Pharmaceutical Equivalence of Generic Essential Drugs
Pharmaceutical Equivalence of Generic Essential Drugs
Pharmaceutical Equivalence of Generic Essential Drugs
The use of multisource essential drugs widely contributes to the accessibility to health care for populations in difficulties in
developing countries or in case of emergency aids. The issue of bioavailability questions the simplistic theories about drugs
interchangeability. Bioequivalence studies must be carried out to ensure the therapeutic equivalence of two pharmaceutic equivalent
drugs. However, by looking at drugs circulation around the world, one realizes that these studies are not systematically carried out.
National regulations set the conditions for the execution of bioequivalence studies but there is no consensus between the various
European States. The subsequent deregulation generates even more confusion in the supply of drugs to developing countries. This
study consisted first of reviewing a few national regulations and second of considering, on a case by case basis, possible exemptions
from bioequivalence studies for active ingredients.
Keywords: Humanitarian aid — Supply — Multisource essential drugs — Generic — Bioavailability — Bioequivalence —
Exemption — Quality.
The concept of essential drug was defined in 1975 in order I. CARE ACCESS AND BIOEQUIVALENCE
to help developing countries to find their way through the
complex supply range from western countries (today, there are 1. ESSENTIAL DRUGS
about 8,000 specialities in France and more than 15,000 in
Germany). As drugs were supplied from many various sources, In order to allow access to health care for everyone,
physical and chemical controls were rapidly established, and developing countries (within the context of their national
highlighted numerous unfortunate cases. This kind of control, pharmaceutical policies) and humanitarian organisations rely
though unanimously accepted by members of Public Health on the essential drugs list drafted by the World Health
and humanitarian organisations, does not solve the problem of Organisation (WHO).
interchangeability of multisource or generic drugs. The essential drugs list, made of under 400 molecules, is
In the case of the registration of generic drugs on the regularly reviewed by the WHO. It is used as a standard by the
European market, regulations demand for bioequivalence studies countries who from there identify their own priorities and make
to be carried out when required. Healthy humans are submitted their own selection. An essential drugs list must cover the
to these tests. The tests are very expensive and not systematically majority of health problems (80 to 90%) that require medical
carried out, and the criteria that allow their exemption vary treatment for people living under normal conditions. The
from one country to the next. This might create problems for therapeutic and economic criteria used to select basic drugs
mutual recognition of registrations within the European Union. means that most of them are available as generic drugs [1].
In addition, purchasers from developing countries only The ninth list of basic drugs (December 1995 [2]) is made
occasionally call for bioequivalence studies. This is due to the of several therapeutic classes as shown in table I. A new edition
fact that the technical specifications of tenders often prevent is currently ready for publication.
pragmatic attitudes towards these studies.
After defining the specifications of the drugs used, we
compared the main national regulations in a non-exhaustive 2. GENERIC DRUGS
way. Our study was based on national lists of active ingredients
and essentially consisted of giving our opinion, i.e. on a case by A generic drug may be defined as a copy of an original
case basis, either supporting an exemption from bioequivalence medicinal drug for which production and marketing have been
studies or, on the opposite, stressing their importance. made possible by the expiration of the protection accorded by
As an alternative, we then looked at the kinetics of dissolution, the patent of the intellectual property covering the active
their relevance and limits. ingredient.
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The concept of copy is defined by general texts pharmaceutical form, if they follow similar or comparable
(Directive 87/21 of 22 December 1986) and by French law standards and if they are intended to be administered through
(article R. 5133-1 of the Code de la santé publique [3]) by the the same route.
terms “speciality essentially similar”, that is to say presenting: Two drugs are therapeutically equivalent if they are
- the same qualitative and quantitative composition of active pharmaceutically equivalent and if appropriate results of studies
ingredients, (bioequivalence studies, clinical or in vitro pharmacodynamic
- the same pharmaceutical form, studies) show that after administration of the same molar dose,
- if the case arises, bioequivalence with the original product their effects, both those concerning their efficacy and safety,
shown by means of appropriate bioavailability studies. are essentially the same [6].
