The 2011 National Biotechnology
Conference, organized
by the American Association
of Pharmaceutical Scientists
(AAPS), attracted almost 2000 bioscientists
and vendors to the San Francisco
Hilton Hotel from May 16 to 18, 2011.
This year, biosimilars was the major track,
with a comprehensive program covering
technical, business, and legal aspects. The
problem is that technology is not able to
deliver identical therapeutics. Most biotherapeutics
are mixtures of closely related
compounds, some of which are probably
more active than others. Today, the state-of-
the-art struggles to deliver material that
is similar to the prior batch from the same
facility and team. Since identical is not
currently possible, “similar” is the next
best alternative. With reason, consumers
might be skeptical about the equivalency
of items produced by different vendors at
different sites using different protocols.
Technical sessions focused on such topics
as method cross-validation, design of
experiments, and method transfer. They
generally reported successful case histories
of problems and solutions. It seems that
the technical issues relating to biosimilars
can be solved with brains, time, and
money. However, this is not the case for
the business and legal/regulatory issues.
Global harmonization was adopted as a
goal for regulation of small-molecule therapeutics.
The effort took two decades, but
it is working and has certainly been worth
the effort. In the area of biosimilars, harmonization
is just a dream. Even the words
are different for Europe, the U.S., China,
Canada, etc. In this report I’ll use the term
“innovator” for the firm that developed
the first or “reference product” (RP), and
“follow on” (FO) for the firm that developed
a “biosimilar” product. “Biobetter” and
“bioinferior” refer to products that are better
or worse than the RP.
The EU seems to have a working process for
premarket review and approval of biosimilars.
The approval process is country specific
and relatively expensive, so some firms
chose not to apply for market approval in
the smaller countries. However, the process
works, with about 14 biosimilar therapeutics
on the market in the major countries
of the EU. Novartis (Basel, Switzerland)
is the most aggressive, with successful registrations
of several biosimilars. Generally,
biosimilars are priced about 30% less than
the RP. This seems to be sufficient to gain
significant (~30%) market share in a year
or two. Biosimilar therapeutics are still very
expensive, however.
This is in dramatic contrast to the situation
in America. As of the conference
date, the route to market approval is convoluted
and has been used for only one
biosimilar. The FDA has proposed a new
route, which is currently in the public
review process. The proposed rule involves
two particularly onerous requirements
that the EU process avoids. The first is
that the candidate biosimilar needs to be
interchangeable with the RP. This means
that one should not expect to encounter
any clinical differences if the biosimilar is
alternated with the RP. Okay, but what
if differences are observed, even rarely?
Then the FDA usually wants the FO to
commit to conducting a postmarket surveillance
(PMS) program. If the drugs are
interchanged, can a PMS program have
any meaning?
The U.S. FDA walks a tight rope between
being an advocate for the consuming public
that needs the drugs, and a hard-nosed
regulator that challenges everything. No
drugs, and patients die. Plus, the drug
developers can hire teams to address issues,
while the FDA appears as a collection of
one-man bands ready to help, for a fee.
The second requirement is an even more
complex maze called the patent challenge
process. According to Jennifer Camacho,
J.D., of Greenburg Traurig (Boston, MA),
the American proposal also has a peculiar
intellectual property protocol. The first
candidate biosimilar cannot be examined
by the FDA until the date the patent
expires. However, the first biosimilar
approved will enjoy a period of exclusivity
for several (perhaps 7) years. During this
time, the biosimilar will be the sole competitor
to the RP.
A similar approach has been tried, and
led to peculiar (anticompetitive) market
behavior, including de facto extension of
the patent period for the RP. Essentially,
two approved firms do not guarantee competitive
or market-driven pricing.
Even worse, the proposed rule demands
that the FO developer provide the innovator
with a complete file describing manufacturing
and QC protocols within 15 days
of filing with the FDA. The innovator is
expected to examine this file and respond
in 60 days with a list of patents that may be
infringed. The FO developer has 60 days
to address each claim in detail, and this
includes explaining why the claim is not
infringed. The innovator has another 60
days to refute the claims of irrelevance.
Then the rule calls for a 15-day period to
negotiate a resolution. The next steps are
less well proscribed, but probably involve
petitions for injunctions. Adding it up,
the process takes more than a year, and
involves thousands of hours of lawyer time.
Each lawyer year can add up to a million
dollars, meaning that a legal team can
quickly run up a tab of $10 million.
