BIOSIMILARS OR FOLLOW-ON BIOLOGICS

The terms "Biosimilar" or "Follow-on Biologic" refer to products that are marketed
after expiration of patents, which are claimed to have similar properties to existing
biologic products. Due to the complexity of biologicsa product can only be made
that is similar, but not identical.
Keeping safety in mind, Genentech believes that:
• Each clinical indication for a biosimilar should be established by indication-
specific clinical trials to ensure the safety and efficacy of the biosimilar;
• Biosimilars should only be substituted for an innovator biologic if comparative
clinical trials demonstrate that substitution is appropriate; and
• Biosimilars should be uniquely identified and should be traceable to ensure
patient safety.

Background
Many small molecule drugs can be taken orally, and tend to work in the body within
cells. Since biologics are significantly larger in size, they are typically injected and
interact within the body in the bloodstream or on the surfaces of cells, rather than
within the cells. In contrast, small molecule drugs are typically composed of only 20
to 100 atoms. Small biologics, such as hormones, are typically composed of 200 to
3000 atoms, while large biologics, such as antibodies, are typically composed of
5000 to 50,000 atoms. To give a sense of size, same-scale computer models of
three drugs — aspirin (a small molecule), somatropin (human growth hormone), and
Herceptin (an antibody) — are presented below with an example of the relative
complexity: The molecules are to scale and the objects are not, but the objects
(bike, car, private jet) indicate relative size and complexity of these molecules.
Manufacturing processes for biologics differ greatly from the manufacturing
processes for small molecule drugs. Small molecule drugs are generally synthesized
using chemical reactions. Biologics, by comparison, are typically produced within
specially engineered cells. Small molecules are well-characterized, and can be
easily purified and analyzed with routine laboratory tests. Biologics — especially
larger biologics -tend to be produced as diverse mixtures of molecules that differ
very slightly from one another, which make them difficult to characterize. It follows
that the properties of the biologic often depend directly on the nature of the
manufacturing process. Furthermore, proteins have unique structural organization
patterns (referred to as "folding") that affect the way that they work in the body;
even biologics that are chemically the same may have differing biological effects
due to differences in the structural folding. An example of this folding effect is the
difference between a raw egg and a cooked one: chemically the two are the same,
but they are physically and biologically very different.

Patient Safety
We believe that because of the differences between biologics, challenging issues
exist relating to the development, approval and marketing of biosimilar products.
We further believe that patient safety must be of paramount consideration when
evaluating these issues.

Need for Clinical Trials and Indication Specific Approval

Due to the complexity of biologics as well as the distinctions introduced by differing
manufacturing processes, Genentech believes that each biosimilar must be shown
to be safe and effective on the basis of its own adequate and well-controlled clinical
studies. We also believe that biosimilar products should only be approved initially
for the indication that is directly supported by the non-clinical and clinical safety
and efficacy data package submitted by the sponsor. When an innovator product
has been approved for more than one indication, any biosimilar product should
likewise be studied in each indication to support approval.

No Automatic Substitution/Interchangeability
In addition, Genentech believes that the differing manufacturing processes mean
that each biosimilar is likely to be inherently different from the corresponding
innovator biologic. As such, pharmacists should not be allowed to freely substitute
the follow-on biologic for the innovator's product. Rather, we believe that
substitution may only be possible if the sponsor performs adequate comparative
clinical trials to establish that its product acts the same as (rather than similar to)
the innovator product in the body and the treating physician agrees to prescribe the
biosimilar.

Product Identifiability and Traceability

Biotechnology-derived products are complex proteins that are extremely difficult for
even the innovator to manufacture. Minor changes in the manufacturing process
can inadvertently result in significant and possibly dangerous differences to the final
product. Therefore, it is critical that products administered to patients be
identifiable and traceable back to the manufacturer. Patient safety interests require
that adverse events be quickly and accurately correlated with the actual product
administered. This correlation is essential to allow for immediate action to recall
products when manufacturing processes resulted in a product causing patients to
experience adverse events.