The legal definition of generic drugs was made in France
after a decree on health expenditures was promulgated and 4. QUALITY OF ESSENTIAL MULTISOURCE DRUGS
ratified on 24 April 1996 by the Council of Ministers [4]:
“The definition of a generic speciality of another speciality is a Due to the specificity of their registration, the quality of a
speciality that has the same qualitative and quantitative generic or a multisource drug depends on the following three
composition of active ingredients, the same pharmaceutical criteria :
form and which bioequivalence has been determined by the - quality of raw material
appropriate bioavailability studies; the different oral - stability studies
pharmaceutical forms for immediate release are here considered - bioequivalence studies
to be the same similar pharmaceutical form.” Problems of raw material and stability are the most common.
The decree dated 13 March 1997 (article R. 5143-9) defines They are indeed easily detected with physical and chemical
the scientific criteria that allow exemptions from bioequivalence methods.
studies [5]. These criteria will be further exposed. According to ICH (International Conference on
Harmonisation), bioequivalence is the third criteria of quality
as it is indirectly related to efficacy [7].
3. MULTISOURCE DRUGS
The WHO prefers the concept of multisource drugs which 5. BIOVAILABILITY, BIOEQUIVALENCE AND ESSENTIAL DRUGS
are equivalent drugs from a pharmaceutical point of view, but
not necessarily from a therapeutic point of view. Multisource Bioavailability means “the rate and extent to which the
drugs that are therapeutically equivalent are interchangeable. active ingredients are absorbed by the body from a
Drugs are pharmaceutically equivalent if they contain the pharmaceutical form and become available at the site of action”
same amount of the same active ingredient(s) in the same and bioequivalence means “equivalence of bioavailabilities”.
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The following forms must undergo bioavailability studies : - narrow therapeutic range,
- orally administered forms with an immediate release and a - pharmacokinetics complicated by a complete absorption,
systemic action intended for serious indications, and/or with a elimination or a high metabolism at the time of first passage,
narrow therapeutic margin; - unfavourable physical and chemical properties,
- products for which the pharmacokinetics are complicated by - widely-known problems of bioavailability,
a weak absorption (< 70%) , a non-linear kinetic or an important - high proportion of excipients in relation to the active
presystemic elimination (> 70%); ingredient;
- substances presenting unfavourable physical and chemical - products with a systemic action that are not intended to be
properties (instability, low solubility, etc.); administered orally;
- non-orally administered forms with immediate release; - products with a modified release;
- systemic action forms with a modified release; - associations in fixed proportions that have a systemic action;
- products described as presenting problems of bioavailability. - products with a systemic action that are not in a solution form.
Products for which there is a risk of suprabioavailability (a The concept of bioequivalence does not fit to this type of
bioavailability superior to the reference product) must also product. The equivalence must be proved through comparative
undergo bioavailability studies in order to reduce the dosage if clinical or pharmacodynamic tests.
need be. These recommendations from the WHO aim at setting the
Great-Britain and Australia have adopted these criteria as limits that should not be overstepped with regards to
national regulations [9, 10]. bioequivalence.
The WHO has drafted a list of recommendations that allows Criteria for exemption
the exemption from bioequivalence studies or on the contrary Italian regulations also admit possibilities of an exemption
their obligation. from bioequivalence studies for drugs with an IV or IM
administration, aerosols, drugs for topical use without any
Criteria for exemption systemic action and drugs intended to be administered orally in
They basically apply to drugs that are intended to be solution form or in tablet form intended to be made soluble
administered through the parenteral tract (IV, IM, SC, etc.) in before absorption (effervescent).
aqueous solution; drugs in orally administered solutions;
powdered drugs intended to be reconstituted in solution; medical Obligation criteria
gas and drugs for auricular, ophthalmic and topical uses and According to the new regulations, any other form of
products for inhalation and spraying. pharmaceutical presentation must be submitted to
Tablets and capsules are often questioned and interpreted. bioequivalence tests against the reference product. Drugs
Yet, texts show that the equivalence can be proved, in some cases, registered under the previous regulations do not however need
by an in vitro dissolution test. This possibility may concern: to undergo bioequivalence tests.
