As appeared in Pharmaceutical Manufacturing
and Packing Sourcer
Issue 6/00
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latest ad campaign)
Clinical Trial Labeling:
Spotlight on a Technology Driven Industry
Introduction
For most lay people, the closest they’ve come to a drug-labeling
dilemma is a Hollywood film classic. I’m referring to Frank Capra’s 1940’s
Christmas movie; It’s a Wonderful Life. In the first reel the director
introduces us to a young Jimmy Stewart, who’s working after school in the
local pharmacy. Tragically, the pharmacist has just been notified that
his only son has been killed in the war.
Bereaved, overwrought, and somewhat tipsy, the pharmacist
incorrectly fills an urgent prescription. Young Stewart witnesses the error
and returns to the pharmacy without delivering the deadly mistake: for
which he suffers a literal boxing to the ears by the irate pharmacist,
until he realizes the boy is not a laggard but a hero. The boy’s hearing
is permanently damaged, but a terrible tragedy was avoided.
Everyone in the worldwide clinical labeling industry is
familiar with that scene, and we cringe every time we see it. In the business
of clinical labeling, one hundred percent compliance is not a goal to be
strategized over and eventually achieved. It is the day to day, 24/7, SOP
of this industry. The alternative is not and never will be an option.
This paper will outline the history, physical properties,
regulatory environment, and future of our unique industry.
Clinical Labeling: A History of Growth via Technology
Over the past fifty years we’ve seen tremendous change
in our industry. From typewriters and rubber bands to semi-automatic filling
to fully-automated print and fill to digitally verified multi-lingual labels
and Web-based ordering: the labeling of new drugs has benefited from growth
via several key technological breakthroughs.
Many of the labeling industry’s leading companies were
born of successful post-World War II printing shops. Two events shaped
the industry into its modern form. Chemical discoveries that yielded new
adhesives and secondly, the graphics and communications capabilities of
the computer.
Until the advent of the modern adhesives industry almost
all labeling was affixed to the container via rubber bands or string. The
industrial revolution and most significantly, World War II saw the refinement
of polymer adhesives that would revolutionize the industry. New polymer
adhesives were now affordable, and drug labeling was as they say, a Killer
App.
Postwar demand for everything was intense, and everything
needed a label. Labeling for medicinals became a specialty. The requirements
for success in this new business were unique. The need for 100% accuracy
was, as always, the standard. These post war entrepreneurs knew the importance
of accuracy and timeliness. They also understood the consequence and liability
for careless errors, and had the confidence to meet it head-on with diligence,
hard work, and ingenuity.
The last decade of the 20th century brought significant
changes in the automation of the clinical trial labeling process. Most
significant is the Squibb story.
Beginning in 1987, Squibb’s Pharmaceutical Research Institute
in New Brunswick, NJ, sought to revolutionize the industry with a fully
automated labeling and fill process. They correctly forecasted the
dramatic growth in new clinical trial drugs, put their operation under
a microscope, and discovered an opportunity for a tenfold increase in productivity.
While always maintaining their goal of absolute product accuracy, Squibb
began by acquiring automatic filling and capping equipment for their clinical
packaging group. The groups clinical programs were growing in number of
patients and new therapies.
After years of experimenting with several three-panel
labels, they chose a vendor that produced a patterned-coated label. In
this new configuration the first panel received a permanent adhesive while
the second and third panels received a temporary adhesive. The first panel,
which was permanently affixed, contained the patient directions and the
coded patient number. The second panel contained the same information as
the first but was separated, attached to the case report form (CRF) and
put into the patients case report file. The third panel was sent to the
sponsor/investigator. It contained the identity of the drug, which was
hidden from the doctor and patient, and thus the term “double blind.” Squibb
and their various vendors successfully and accurately met a challenge and
advanced an industry to its next level.
Unfortunately and ironically, today’s clinical trial drugs
often require multiple label panels on one container, especially for clinical
trials that require multi-lingual panels. As a result of the quantity of
information required, we have to guard against a reversion back to the
rubber band and string era. This challenge is being met as usual, via technology
and the Expanded-Content Label (ECL).
The advancements in technology, such as thermal and laser
printing, combined with the accuracy of computer generated medical and
drug data, have allowed everyone connected with the dispensing of clinical
trial drugs to breathe a little easier.