Post-Marketing Risk Management Plans Required

Post-marketing risk management plans must be an essential element of any
approval of a biosimilar product. Although we believe that follow on products must
contain their own adequate and well-controlled trials, we recognize that because
they would be approved based in part on the prior approval of the innovator
product, sponsors might be allowed to submit less data than that of the innovator to
support approval of their products. As such, biosimilar manufacturers would have
less experience with their products upon approval. In order to protect patients from
products with less complete data packages, Genentech believes that continued
assessment of the product after approval is necessary, and recommends that
biosimilar sponsors be required to have risk management plans in place to
compensate for this gap in data by collecting the additional necessary experiential
information.

Similarity and Comparability are Distinct Concepts

In addition, Genentech believes that the concepts of similarity and comparability
are distinct and must be properly applied to any approval process of a biosimilar
product. Manufacturers of innovator products are permitted to make post-approval
manufacturing changes to their products based upon a showing of comparability
between the two products. This approach is appropriate because innovator
manufacturers possess a thorough and robust body of knowledge about the process
used to manufacture the original product, which can be applied in support of
subsequent modifications to the manufacturing process. In contrast, a biosimilar
product would be approved based on an analytical determination that the product is
similar to the innovator product. Due to the importance of trade secret protections,
the biosimilar sponsor would not have access to the cell line or the critical
manufacturing processes that are essential to production of the innovator product.
As a result, new clinical data will be needed to support similarity to an innovator
product. Furthermore a complete analytical comparison with the Reference Product
is necessary to support approval of a biosimilar.