- drugs with fast dissolution kinetics;
- drugs with various dosage, with a same formulation produced 1.1.4. Canada [1]
by the same manufacturer when:
- the qualitative composition of the various dosages is basically Today, the bioequivalence of a drug must be proved when
the same, it is thought that it has not been commercialised in Canada long
- the active ingredient/excipient ratio is mainly identical for enough and in sufficient amounts to ensure its innocuity and its
all dosages, efficacy.
- a bioequivalence study has been carried out on at least one Bioequivalence can be proved by comparative bioavailability
of the dosages; tests, or by clinical tests. Scientific criteria similar to the ones
- in the case of systemic action drugs, if studies show that the of the European Community and Australia have been set up to
pharmacokinetics was linear throughout the whole therapeutic decide when the bioequivalence of drugs that are not considered
field. as new must be proved in vitro.
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from bioavailability tests. Thus, France distinguishes itself Criteria for exemption
from European recommendations. Bioavailability studies may not be essential for oral forms
Criteria for exemption administered in solution, providing that the excipients do not
These criteria are itemised in decree No. 97-221 [5]. The modify absorption. They are also not essential for solid oral
exemption from bioavailability studies is submitted, for forms with an immediate release.
each case, to the director of Afssaps (Agence française
de sécurité sanitaire des produits de santé). A speciality Obligation criteria
can be exempted from bioavailability studies if it is produced by In Germany, bioavailability studies are generally required
the same manufacturer in the same plant and if its file is a for oral forms with a modified release, but also drugs
duplicate of the file of the reference speciality. Other cases administered through the rectal or vaginal tracts, preparations
of possible exemption from bioavailability studies: drugs for with a topical use with systemic passage, preparations intended
which the bioavailability cannot be different from the reference to be absorbed by the respiratory or oral mucous membrane, IM
speciality; drugs for which the active ingredient (as far as its or SC injectable preparations, except for aqueous solutions.
toxicity and specific requirements are concerned) should not The following active ingredients presented in immediate
reveal differences in terms of therapeutic efficacy or side release oral form are generally submitted to bioavailability
effects. For solid oral forms, in vitro dissolution comparison studies: antiarrhythmic, antidiabetic, antiepileptic,
tests must show the equivalence of their dissolution. anticoagulant, drugs with an anti-infectious action, broncho-
As far as the exemption from bioavailability studies is dilatators, cardiac glucosides, substances with an hormonal
concerned [11], French regulations consider the drug from the effect.
point of view of its therapeutic efficacy and of its risks. Table II
sums up the possibilities for exemption. 2.2. The Netherlands
Obligation criteria
Obligation criteria Modified release forms must be submitted to bioavailability
Bioequivalence studies are imposed when at the same time: tests, like solid oral forms containing a substance that does not
- specialities may be bioinequivalent, belong to the described list.
- therapeutic and/or side effects closely depend on the time
related amounts of active ingredient released in the body. 2.3. United States [17]
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bronchodilatators, cardiotonic glucosides, corticoids, hormonal study is not always carried out on drugs that are intended to be
action products. sent to developing countries. Indeed, these drugs are found in
The substances which are not on this list are submitted to the supplies of most open tenders and this for three intimately
individual tests in order to determine if they should or should linked reasons:
not undergo bioequivalence tests. - such studies are very expensive in Europe and highly increase
drug prices. This situation leads to a potential reduction of drug
3. DISCUSSION accessibility and also to less price competitiveness. The
requirements of some tenders do indeed favour low prices
This inventory of regulations shows that the requirements against quality;
for the exemption from bioequivalence studies of a - international tenders maintain a constant pressure on prices
pharmaceutical product differ from one country to the next. A reduction and on the deregulation of the market for raw materials
few differences remain, even for the most general concepts that which are often of varying quality. Because of the influence of
consider the pharmaceutical form or in terms of risk for the the quality of raw materials on bioavailability, manufacturers
patient: hesitate to perform bioequivalence studies;
- the forms for a parenteral use for example: the WHO and the - drugs for which this kind of study could be replaced with an
European legislation exempt any kind of forms for parenteral in vitro dissolution study are not clearly specified. Moreover,
use from bioequivalence studies. The Italian legislation only there is no international consensus between various regulations.