U.S. Regulations Governing Clinical Trial Labeling
There is one absolute when dealing with the FDA or any
overseas regulatory authority and it’s grounded in common sense: every
drug must be correctly labeled and when possible, permanently affixed to
the container. Obeying this simple rule doesn’t appear at first to
be much of a burden on sponsors and investigators. However, add to this
equation the following: more and more FDA mandated information must appear
on the label, the growth of multi-drug trials, and multi-lingual trials,
and you have a potential labeling nightmare. Several international trade
associations, working with the International Commission on Harmonization
(ICH) as well as those in private industry continue to work to find the
best solutions.
As of this writing and at the end of April, the U.S. Government
will release the 2000 edition of the Code of Federal Regulations. The CFR
provides the public with the day to day regulations of various Federal
Government agencies. Title 21 of the CFR is entitled Food and Drugs and
contains the forms and procedures to be followed by persons or corporations
in the food and drug business. Suffice it to say that while every April
brings springtime and Apple Blossoms to Washington DC, it also brings more
and more regulations that must be read, studied and interpreted by the
rest of the world. There is hope though.
Thanks to the achievements of the International Commission
on Harmonization (ICH), the Food and Drug Administration (FDA), and its’
counterpart in Europe, the European Agency for the Evaluation of Medicinal
Products, our industry is moving closer to the goal of unified and simplified
clinical trial procedures. The CFR, mentioned earlier, specifically addresses
the ICH’s efforts as follows:
Sec. 26.48 Harmonization.
During both the transitional and operational phases of
this subpart, both parties intend to continue to participate in the activities
of the Global Harmonization Task Force (GHTF) and utilize the results of
those activities to the extent possible. Such participation involves developing
and reviewing documents developed by the GHTF and jointly determining whether
they are applicable to the implementation of this subpart.
Citations of several of the more important U.S. labeling
regulations are listed at the end of this article.
Physical Properties of the Modern Clinical Trial Label
The Squibb experience of using two types of adhesives
on one label, permanent and removable,
was only one of the new advances this venture produced.
It also resulted in changing the very structure of the label.
Through the use of special chemicals within the label
itself, they raised the bar regarding clinical trial confidentiality. This
is how it worked: the third panel of Squibb’s three-panel label contained
the name of the drug under investigation. This information was hidden within
a pocket built inside the overprinted label stock. The back of the pocket
had an on-press application (OPAS) chemical coating. When pressure was
applied to the top of the pocket, the coated-back sheet and chemical coating
interact to produce a readable image. After testing and more testing the
system worked and the clinical trial labeling business took a giant step
forward.
As mentioned, adhesion is one of the most important physical
properties of any clinical trial label. Many of the human and financial
risks associated with mislabeling an investigational new drug can be ameliorated
as long as the package contents are correctly manifested on the label.
If Jimmy Stewart’s character were in a modern-day clinical trial setting,
he might also want to tell the grumpy pharmacist, “ ...you also almost
cost ABC BigPharma Corporation, a $100 million investment!”
Unlike most product labeling, clinical trial labels must
occasionally perform under extreme environmental conditions. Usage and
storage conditions are critical when making a labeling decision. Certain
adhesives work better in refrigerated conditions. Storage conditions of
labeled drugs must be sensitive to temperature, humidity, and the external
environment. In addition, the safety and security protocol procedures must
withstand a variety of these usage conditions.
Labels must also conform to the container designated to
carry the drug under study. Some choices available at this writing are
high and low density polyethylene bottles, glass bottles, metal (usually
aluminum), polyethylene or tyvek bags, coated or uncoated SBS board, and
corrugated board.
As always during any clinical trial, sponsors and investigators
are responsible for choosing the proper container and verifying that it
meets the labeling and storage protocol and the label supplier’s capabilities.
Label face materials once meant a black or red typewriter
ribbon. Sponsors now have a choice of:
EDP, litho (plain or opaque), laser (plain or premium),
thermal (plain or opaque), Kimdura (plain or opaque), plus a variety of
other synthetic materials. The longevity of the printed information must
also take into consideration extreme environmental conditions.
The choice of the best label adhesive has been expanded
to include permanent, removable,
patterned, multiple, and refrigerated-extreme environments.
