Clinical Trials: World Market 2010-2025; Visiongain 20093	“Trends, Charts and Maps.” Clinicaltrials.gov. U.S. National Institutes of Health,accessed 21 June 2018. https://www.clinicaltrials.gov/ct2/resources/trends
4	“Tracking Trial Cost Drivers: The Impact of Comparator Drugs and Co-Therapies.”
PharmExec.com. Pharmaceutical Executive, accessed 21 June 2018.
http://www.pharmexec.com/print/203238?page=full&id=&sk=&date=&=&pageID=3

There are several reasons why the market for comparators is growing:•

For one thing, more clinical trials are being conducted today than everbefore and more of those trials are using active comparators. According to
ClinicalTrials.gov, the registry of clinical trials underway in the UnitedStates and around the world, 47,448 studies of the 276,190 studies
registered on the site were recruiting participants in mid-2018. Bycontrast, the total number of registered studies in 2008 was 35,742.3•

The proportion of studies using comparators and co-therapies has also
skyrocketed. An estimated two-thirds of clinical trials today involve theuse of comparators and co-therapies.4•

Many of these trials are taking place in emerging markets of Asia,
Eastern Europe and Latin America The inclusion of emerging markets inclinical trials has served to increase the size and complexity of clinical
trials, particularly from the standpoint of sourcing comparator.

•

In conducting comparative studies, biopharmaceutical companies are also
responding to a growing chorus of demands from patients, healthcare
professionals and payers for demonstrably better treatments for diabetes,
cancer, Alzheimer’s disease and other serious medical conditions.

•

Demonstrating medical differentiation through comparative studies
is crucial for the success of new pharmaceutical products. In fact,demonstrating the differentiation of a drug candidate is becoming a
prerequisite for formulary inclusion, healthcare reimbursement and, insome cases, successful licensure.

Comparators are by definition more expensive than placebos, making thema significant line item in development budgets.

4

Options for sourcing comparators
Sponsors and supply chain managers rely uponfour suppliers of comparator drugs for clinical trials.
They are:
Biopharmaceutical companies: Individual drug companies may negotiate
directly with other companies, agreeing to supply comparator drugs for eachother’s clinical trials and those of partner firms.
Pharmaceutical wholesalers: Although pharmaceutical wholesalers arereliable sources for comparator drugs, their role is strictly that of supplier.
They are generally unaware and insensitive to the challenges of conducting
global clinical trials, such as managing expiry dating and securing resupplies.
Sourcing specialists: While these companies specialize in obtaining
drug supplies for clinical studies and have a general understanding ofclinical supply chain, many are relatively new to the industry. Often small andprivately owned, they may not offer the security and service level desired bymost sponsors.
Clinical supply chain specialists: Because comparator drugs have grown
more important to the success of a clinical study, many sponsors now rely on
vendors that make comparator sourcing an integral part of their overall supply
chain services. Dedicated vendors, such as Thermo Fisher Scientific, provide
fully integrated clinical supply chain management that includes the full rangeof services—comparator sourcing, clinical ancillaries sourcing, clinical supply
optimization service, blinding, packaging, labeling and distribution. Thisapproach ensures the comparator is managed properly and makes the entire
supply chain more efficient, saving time and costs.

There are three primary sourcing options forcomparators. They are:Central Sourcing: The sourcing of a commercial drug in a single country foruse in all of the countries participating in a particular clinical trial. Example:
A drug that is manufactured in the United Kingdom is shipped to a labelingfacility, where a global booklet label is applied. The drug is then distributed toall of the countries in which the trial is being conducted.
Local Sourcing: The purchase of a commercial drug within a single country foruse in that same country. IMP is a good option for local sourcing when it does
not require blinding, repackaging or manipulation. In this form, the productin the local language is supplied open-label. IMP is another good option for
local sourcing, examples include rescue medications, background therapy,
chemotherapy, co-medications and standard-of-care medications. Example:
A chemotherapeutic agent is sourced in Russia for use in a clinical trial that isunderway at Russian investigator sites.
Hybrid Sourcing: A commonly used combination or blending of local andcentral sourcing, such as sourcing a drug in one European Union (EU) country
for use across the EU. Example : A drug is sourced in the UK, where it ispackaged, labeled and shipped to all EU countries that are participating in aclinical trial.