exempt from bioequivalence studies the forms that are intended The second kind of problem concerns the physical and
to be injected in IV or IM injections. In fact, for forms chemical quality of the drugs. The multisource drugs market is
administered in subcutaneous injections, there is a real absorption international, therefore regular controls should imperatively be
phase that can thus directly have an influence on the carried out. It is indeed difficult for manufacturers to rely on a
bioavailability; constant supply of raw material. The control laboratory of
- we can also notice various interpretations as far as aerosols CHMP systematically checks the drugs that are bought. Most
are concerned. The WHO and Italian regulations exempt aerosols of the found non-conformities concern dissolution tests. The
from bioequivalence studies, whereas European regulations dissolution of the active ingredient is in fact an essential factor
only exempt medical gas from bioequivalence studies. of its absorption and it is therefore a parameter that is closely
linked to bioavailability.
III. THE STRATEGY OF THE CHMP: SOLID ORAL The WHO stipulates that in vitro dissolution tests may be
useful to show the equivalence between two multisource drugs.
FORMS FROM THE ESSENTIAL DRUGS LIST
It is however advisable to use this test as rarely as possible and
especially not as the unique proof for capsules and tablets, the
The Centrale Humanitaire Médico-Pharmaceutique two pharmaceutical forms for which the dissolution test mainly
(CHMP) has authority to supply non-profit making organisations applies. Solid oral forms represent the higher percentage of the
with essential drugs, medical equipment and laboratory reagents. pharmaceutical forms used for humanitarian aid. Therefore, the
As far as essential drugs are concerned, its main mission is dissolution test remains essential in evaluating the bioavailability
to stock up with drugs at the best price and make sure of their of an active ingredient.
quality, especially with the help of its control laboratory.
As a supplying organization with a strictly humanitarian
1. THE POSITION OF CHMP TOWARDS BIOEQUIVALENCE
aim, CHMP is confronted to two kinds of problems.
STUDIES [6, 13, 17, 18]
First, CHMP faces contradictory situations at tenders level:
while some demand bioequivalence studies on every single
drug, some do not require any. The wording of those tenders Thanks to its experience, CHMP can evaluate the various
shows the lack of knowledge of the issuers of the tenders legislations with regards to bioequivalence and therefore adopt
regarding the reality of the market. CHMP wants to lay stress a clearer position.
on the importance of “price-efficacy-risk” issue, without which Table III lists the active ingredients available in solid oral
tenders tend to be devoid of interest. It is important to act with forms with an immediate release which can be exempted from
discernment when it comes to products that may present bioavailability studies according to CHMP. Table IV lists the
bioavailability problems and with products known for their active ingredients in a pharmaceutical form which must prove
easy absorption and rapidly maximal bioavailability. Today, it bioequivalent to the reference product.
is important to clarify the notions of interchangeability and For solid oral forms with an immediate release, CHMP
bioequivalence of multisource drugs. Bioequivalence is considers the criteria listed in table V to give a ruling on the
especially important in the case of the use of antibacterial and obligation or the exemption from bioequivalence studies.
antiparasitical drugs. In these cases, insufficient bioavailability When a judgement on the necessity or not of bioequivalence
could mean inefficacy such as resistance to treatments, a studies is passed, there are three different scenarios:
situation that would plunge the nursing team into a state of utter - when national lists agree: we have considered the option of
confusion. national legislations agreeing to clearly exempt or to make
In the case of generic or multisource essential drugs, a bioavailability studies obligatory;
bioequivalence study is obviously the best way to show - when national lists disagree: some active ingredients are
interchangeability and therefore efficacy. Unfortunately, this exempted from bioequivalence studies for a particular national
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Table III - Active ingredients exempted of bioequivalence not study by CHMP [1, 12-16].
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Table IV - Active ingredients for which bioequivalence study is obligatory for CHMP [1, 12-16].
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Table IV - Active ingredients for which bioequivalence study is obligatory for CHMP [1, 12-16] (continuation).