No Reliance on Trade Secret or Confidential Commercial Information

Finally, we believe that regulatory agencies should not refer to or rely on innovator
trade secrets and confidential commercial information to approve a biosimilar
product.
Genentech has urged FDA to engage an inclusive public process to discuss these
issues before moving forward with any proposal to permit the approval of follow-on
biologics. David Schenkein, MD, Genentech's senior vice president of Clinical
Hematology and Oncology , testified (link) on behalf of the Biotechnology Industry
Organization (BIO) at a May 2, 2007 biosimilars hearing before the House
Committee on Energy and Commerc's Subcommittee on Health Genentech
participated with BIO in providing formal comment to the Federal Trade Commission
(FTC) on September 30, 2008.
We will continue to encourage and participate in public discussions of the technical
and legal complexities involved with establishing an approval pathway for
biosimilars.
Biologics: Can There Be Abbreviated Applications, Generics, or
Follow-On Products?
Jul 1, 2003
By: Christopher Webster, Thomas Copmann, Robert Garnick, James Green, Mark
Hayes, Gillian R. Woollett, Anthony Lubiniecki, Genesio Murano, Kenneth
Seamon, Diane Zezza, John Landis
BioPharm International.
During the past few years, several people and organizations have stated public
positions on the feasibility of creating a legal and regulatory framework for the
facilitated approval or licensure of biologics, based on abbreviated applications (1-3).
However, public debate on follow-on biologics is difficult because of the considerable
complexity of the interrelated technical, legal, and regulatory issues. Inappropriate
use of biologics terminology and misconceptions of the regulatory grounds for safe
approval of biologics result from an incomplete understanding of the basis for
approval of existing biologics within the same therapeutic category. We seek to
clarify some of these issues in this article. We maintain, however, that the regulatory
process for the approval of biologics must be shaped by three cardinal principles:
• The safety of patients is of primary concern. Biologics are associated with
clinical issues not shared by chemical drugs. This necessitates appropriate
clinical testing of all follow-on products.
• The approval process for any biologic should recognize the ownership and
value of the innovator's intellectual property, including data submitted for
regulatory approval and licensure.
• All aspects of the regulatory framework should be supported by sound science
of the same rigor as that used in the original approval of the innovator's
product.
Definitions1. What is a biologic?A biologic is a prophylactic, an in vivo
diagnostic, or a therapeutic substance that can be made only by a living
system and that has a large, complex, inherently heterogeneous molecular
structure.
Biologics have been defined in disparate terms, depending on the scientific,
regulatory, or legal context - no comprehensive and universally precise definition
exists. For the purposes of discussion of follow-on biologics, we use the following
operational definition:
A biologic is a prophylactic, an in vivo diagnostic, or a therapeutic substance that:
• is produced only by a living system, but is not simply a metabolite,
• is stated to contain a single substance that has documented biological activity
or activities,
• has a relatively large molecular weight with a high structural complexity
compared with biologically active substances that can be made by chemical
synthesis (in practice, this means that biologics will seldom have molecular
weights less than 5 kDa),
• is inherently heterogeneous in the molecular species present and has an
impurity profile that depends critically upon the processes used to make and
test each batch,
• has activity that is often very sensitive to physical conditions (temperature,
shear forces, phase) and enzymatic action,
• usually requires bioassays for batch release and stability assessment, rather
than chemical tests for identity and purity.
2. What are "generic biologics"?A "generic" drug is approved by reference
to a strict definition of sameness to the innovator's product. Sameness,
however, cannot be determined for biologics from different manufacturers
because of the complex nature of the products and their manufacturing
processes. Therefore, "generic biologics" produced by different
manufacturers cannot exist.
The phrase "generic biologics" is often used to mean products that would be copies
of, and be competitive with, biologics produced by pioneers (that is, innovative
companies that developed and produced the first version of a particular product).
FDA would approve these products by reference to the clinical data generated by the
pioneer. This designation is derived from the regulatory process for approval of
generic (chemical) drugs, which was created by the Hatch-Waxman amendments
legislation of 1984 (4) and is codified in §505(j) of the Food, Drug, and Cosmetic Act
(FD&C) (5). However, because of major technical differences between drugs and
biologics, FDA stated that the regulatory process under §505(j) would not be
appropriate for the approval of biologics because it would result in the approval of
unsafe products (6). More recently, FDA Commissioner Mark McClellan stated that,
"As a scientific matter, it is true that certain biological products, due to their inherent
structural complexity, heterogeneity, and manufacturing process, do not currently
lend themselves to being copied generically" (7).
Because the "sameness" standard under §505(j) defines the correct use of the word
"generic," and the properties of biologics do not allow the standard of "sameness" to
be met, there can actually be no "generic biologics."
3. What are "follow-on biologics"?"Follow-on biologics" are second and
subsequent versions of biologics that are independently developed and
approved after a pioneer has developed an original version. Follow-on
biologics may, or may not, be intended to be molecular copies of the
innovator's product. They do, however, depend on the same mechanism of
action and are intended to be used for the same indication.
Currently, follow-on biologics are approved or licensed by submitting to FDA a full
product license application - either a New Drug Application (NDA) or a Biologic
License Application (BLA). Those products that have been approved or licensed are
not copies of the original, innovative product. They resemble instead the innovative
products in much the same way that members of a class of drugs resemble each
other (statins, triptans, and H2 antagonists, for example). It is possible that some
follow-on products could be approved safely on the basis of fewer or smaller efficacy
studies than were required for the approval of the pioneer. Table 1 gives some
examples of innovator and follow-on biologics.
The concept of "follow-on biologics" or "generic biologics" does not include the
special circumstances in which a manufacturer may make changes to its production
process without conducting new clinical trials (see the answer to Question 10 for
further explanation).
Follow-on Biologics4. Why would follow-on biologics matter to the
innovator industry? With the success of the Human Genome Project and
investments in genomics, bioinformatics, and proteomics by
pharmaceutical companies and others, biotechnological medicines
(therapeutics and preventives) present new opportunities for innovation
and powerful, new therapeutic modalities. These therapies have already
provided important new treatment options and, in some cases,
revolutionized the standard of care for certain diseases. The promise of
these modalities is even brighter. Patient confidence in the safety and
efficacy of these products, however, must be maintained.