As the cost of bringing a new drug to market increases,
so does the importance of maintaining label protocol with the blinding
method chosen. The inherent risks of dealing with real people with real
diseases, demand that the labeling decision protect confidentiality. The
labeling choices include glued pocket, scratch-off laminate and disclosure
envelopes.
Like any industry, the clinical labeling industry has
their share of buzzwords, like
ScratchGuard ™, Expanded-Content Label, (ECL), Multi-Lingual,
Tamper-Proof, etc. These speak to the direction all successful industries
take: keep identifying customer needs and discover better ways to satisfy
them.
Beyond Y2K for the Clinical Labeling Industry
Intra-industry stories like Squibb have more recently
been replaced by several negative exposés on the clinical trial
process itself. As a result of some unfortunate trial outcomes, the general
media’s interest in the clinical trial process has been piqued. And not
surprisingly, the general media overlooks the facts in favor of the sensational,
which is usually an unhappy trial participant.
There are some exciting developments in Clinical Trial
Management that should reassure the general public and bring the process
itself out of the 20th century. Electronic Data Collection promises to
provide the level of data security and impartiality that all trial participants
deserve. EDC involves the collection of real-time patient data using Electronic
CRFs and distribution of information using secure Internet links.
Also on the positive side, Wall Street’s interest (though
fickle at times) in biotech and in the drug discovery business, has provided
our industry with a healthy dose of good PR.
We expect the future will bring more regulations both
here and overseas as we see more and more clinical trials following the
international route to patient enrollment.
The financial stakes are growing daily, the human genome
has just been completely deciphered, and the labeling industry will respond
as they have for years with new products, new services, and new solutions
to meet the requirements of the world’s biotech and pharmaceutical industry.
Other Resources:
The US Government has provided all of us with a unique
resource, the Government Printing Office. Fortunately you needn’t fly or
drive to DC and search through the nation's congressional archives. The
GPO also has the responsibility for making available to the public all
relevant regulations via the Internet. The citations listed below can be
accessed from the following Web site: www.gpo.gov. Follow the links to
the Code of Federal Regulations-Search Page, and enter in the search box
the following:
“clinical”AND”trial”AND”labeling”
(Or just click here: http://www.access.gpo.gov/nara/cfr/index.html#page1)
The following references are a portion of the results
of the search mentioned above:
TITLE 21--FOOD AND DRUGS, PART 201—LABELING,
Subpart A--General Labeling Provisions
Subpart B--Labeling Requirements for Prescription Drugs
and/or Insulin
201.58 Requests for waiver of requirement for adequate and well-controlled
studies
to substantiate certain labeling statements.
Subpart D--Exemptions From Adequate Directions for Use
201.125 Drugs for use in teaching, law enforcement, research, and
analysis.
Subpart F--Labeling Claims for Drugs in Drug Efficacy
Study
201.200 Disclosure of drug efficacy study evaluations in labeling
and
advertising.
TITLE 21--FOOD AND DRUGS, PART 312--INVESTIGATIONAL NEW
DRUG APPLICATION
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
Subpart D--Responsibilities of Sponsors and Investigators
312.57 Recordkeeping and record retention.
312.88 Safeguards for patient safety.
312.120 Foreign clinical studies not conducted under an IND.
..............................................................
Reference
1. Packaging Digest, September 1990, pg 82
2. Code of Federal Regulations, April 1999 Title 21 Part
201, Subpart A
3. Code of Federal Regulations, April 1999 Title 21, Sec
26.48
4. Code of Federal Regulations, April 1999 Title 21 Part
312, Subpart D
About the Author
Mr. Richard Bolnick is the President of Citation Clinical Labeling Systems
of Farmingdale, New York. A 1987 graduate of The University of Pennsylvania,
Mr. Bolnick majored in Sociology and Entrepreneurial Management and received
a Bachelor of Arts degree. Since joining Citation in 1987, Mr. Bolnick
has been co-awarded two patents in the clinical labeling field. In 1997
Mr. Bolnick became President of Citation. (Click
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By: Karl Schroff for:
Richard Bolnick, President
Citation Clinical Labeling Systems
125 Gazza Blvd
Farmingdale, New York 11735
Tel: 631 293 4646
Fax: 631 293 4277
E-mail: info@clinicaltriallabels.com
Web address: www.clinicaltriallabels.com |