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legislation but not for another one. In that case, we have problems. It is generally prescribed in high doses for indications
considered each listed criteria to give a ruling on the appropriate- that do not affect the vital prognosis. Indometacin shows a
ness of the studies. The risk for the patient remains the classical pharmacokinetic and a fast kinetics of dissolution. In
discriminating criterion; case of bioinequivalence, the risks of an alteration of efficacy
- when the active ingredients are not itemised on any list: these and the risks of an increase in side effects are weak.
active ingredients have been submitted to tests, considering Moreover, the problem of a mass treatment with risks of
each criterion of table V. They are generally intended to cure induction of resistance does not arise. Thus, CHMP considers
tropical or rare diseases in the developed countries. Thus, they that this drug can be exempted from studies.
are not to be found in the national list, but on the other hand, they Finally, let us consider the case of niclosamide which is not
belong to the essential drugs list. That is why we have listed listed in any national list. Although it has an antiparasitical
them. action, this active ingredient is hardly absorbed: it has a direct
We have taken three examples to illustrate the position of impact on parasites. The systemic passage is thus very weak
CHMP. and does not influence activity in any way. The bioavailability
The first example is about chloroquine, an active ingredient represents the amount of active ingredient in the blood, that’s
used to treat paludism. In the USA, chloroquine tablets are why it can not be measured out.
exempted from bioequivalence studies. They are compulsory Therefore, bioequivalence tests are by definition useless.
in Germany, whereas The Netherlands and Canada have not yet
come to a decision about the subject. Each criterion of table V
has been appraised by CHMP: 2. THE POSITION OF CHMP TOWARDS DISSOLUTION
Chloroquine, a substance with a large therapeutic window, TESTS[6]
is not described as being problematic with regards to
bioavailability. Its indications do not directly affect the vital In order to guarantee the specificity of an essential drug, i.e.
prognosis. Its absorption is fast and its pharmacokinetics is its accessibility for the most destitute people, the exemption
classical. Moreover, active doses are distinctly superior to from bioequivalence studies may be envisaged for the products
2 mg. which are described in a national legislation as non-problematical
And finally, in case of bioinequivalence, the side effects are with regards to bioavailability.
slightly increased. For solid oral forms, national regulations advocate the use
The treatment of an entire population with chloroquine of in vitro dissolution tests for development and quality control.
tablets with an insufficient bioavailability would however Several studies demonstrate the importance of the information
create an important risk of inefficacy, and especially an induction given by this test. It can help to synthesize information about the
of resistance to the antipaludism drug. This risk being prejudicial raw material, but also about the formulation and the pharmaco-
on a large scale, CHMP considers that chloroquine tablets must technical features of the form.
undergo a bioequivalence study to make sure of their This test may be considered acceptable in the following
interchangeability. cases:
Indometacin is an anti-inflammatory and non-steroidian - drugs for which in vivo tests are not demanded;
substance for standard use. It is listed under capsule form in the - various dosages of the same formulation produced by the
essential drugs list. The USA and Canada think that same manufacturer in the same plant, when:
bioequivalence studies must be performed. Germany and The - the qualitative composition of the various dosages is basically
Netherlands consider that the tests are not compulsory. the same,
To take a stand, CHMP refers to the criteria of table V. - the ratio of the amounts of the various excipients is the
Indometacin, an active ingredient with a wide therapeutic same,
window, is not described as showing special bioavailability - an appropriate bioequivalence test has been carried out on
at least one of the dosages of the formulation,
Table V - Obligation or exemption criteria of bioequivalence studies for
- the pharmacokinetic is linear on the entire therapeutic
CHMP. range.
CHMP control laboratory compared the kinetics of
Criteria Exemption Obligation
dissolution of chloroquine multisource tablets, according to the
Therapeutic margin wide narrow method suggested by the USP. The results are shown in
Risk of efficacy modification weak high figure 2.
Out of six generic drugs tested against their market
Well-known bioavailability no yes
problems references, only one shows a dissolution profile that may be
Kinetics of dissolution fast slow
perfectly superimposed. Generic No. 5 shows a kinetics of
dissolution which profile is clearly inferior to the reference
Serious indications no yes
product. This generic is therefore not equivalent to the reference
Pharmacokinetic classical complicated drug with regards to in vitro dissolution.