Table 1.
Some
examples of
innovator
and follow-on
biologics
Another more subtle concern exists for regulators and the pharmaceutical industry.
Chemical drugs have simple chemical structures, which can be completely
characterized and specified. The Hatch-Waxman Act, therefore, established very
rigorous standards of identity (sameness) of generic drugs to innovator drugs for the
approval of those generics under §505(j) of the FD&C. Biologics and biotech drugs
cannot be approved under §505(j) the same way, except by attenuation or violation
of that sameness standard. Unlike chemical drugs, individual batches of biologics are
heterogeneous at the molecular level as a result of the inherent random variability in
the living processes by which they are made. These molecular differences are even
greater between versions of the same molecule produced by different
manufacturers. Therefore, approval of biologics under §505(j) would not only mean
approval of products with uncertain clinical properties but would also set a
precedent under which drugs significantly different from the innovator drug could be
approved as generics. That would destroy the careful legal balance between the
innovator and generic industries that was framed in the Hatch-Waxman Act and
would have adverse consequences for the control of drug costs and public health.
5. Does the recent move of therapeutic product review from the Center for
Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation
and Research (CDER) indicate a change in the standards for approval of
follow-on biologics? There is no evidence to support this speculation.
Both CBER and CDER have been intimately involved in the creation of harmonized
standards for biotechnological and biological products as part of the International
Conference on Harmonisation (ICH) and under the FDA Modernization Act of 1997
(FDAMA) during the past decade. In announcing the recent move of CBER's Office of
Therapeutics Research and Review (OTRR) to CDER, Lester Crawford, FDA deputy
commissioner stated, "Current FDA policy on generic biologics will not be affected by
this decision" (8). As quoted earlier, FDA Commissioner Mark McClellan has agreed
that biologics do not lend themselves to being copied generically (7). This position
has been common to both CBER and CDER for many years and is manifest in the
fact that neither Center has approved any follow-on protein therapeutics under
either the Public Health Service Act (PHS) or the FD&C Act. So despite the recent
reorganization within FDA and the possibility of more in the future, there is presently
no evidence that the standards by which biologics are approved are going to
change.
6. Safe (chemical) generic drugs have been on the market for years,
proving that abbreviated data packages (that is, with no safety and
efficacy testing) can ensure the safety of generics: Why not apply this
approach to biologics as well?Safe generic drugs have been approved with
abbreviated data packages because it is possible to show that the generic
product is chemically and pharmaceutically identical to the pioneer's
product, to within very tight confidence limits. Therefore, it is scientifically
reasonable to expect that the clinical properties of the pioneer's product
will be shared by the generic. Because the follow-on biologic cannot be
shown to be identical to the innovator product, this relationship does not
hold for biologics.
The manufacturing process for each biologic defines, to a significant extent, the
product because biologics are based on living cells or organisms whose metabolisms
are inherently variable. Moreover, apparently small differences between
manufacturing processes can cause significant differences in the clinical properties
of the resulting products. For example, when the manufacture of tissue plasminogen
activator (tPA) was changed from production in roller bottles to production in stirred
bioreactors (tanks), the resulting product showed differences in its glycosylation
pattern and degree of internal cleavage and possessed a different pharmacokinetic
profile and dose response in humans.
There will always be differences between manufacturing processes designed by
different manufacturers, especially those in competition with each other. As we
stated, it is not possible to predict what the effects of these differences might be on
the clinical properties of the two products. Therefore, it is not scientifically
reasonable or safe to simply expect that the clinical properties of a pioneer's product
would be shared by the follow-on product. The only way to characterize the clinical
properties of the follow-on product is to evaluate them in appropriately designed
clinical studies.
7. There are several versions of recombinant insulin, human growth
hormone, and alpha-interferon on the market - so don't we already have
generic biologics?These products are not generic, because the approval or
licensure of each product was based on evaluation of full sets of
independent data.
Different manufacturers - as independent innovators - have developed each of these
products and compiled complete regulatory applications, based on unique product,
process, and clinical data sets. These applications received full and independent
review by FDA. They cannot be presumed to be substitutable for each other (that is,
they are not AB-rated, for bioequivalence, in FDA's Orange Book) (9), but they can
represent therapeutic alternatives. A label claiming substitutability can only be
supported by an appropriate clinical trial comparing the safety and efficacy of the
product directly.