5

Seven common missteps in comparator sourcing
Often unaware of regulatory andother requirements regarding thetransportation and use of comparator
drugs, sponsors inexperienced insourcing comparators may makeincorrect assumptions and costly
missteps. Here are some examples:
1. Taking a tactical approach by focusing
exclusively on cost: Although cost is a key
factor in clinical development, the cost of aclinical study is assuredly more than the priceper-milligram of comparator drug. At a time
when Good Manufacturing Practice (GMP)and Good Clinical Practice (GCP) are moreclosely linked than ever before, a strategic,
fully integrated team approach is required fora successful trial. Such an approach requires
taking all key factors into account, such as
expiry dates and resupply requirements.
The ultimate goal is effectively managing theclinical supply chain from day one throughtrial completion. Failure to think long-term
could result in study delays, or even cause atrial to grind to a costly halt. The notion of the
procurement department acting independently
to source comparator at the lowest pricepossible can be both short sighted and risky.
2. Failing to consider all viable sourcing options:
While sourcing comparator drug from the UnitedStates for a U.S. study is an intuitive choice,it may not be the only—or the best—strategic

option. Out of habit, many sponsors neglect
to consider other viable options, such as thepossibility of sourcing comparator for a U.S.
study from the European Union. European drugs
are often identical and typically less expensive,
which may make sourcing comparator from
Europe a cost-effective option. Using drug
from Europe for a U.S. study requires either
accompanying documentation to assure
pedigree or confirmatory testing to establishthat the product is identical.
3. Making assumptions about the availabilityof comparator drugs: For commercial andregulatory reasons, every drug may not be
available in ample supply in every market.
Even if a comparator is available in a particularcountry, it may not be possible to source or use
it in a clinical study. Sponsors may find that thebest laid plans to acquire comparator require
adjustment. Some real-life examples:•

Plans to source the entire comparator
supply for a global trial from Portugal
changed upon learning how difficult it is toexport pharmaceuticals from the country•

Sufficient quantities of comparator for a
multi-country trial were not available in Italy,
which had been identified as the preferred
single source of the product•A wish to import comparator to Ukraine foruse at clinical sites was scuttled when it
was discovered that the country requires
in-country drug sourcing for studies

4. Requesting comparator from multiple sources:
A series of simultaneous requests to wholesalersand suppliers for supplies of comparator canbe counterproductive. Such requests inevitably
make competitors aware of plans to mount acomparative trial, often leading them to block or
at least delay access to comparator. Prolonged
delays often compel a sponsor to abandon plansfor use of that comparator, threatening the entire
development strategy.
5. Overlooking other necessary trial
components: It’s important to note that sourcing
comparator may also involve the sourcing of
co-medication or background medication,
rescue medication, and ancillary supplies suchas needles, tubing and IV bags for biologic
comparators.
6. Expecting one size to fit all: If the globalizationof clinical trials means only one thing, it would
be that one size most definitely does not fit all.
Even though the same comparator may beavailable in multiple markets, its presentation,
strength, packaging, trade name and price may
be different in each. If repackaging and relabelingof comparator are required, as they frequently
are, it’s critical to be aware of local regulations
with respect to translation and relabeling.
7. Bringing a vendor aboard late in the
game: All too often, a sponsor engages witha provider of comparator drugs late in thedevelopment process and after key details
have been finalized. At that point, there is little
opportunity for the supply chain manager tooffer recommendations that could increase theefficiency and cost-effectiveness of the trial.

6

Anticipating challenges of comparator drugs
As planning begins for trials involving comparators,
it pays to anticipate and address potential stumbling
blocks as early in the process as possible:

Failure to meet blinding requirements: Comparator drug requires the samelevel of attention as investigational drug, and if blinding is required it may
require more attention. Failure to manage blinding properly could jeopardize
the entire trial. Depending on the dosage form, there are multiple options withrespect to blinding:Inaccurate forecasting: A common pitfall is variation in comparator demand.
It’s difficult to project the pace of recruitment in large trials involving dozens
of countries and hundreds of sites. Recruitment that occurs faster or slower
than anticipated impacts the delivery of comparator supplies, which may berequired sooner or later than scheduled. It’s important to secure adequate
supplies of comparator in advance, while using modeling tools to constantly
adjust the forecast.

•

Sourcing unlabeled comparator from a manufacturer is without a doubt
the most direct option. Another option is sourcing bulk comparator, which
can be used to produce blinded comparator.