Another major problem is the nature
of the biosimilars business. Ronny Gal
(Bernstein Research, London, U.K.)
compared business plans for biosimilars
around the globe. He also evaluated the
biosimilar route to the biobetter or innovator.
The biosimilar route doubles the
analytical and characterization time,
since one must characterize both the RP
and the biosimilar candidate. The analytical
cost may be offset by avoiding the
need for clinical trials for the biosimilar.
However, Gal has not seen a devel-
2011 AAPS National
Biotechnology Conference
Focuses on Biosimilars:
Biobetters May Be a Better Bet
by Robert Stevenson Technical
Article
opment time line for biosimilars that is
shorter than a biobetter approach.
Then there is the price issue. Introducing
a biosimilar is supposed to reduce the
price through market competition, but
by how much? Business plans often adopt
a plan to sell at a 30% lower price than
the RP. But is 30% enough to attract the
business? Is it enough to force the innovator
to reduce its monopolistic pricing?
So far, it has not. Gal feels that the price
differential will need to be more like
70% to have a quick impact. Plus, the
innovator is in control and can cut the
price of the RP. This makes the top line
number of a biosimilar business model
vulnerable to short-term competitive
moves, such as reducing prices to bankrupt
an FO.
Gal also observed that the regulatory process
is not harmonized. So, how should
one proceed? He recommended developing
a three-pronged approach to developing
three biobetters—one for Europe,
another for the U.S.A., and still a third for
the rest of the world (ROW). Each could
be optimized for the idiosyncrasies (mostly
regulatory) of the markets. The advantages
include decoupling the regulatory
process, protecting price, shorter development
time, and longer period of exclusivity.
The only detriment is that biobetters
probably cost about $300 million each to
develop, compared to $100 million for
biosimilars using the European approval
model. The take-home is that the technical
part of biosimilars is probably the rate-limiting
but less risky part of a business
plan. Intractable legal and business issues
may combine to kill biosimilars, especially
in the U.S.A., for not offering an attractive
risk/reward ratio.
Innovative new instruments
For the first time this year, I found an exhibition
with several innovative new products,
which include the following.
Beer’s law was old when I was in high
school. What can possibly be new with
such a simple relationship? Well, there
is something that may even be patentable
and, even better, very useful. It led CTechnologies, Inc. (Bridgewater, NJ) to
develop a variable-pathlength cell for UV-VIS spectrometry called the SoloVPE.
The sample cell pathlength can be varied
from 10 μm to 20 mm in 5-μm steps. It
uses a micropositioner in the z direction
to raise and lower an optical fiber. The
sample cuvette rests on a light sensor. A
flexible optical fiber routes monochromatic
light from the Carey 50 UV-VIS spectrometer (Agilent, Santa Clara, CA)
to the sample cell. The advantage is that
the measurement pathlength can be varied
so that the absorbance signal can be
optimized, even for opaque samples. This
avoids the need for dilution. Some materials
are concentration sensitive, so dilution
changes the composition.
But wait, there’s more: The pathlength is
really not an issue. Beer’s law states that
A = Ecl, where A = absorbance, E = extinction
coefficient, c = concentration, and
l = pathlength. If one makes an absorbance
measurement at several different
pathlengths and plots the response versus
pathlength, one gets a linear line of the
form m = Ec, where m = slope. The slope
provides redundant information over single
measurements, which improves accuracy.
Plus, it can confirm that the measurement
is being made in the linear range. One still
needs to know the value of E to get c. In
many cases, the E value is determined from
standard solutions. For other analytes, such
as proteins and larger peptides, a suitable
reference material may not be available.
However, one can use the Edelhoch relationship1
to calculate the E of the denatured
protein in 6 M guanidine hydrochloride
at 280 nm and bridge this to the matrix
by ratioing the slopes.
Dual polarization interferometry (DPI) sounds frightfully esoteric. Fairfield
(Manchester, U.K.) introduced a third-generation
instrument that provides
label-free, quantitative analytical data of
molecular systems by optically probing the
structure of a protein in two dimensions.
Two beams of perpendicularly polarized
light impinge upon the protein immobilized
on a microscope slide. From the output, the
thickness/size and refractive index of the
analyte can be derived. The DPI resolves
differences in molecular structure as small
as 0.1 Å. This resolution enables tracking
conformational changes in proteins, which
usually involve size changes of 0.1 nm.