8. Because there can be only one innovator for each biologic, aren't follow-
on products generic biologics?It is not accurate to say that there can be
only one innovator for each biologic.
There are many instances of multiple manufacturers of therapeutically alternative
biologic products on the market (growth hormone, insulin, Factor VIII, erythropoietin,
and tPA, for example). Each of these alternative biologics were independently
studied and demonstrated to be clinically safe and effective. Independent clinical
trials were conducted for each. Interestingly, even though these products might
appear to be similar, there can be differences between their clinical properties. For
example, Betaseron (Berlex Laboratories) and Avonex (Biogen, Inc.) are both
versions of beta-interferon used to treat multiple sclerosis. Avonex has 166 amino
acids, whereas Betaseron has 165; Avonex is produced in mammalian cells, whereas
Betaseron is produced in bacteria. Incidents ofpatient adverse events differ between
the two products. These differences between the products are of the same order as
differences between members of a drug class (see the answer to Question 3).
Likewise, the amino acid sequences of the alfa-interferons Intron A (Schering
Corporation) and Roferon (F. Hoffmann-La Roche Ltd.) also differ by one amino acid.
The licensure by CBER of these two products on the same day - on the basis of
independent clinical trials - shows clearly that there can be multiple innovators for
each biologic.
9. In Europe, a product made by recombinant technology (Forcalcitonin)
was shown to be bioequivalent to the pioneer's product and was approved
on the basis of an abridged application. Isn't this a true generic
biologic?Forcalcitonin (Unigene Laboratories, Inc.) is not a true generic
biologic.
Forcalcitonin is produced by expression of the gene for calcitonin from salmon, but
the product is an oligopeptide containing only 32 amino acids, which does not satisfy
our definition for a biologic (see the answer to Question 1). Forcalcitonin can be
produced by means other than a living system; indeed, the pioneer's product,
Miacalcic (Novartis), is produced by chemical synthesis. Forcalcitonin and Miacalcic
are drugs (pharmaceuticals). The fact that Forcalcitonin was produced by
recombinant technology is not relevant to the discussion of generic biologics.
Comparability10. An innovator is able to make changes to its
manufacturing process without doing further clinical trials. Why can't a
generic manufacturer set up a new plant and make the same product
safely?It is not true that an innovator can always introduce process
changes without doing clinical trials. Whether that can be done depends
on the nature of the change and the results of comparative product
characterization studies. FDA still requires clinical validation of process
changes in some cases.
The innovator has a comprehensive database of every step of the manufacturing
process and key intermediates and has established many in-process controls and
reference standards. Generally, changes are minor alterations to a well-understood,
extensively validated and licensed process, with all other aspects of production
remaining unchanged. The innovator is able to compare product made before and
after the process change and show that the change has had essentially no effect on
the product made. By contrast, a follow-on manufacturer does not have access to
the pioneer's data, key intermediates, reference standards and reagents, and the
complex or unique validated methods (such as bioassays) that would enable a
comparison of the follow-on process with that of the innovator's. Even if all the
pioneer's manufacturing data were available, the inherent differences in production
and analytical methodologies, facilities, and reagents between manufacturers would
render the data nontransferable (see the answer to Question 6).
Comparability of a product made before and after a process change
(intramanufacturer) is a different concept from establishing the equivalence of two
products made by different manufacturers by necessarily different processes
(intermanufacturer). On this basis, the transfer of a manufacturer's process between
facilities can be supported by a demonstration of comparability, whereas the
establishment of a (new) process by a different manufacturer cannot.
11. FDA approved a biologic (Avonex) on the basis of clinical data that
were generated with product made by one manufacturer and transferred
to product made by another manufacturer. The second manufacturer
showed that its product was the same as that of the first manufacturer and
that the transfer of clinical data generated by the first manufacturer was
scientifically reasonable. Doesn't this prove that transference of clinical
data between products made by different biologic manufacturers is
possible?The circumstances of the development and approval of Avonex
were unique and do not support a general case that transference of clinical
data between products made by differentbiologic manufacturers is
possible.
In the Avonex case, the two manufacturers were not in competition with each other.
The consequence of this was an unrestricted flow of manufacturing information and
key intermediates between contractually bound companies. It was this exchange
that enabled the second manufacturer (Biogen, Inc.) to show that its product was
indistinguishable from that of its partner Bioferon (a German company in which
Biogen held 50% of the equity), which had manufactured the earlier batches of the
product. FDA allowed the clinical data generated with Bioferon's product to be