Resistance induction no yes The laboratory also studied the kinetics of dissolution of six
Weak strength (< 2 mg) no yes sets of generic indometacin capsules against their market
Product non absorbed yes no references. The results are shown in Figure 3.
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110
110
100 100
90 90
80
Dissolving %
80
70
60 70
dissolving %
50 60
40
30 50
20 40
10 30
0
0 10 20 30 40 50 60 20
10
Time (min)
0
Generic 1 Generic 2 Generic 3 Reference 0 10 20 30 40 50 60 70 80 90
110
100
90
80
Thus, bioequivalence studies obviously appear to be the
Dissolving %
70
60
only way to determine the equivalence of two tetracyclin
50 capsules.
40
30 For CHMP control laboratory, the dissolution test is very
20
10 useful in order to show the equivalence between two drugs, but
0
0 10 20 30 40 50 60 must be used with care. Whenever it is possible, the dissolution
Time (min) mediums that are generally used refer to the specific monographs
Generic 1
Reference
Generic 2
Generic 5
Generic 3
Generic 6
Generic 4
of the pharmacopoeias. They must absolutely not contain more
than 5% of an organic solvent in order to respect biological
Figure 3 - Dissolution kinetics of indometacin capsules. realities as much as possible.
The test must then be carried out in strictly similar conditions.
As for chloroquine, the profiles of dissolution can not be It must show an equivalence of the profiles of dissolution and
superimposed. The curve of dissolution of generic drug No. 1 not only an equivalence of a certain aspect at one time decided
is statistically identical to the reference one. For generic drugs by the pharmacopoeias. Indeed, occidental pharmacopoeias do
No. 4 and 6, the curves are not statistically different from the not deal with the dissolution test in the same way. The
one of the reference drugs. After we studied the granulometrical instrumentation that is used is about to be harmonised between
features of the powders contained in the capsules, we were able the USA and Europe. The European Pharmacopoeia only
to reveal that the formulation of the mixing and the decrees general recommendations. The British Pharmacopoeia
granulometrical distribution were two parameters intimately (BP) describes operating methods for several products. On the
linked with the kinetics of dissolution. other hand, USP is better informed on dissolution tests. However,
We set that generic drugs No. 1, 4 and 6 had profiles of dissolution mediums, time of sampling and conditions of
dissolution comparable to the one of the reference product. measurement do vary.
They complied with bioequivalence studies. The dissolution The dissolution mediums used are not standardised yet and
test is thus discriminating enough to highlight differences in they have a direct influence on the discriminating power of the
formulation. Moreover, it gives a more accurate idea of test. It is therefore easy to lower the discriminating property of
bioequivalence because there is a correlation between both a dissolution test to show the equivalence of two kinetics of
types of studies. Thus, it is easy to make sure of the equivalence dissolution between two products.
of two drugs through a dissolution test. Indometacin capsules On the contrary, a very discriminating medium can show
can therefore be exempted from bioequivalence tests. significant differences between two samples, whereas those
Let us take a final example: the case of tetracycline capsules variations are not or hardly pointed out in an in vivo test. Thus,
for which a dissolution test was carried out according to the the problem rests on a possible in vitro/in vivo correlation that
conditions of the British Pharmacopoeia. The results are is often not easy to demonstrate.
presented in Figure 4.
After a granulometrical analysis of every sort of powders *
contained in the capsules, it was shown that there are huge * *
differences within generic drugs. The dissolution test does not
point out those differences. For tetracyclin, it is not discriminating For several years and in every country of the world,
and thus, does not enable one to set an in vitro/in vivo correlation. pharmaceutical authorities have been busy regulating
On the other hand, it is possible to make it more discriminating bioequivalence studies.
if one modifies the composition of the dissolution medium. The evidence has proved that they were not systematically
However, playing on the discriminating power of the test in necessary but the relatively recent arrival on the market of very
order to achieve better results is something really awkward. numerous generic drugs increases confusion. The access to
Indeed, we would move away from the real in vivo conditions health care for the most destitute populations is directly
and the test would become devoid of interest. subordinated to the price of the drug, explaining why the
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REFERENCES
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