•

Filling areas of engraving or over-coating a tablet is usually successful, but
it may still be possible to see through to the engraving or printing below.
Filling engraved areas may also add weight, affecting the dissolution rate.
Many of these trials are taking place in emerging markets of Asia, Eastern
Europe and Latin America. The inclusion of emerging markets in clinical
trials has served to increase the size and complexity of clinical trials,
particularly from the standpoint of sourcing comparator.

•

De-inking uses ethanol to wipe printed inscriptions, such as commercial
logos and identifiers, from capsules. This must be done carefully, however,since alcohol may also remove the capsule coating, revealing the coretablet beneath.

•

Over-printing with confusion text to obscure the original printing on acapsule can also work. Here again, care must be taken to over-print with
precision in order to prevent trial participants from being able to discern
the original text.

•

Over-encapsulation—a highly customized process of concealing tablets,
capsules or other solid dosage forms inside a hard gelatin capsule shell -is the most common choice in blinding solid dosage forms.

•

De-labeling and relabeling involve the removal and replacement of labels,
a process that is frequently used in blinding liquids, vials and syringes.

Problems with placebo production: Trials may require a matching placebo
for comparator. The easiest way to obtain a matching placebo is from thecompany that manufactures the comparator. It comes as no surprise, however,that biopharmaceutical companies willing to manufacture placebos for studies
evaluating new doses or indications of their own drugs are unlikely to do sofor studies being conducted by competitors. Generic manufacturers may be
another potential source of matching placebos. Whatever the circumstances,manufacturing a matching placebo requires procurement of identicalcomponents, whether the placebo takes the form of a tablet, capsule,prefilled syringe or inhaler device. This process can be highly complex if thecomparator differs in presentation from market to market.

7Anticipating challenges of comparator drugs (continued)
Changing regulatory environments: Regulatory requirements differ frommarket to market. Furthermore, they can evolve and continuously change
without notice, particularly in emerging markets, where the volume of clinicalstudies is escalating. Understanding the regulatory environment for every
country in which a clinical trial is taking place safeguards against errors thatcan cause delays.
Customs delay: Suffice to say that no one wants to see a supply ofcomparator perish on the tarmac should a customs official take issue
with product declarations and delay clearance for a week. Most customs
issues boil down to three causes: incomplete/inaccurate documentation,
bureaucratic process or inexperience. In emerging markets where clinicalstudies are being conducted for the first time, a combination of all three may
come into play. Remaining vigilant and informed about evolving customs
requirements is mandatory.
Counterfeiting: Prescription drug counterfeiting is escalating globally, withcounterfeit products having been detected in every region of the world.5
In a 2017 report, the World Health Organization (WHO) said that one in 10
medications in low- and middle-income countries are either substandard orcounterfeit.6 Data on counterfeiting, illegal diversion and theft incidents showthat incidents have soared by 60 percent in the past five years, climbing
to 3,509 incidents in 2017 from 2,193 incidents in 2013, according to thePharmaceutical Security Institute.6 With 1,677 incidents of pharmaceuticalcrime, North America topped the list of troubled regions in 2017, followed by
Asia with 768 incidents.5 Though no precise figure for the extent of counterfeit
medicines is possible, the problem tends to be greatest in developing
countries where regulatory and legal oversight is weakest. Trusted supply
sources and the capacity to confirm authenticity through testing are importantsafeguards for preventing counterfeit drugs from entering the supply chain.

Expense and availability of biologics: The substantial increase in thenumber of studies for temperature-sensitive biologic products, which requirecold-chain storage, packaging and transportation, makes comparators highly
expensive and logistics challenging. By 2020, for example, more than half ofbest-selling drugs will be cold-chain products. A major contributing factor is
the growth of the global biosimilars market, which could reach $35 billion by
2020.7 Continued strong growth in vaccines is also driving growth. In 2017,
264 vaccines were in development to prevent and treat diseases, according
to the Pharmaceutical Research and Manufacturers of America (PhRMA).8

Clinical supply costs
10% comparator

50% comparator

PAST

TODAY

90% trial cost

50% trial cost

Cost of comparator
Up to 50% of total
clinical supply cost
can be spent on thecomparator drugs9