transferred to Biogen's product, as process comparability had been demonstrated.
Interestingly, Biogen's first attempt to manufacture the same product that Bioferon
produced failed, in spite of Biogen's advantageous relationship. The demonstration
that the two versions of the product were the same occurred only during the second
manufacturing attempt.
Clearly, the relationship between the parties in the Avonex case is completely
different from the competitive relationship that would exist between a pioneer and a
follow-on manufacturer.
12. Modern analytical technology allows manufacturers to test for all
impurities in a well-characterized biotechnology product, unlike the older
biologics. Is that not a rationale for a "specified biotech
product?"Manufacturers do not test for all the impurities in a biologic -
they test for those impurities that they know to be relevant to the process
used and for which analytical tools (usually dedicated and specially
developed) are available.
Methods to detect and quantitate impurities in the molecules of a biologic are not
well-developed, particularly for those impurities that are process-dependent. This is
another key distinction between biologics and chemical drugs, in which impurities
can be more sensitively identified and monitored. The ultimate demonstration of the
safety and efficacy of the product is in the human clinical trials. If the outcome of
these clinical trials were predictable, even the innovator of the product might not
need to perform these tests. For example, manufacturers could demonstrate only
that there were no physicochemical differences between their products and the
natural substances that they are intended to replace, and this would be sufficient.
13. Can't the same analytical methods and standards be used for different
processes and products, that is by the innovator company and by a
subsequent follow-on manufacturer?Reagents, test methods, and
reference standards are developed specifically to suit the process being
used and the product being created and are not generally applicable to
any process or product.
Specifications for one product and process are idiosyncratic and unlikely to be
applicable to a process using a different cell line, recombinant construct, purification
process, and validation profiles or being manufactured in different facilities and
evaluated by different analytical methods (10). Because of the inherent
heterogeneity of biologics, it is not possible to analyze and characterize them with
such precision that no clinical differences would result from two products that are
indistinguishable by in vitro tests. If this were not so, the present regulatory rigor
that innovators encounter when introducing process changes would not be
warranted. Recognizing these points, the leaders of the international regulatory
community (in the United States, the European Union, and Japan) have agreed to the
ICH guidance document (Q6B), which specifically states that a set of specifications is
unique to each product and to the process used to generate the product (including
its validation) (11).
Bioequivalence14. Isn't it true that establishing bioequivalence for
biologics is no more difficult than for drugs - in fact, it may be easier
because biologics are usually injected directly into the
bloodstream?Establishing bioequivalence (the same rate and extent of
absorption) is relatively complicated for biologics, and for many biologics,
it may be impossible to establish bioequivalence at all because:
• Biologics are heterogeneous (mixtures of many different molecules) and may
include polymers or complexes. Such subtle variations in the product can
result in a significant impact on the bioequivalence of even so-called
"specified" biologics.
• Mechanisms for clearance and metabolism of many biological molecules are
still not well-defined. The levels of drug determined in bioequivalence studies
are strongly method-dependent and may not reflect the biological activity of
the moiety that results in efficacy. In addition, for many specified biological
molecules, a good correlation between biological activity and the drug level in
plasma has not been established.
• Some molecules have long half-lives (greater than two weeks), and the use of
a two-period, crossover design with a standard wash-out of five half-lives may
not be feasible.
• Some molecules are particularly toxic or are used in life-threatening situations
in which it may not be feasible to carry out any type of crossover study
because of disease progression, and it may not be ethical to carry out such a
study in normal subjects.
Sometimes, the use of pharmacodynamic or surrogate end points can facilitate
bioequivalence evaluations of biologics. However, in many cases there is no
alternative to an appropriately designed clinical trial for establishing therapeutic
equivalence. It is also important to remember that even when bioequivalence of two
versions of a biologic can be established by conventional techniques, these data
provide no information about the safety of the products (see the answers to
Questions 6 and 15).
15. Wouldn't testing of both the efficacy and safety of a follow-on biologic
require only a few patients?Safety is paramount and can only be
established if a statistically relevant number of patients are tested.
Similarly, demonstrating efficacy requires a statistically relevant number
of patients, which may be greater or less than the number needed for the
innovator product.
Efficacy can be established in a small number of patients only if a precise end point
or a validated surrogate for a clinical outcome is established and endorsed by FDA