Improved detection sensitivity of
biomarkers
Some say that low-abundance proteins are
responsible for many disease states. The
problem is finding them in the presence of a
high-abundance population. Thus, the assay
system must efficiently select the analytes
and discard the extraneous material. For best
discrimination, single-molecule quantification
is ideal. Singulex® (Alameda, CA)
introduced a general assay platform called
the Erenna® Immunology System for biomarker
quantification. Magnetic microbeads
are labeled with capture antibodies for the
biomarker. As many as 50 different beads can
be used for multiplexing. The sample, which
can be as small as a microliter, is added. After
a short incubation, the beads are harvested,
washed to reduce nonspecific adsorption,
and tagged with a reporter fluorophore.
Next, analytes are displaced from the microbead.
The solution is aspirated into a capillary
laser flow counter with an interrogation
volume in the low-microliter range. Individual
molecules are counted and recorded
digitally. The effective dynamic range is 104.
More than 30 assays have been developed.
One study of kinase profiles showed significantly
different patterns for normal tissue
than for primary and metastatic cancer tissue
involving 3–10 cells.
Mass measurement on a whole new
scale with resonant mass
Affinity Biosensors Inc. (Santa Barbara,
CA) introduced a new microfluidic instrument
for measuring the mass of individual
small particles. The tag line says it all:
“Mass measurement on a whole new scale.”
Imagine a nanoscale diving board. It has
a natural oscillating frequency depending
on the mass. Now imagine micromachining
a flow channel just inside the perimeter
of the diving board. When this channel is
filled with a flowing pure liquid, the board
has a stable oscillating frequency. However,
should a particle enter the flow channel,
the mass and hence frequency changes. If
the density is higher, the frequency is lower.
If it is lighter, such as an oil, the natural
frequency increases. Frequency can be measured
very accurately. The instrument is
called ARCHIMEDES, and it measures a
variety of submicron and subvisible particles
as well as living bacteria and other
cells one by one. The lower limit is about
a femtogram. Affinity claims this is about
one million times lower than that which
can be obtained with quartz crystal microbalances.
Biological samples such as living
cells can be measured in physiological conditions.
The “board” is called the resonator;
it is about 100 μm long and weighs a few
nanograms. The technique is called resonant
mass measurement.
Mechanical lysis for the laboratory
Microfluidics (Newton, MA) introduced
the LV1 Low Volume Microfluidizer® Processor
for lysis of cells in samples as small as 1
mL. Mechanical lysis releases proteins without
denaturation, even from yeast and algae,
with >99% efficiency in a single pass. The
short residence time and processing cycle
(<90 sec) also improve sample integrity.
Inverse GC for characterization of
materials
Inverse GC (iGC) was popular in the
1970s for characterization of polymers
and fibers. It involved packing a short
column of the test object, installing the
column in a GC, conditioning the material,
and then injecting a probe molecule.
The response is a peak that is perturbed
by interaction with the sample. Surface
Measurement Systems (Wembley, U.K.)
introduced a Surface Energy Analyzer that
greatly expands the information content
of iGC. Treatment of solids can change
the surface energy, which can affect the
physical properties of the powder as well
as the dissolution rates. One example compared
the surface energy distribution for
micronized and crystalline budesonide.
This is obtained by making repeated injections,
increasing the volume of the probe,
and measuring the incremental difference.
Other measurements include calculating
the glass transition temperature as a function
of relative humidity, and Hildebrand
solubility parameter for polymers.
Another instrument, called the Advantage Automated Multi Vapor Gravimetric Sorption Analyzer (Micromeritics, Norcross,
GA), measures adsorption of test
probes such as water on solid samples.
The output can provide BET surface area,
amorphous content, isotherms, and heat of
sorption. It seems that the formulation and
materials scientists are developing a repertoire
of tools to help in designing stable
and effective formulations.
In 2011, AAPS celebrates its 25th anniversary,
an achievement that its entire
staff can be proud of. Programs such as the
National Biotechnology Conference are
clearly effective in providing a forum for
discussions of topics related to the pharmaceutical
sciences. The AAPS team should
be especially pleased with the breadth
of the program offered this year, which
included regulatory and business speakers
to help scientists understand the complex
world of biopharma. In 2012, the National
Biotechnology Conference travels to
San Diego’s Sheraton Hotel. The dates
are May 21–23, 2012. Please check www.aapspharmaceutica.com for details.
Reference
- Edelhoch, H. Biochemistry1967, 6, 1948–
54 (as reported in applications note from C
Technologies, Inc.).
Dr. Stevenson is Editor of Separation Science,
American Laboratory/Labcompare; e-mail: [email protected].