5	“Total Number of Incidents” and “Incidents – Regions of the World”. Psi-inc. Pharmaceutical Security Institute, accessed 21 June 2018. http://psi-inc.org/incidentTrends.cfm http://psi-inc.org/geographicDistributions.cfm
6	“1 in 10 medical products in developing countries is substandard or falsified.” who.int. World Health Organization, accessed 21 June 2018. http://www.who.int/en/news-room/detail/28-11-2017-1-in-10-medical-products-in-developingcountries-is-substandardor-falsified
7	“Enhanced Cold Chain Capabilities.” Clinical leader.com. Clinical Leader, accessed 21 June 2018. https://www.clinicalleader.com/doc/enhanced-cold-chain-capabilities-0001
8	“2017 State of Vaccines.” PhRMA.org. Pharmaceutical Research and Manufacturers of America, accessed 21 June 2018.https://catalyst.phrma.org/new-report-and-event-examine-the-new-era-of-vaccines
9 Tufts CSDD Comparator and Co-Therapy Sourcing Study, Ken Getz

8

Case study: Supplying the EU from Asia
Through a combination of global
market research and the ability toleverage its considerable networkof contacts, Fisher Clinical Services
Comparator team is often able
to offer clinical trial sponsors
innovative solutions to sourcing
challenges. One large study recently
conducted by one of our EU-based
trial sponsors gives new meaning
to the term ‘creative sourcing’.

The sponsor required EU product as comparator
for the study, but had established the goal of
paying less than the price set in the EU. Our
research identified two potential alternative supply
sources in major markets—the United States andIndia. The U.S. drug differed so significantly fromthe EU product that it was deemed not to be a
viable option. As it turned out, India actually used
EU product, which was available at a 20 percent
savings compared with the cost to purchase it
in the EU.
Ultimately, the Fisher Clinical Services comparator
team sourced the product from India. Working
with a local regulatory authority in Europe, our
Qualified Person (QP) confirmed the requirements
for releasing the imported drug so that it could be
used in an EU clinical trial. Lancaster Laboratories
in Ireland then conducted reduced analytical
testing. The testing successfully completed, wearranged for QP release and the drug from Asia
was ready for use in the EU.
This product required cold chain (2°C to 8°C)
handling and had to reach clinical sites. The
comparator team engaged the logistics teamwithin Thermo Fisher Scientific Pharma Services
organization to transport the comparator product.
The sponsor received temperature tracking datafrom point of shipment release to delivery until alldeliveries were complete.

9Getting it right: Five essential elementsof successful comparator sourcing
1. Begin planning well in advance.
Begin planning a comparator sourcing strategy
in Phase 2 for a Phase 3 trial, for example, or
when the protocol is in development. Advanceplanning provides maximum flexibility and options.

2. Identify relevant facts.
For planning purposes, it’s necessary to identify
key details about the study—including the numberof sites and subjects, duration, strength andmaximum volume of comparator—in order toaccurately predict supply needs and conduct themarket research necessary for reaching optimal
sourcing solutions.

3. Take a strategic approach.
Sourcing comparator for clinical studies is not
merely a tactical or procurement issue. Taking
a strategic approach involves taking every
factor into consideration to create a customized
comparator sourcing plan that includes multiple
options. Remember, the ultimate goal is managing
supply chain from day one through the conclusionof the trial.

4. S elect a known, trusted andexperienced partner.
The rule to follow is a simple one: The fewer
the handling points when conducting acomparator trial, the better. Through its Thermo
Fisher Scientific Fisher Clinical ServicesSM
offerings, Thermo Fisher Scientific provides afully integrationed approach to supply chain
management—including sourcing, blinding,packaging, labeling and distribution—making
the process time- and cost-efficient.

5. Maintain an open mind.
Depend upon a knowledgeable and experienced
partner to make strategic recommendations
about sourcing comparator that can offer theadvantage of time- and cost-savings. That’s atrue win-win.

Clinical trial sponsors can experience a de-risked
supply chain through:•Our unmatched geographic footprint, with thecapabilities and capacity for central and local
sourcing, regulatory support and transportation
management in Asia, Latin America andEastern Europe, as well as the United Statesand European Union•

Our established sourcing network, including
trusted industry relationships that enable it
to source product directly from innovator
companies at optimal pricing, thereby reducing
both costs and the risk of counterfeit product•

The financial strength necessary to support
procurement activities in an efficient way that
limits financial risk10

+1 919 226 3200 • thermofisher.com/patheon • pharmaservices@thermofisher.com© 2021 Thermo Fisher Scientific Inc. All rights reserved.
Published 09/21