(for example, the viral load of HIV is more readily established than the morbidity or
mortality for AIDS). For a pioneer sponsor, testing a relatively small number of
patients in safety studies may be acceptable so that a breakthrough product is
allowed to reach the market, especially if there is no therapeutic alternative. This
consideration does not apply to a follow-on product because the risk-to-benefit
balance is less compelling when patients are already being treated.
The presence of different impurities in a follow-on product would be particularly
pertinent to safety and can only be established in human clinical trials. Another
important consideration in showing the safety of a follow-on biologic for treatment of
chronic conditions is the demonstration of its safety in patients who have already
been treated with another similar product ("switching" safety). Therefore, the
number of patients required to show the safety of a follow-on product will generally
be a significant percentage of the number enrolled by the pioneer and may even
exceed that number.
The efficacy of follow-on products must usually be determined by comparative
clinical studies against the pioneer's product. Comparative studies should be the
basis for any official recognition of substitutability. These studies are particularly
relevant to products for which bioequivalence is not a validated predictor of efficacy
and cannot be demonstrated formally.
Rationally, the quantity of data required to license follow-on biologics will vary for
each product and will depend on each product's complexity and on how much is
known about the product's mode of action. It would be important that this need for
flexibility not be constrained by rigid legislative language.
Manufacturing16. Isn't it true that facilities for making biotechnological
medicines can be built and operated just as easily as those for
drugs?Manufacture of biological products depends on rigorous controls
and repeated in-process testing, so the facilities must be more integrated
than is the case for drugs.
The potential for microbiological contamination of starting materials, the delicate
nature of biological macromolecules, and the extreme sensitivity of the living cells
that produce biologics impart complex requirements for fermentation, aseptic
processing, storage, and testing. For example, a typical manufacturing process for a
chemical drug might contain 40–50 critical tests. The typical process for a biologic,
however, might contain 250 or more critical tests. These issues translate into very
specialized engineering and process designs that transcend plant and machinery to
encompass subtle human factors. Consequently, construction and validation of new
facilities is disproportionately expensive and time-consuming. This is, in part, why
there is, at present, a global shortage of biomanufacturing capacity.
Manufacturing changes for drugs, although still onerous, can be more readily
accommodated than those changes for biologics. Drug batches are released
according to specifications for the drug substance and the final product, without the
emphasis on extensive characterization and critical testing required of biologics.
Required Regulatory Essentials Understanding these issues, it is clear that
approval or licensure of each follow-on biologic must rely on specific clinical data
that support its safety and efficacy. Assessments cannot be based solely on
examinations of data relating to other members of the same class of drugs.
Whether two or more biologics can be substituted for each other safely is a second
order issue:
In most cases, the only satisfactory basis of assessment will be direct comparison in
appropriately designed trials.
Just as manufacturing and quality data from comparability studies reduce risk when
conducted to support changes to the product or process of a licensed biologic, data
from clinical trials are needed to support independent approval and licensure of
follow-on products or approval of the substitutability of similar products within a
class of drugs. Absence of such data constitutes substantial risk.
References (1) Bende, S., presented at the Hatch–Waxman Update 2002
conference (FDLI, Washington DC, December 2002).
(2) "Generic Biologics: Xigris Approval Suggests Precedent for FDA, GPhA Says," FDA
Week, p. 32 (16 December 2002).
(3) Hatch, O., FDA Week, p. 16 (12 August 2002).
(4) "The Drug Price Competition and Patient Term Restoration Act of 1984," U.S.
Code Title 35, Section 156 (Hatch–Waxman Act, S-1538, HR-3605, 24 September
1984).
(5) "Federal Food, Drug, & Cosmetic Act," U.S. Code Title 21, Section 355(j) (1938,
revised 1999).
(6) Zoon, K., "CBER Chief: Generic Biologics a Problem from Scientific
Standpoint," FDA Week, p. 18 (20 April 2001).
(7) McClellan, M., "FDA Generic Biologics Policy May Change Under McClellan," Pink
Sheet, p. 7 (14 October 2002).
(8) Crawford, L.M., "FDA to Consolidate Review Responsibilities for New
Pharmaceutical Products,"FDA News (6 September 2002).
(9) CDER, Electronic Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations (FDA, Rockville, MD, updated 29 May 2003). Available
at www.fda.gov/cder/ob.
(10) Copmann, T. et al., "One Product, One Process, One Set of Specifications: A
Proven Quality Paradigm for the Safety and Efficacy of Biologic Drugs," BioPharm
14(3), 14–24 (March 2001).
(11) ICH, Q6B:Specifications for New Drug Substances and Products: Test Procedures
and Acceptance Criteria for Biotechnological/Biological Products, CPMP/ICH/365/96
(Geneva, 1999). Also Federal Register 64(159), 44928–44935, Doc. 99-21352 (18
August 1999). This is a test.