1. One mans’ supergeneric is another mans’ life cycle management.
Malcolm S F Ross
Generapharm-Training and Consultancy
Rümelinbachweg 16
Basel 4054
Switzerland
Email: m.ross@generapharm.eu
Generic Pharmaceutical companies are not regarded as innovators but as simply
copiers of originator products to be launched at patent expiration. However in terms
of scientific skills many Generic pharmaceutical companies have developed excellent
innovative skills as a result of their need to navigate around generic defence patents
of the originator companies. More patents per product both in terms of drug
substances (process patents and polymorph patents) and formulations are issued to
Generic companies than to the classical innovator companies. This alone
demonstrates the technical knowledge and skill sets available in these companies. To
move into the completely innovative model, e.g. new chemical entities, requires a
completely new set of skills, both in terms of knowledge base, project and risk
management, clinical data evaluation etc. However, with relatively little investment
Generics companies could move into the “supergeneric” space.
Keywords: Generic drugs, Supergeneric drugs, Value added generics, Pharmaceutical
Industry, Business models.
Introduction
Pharmaceutical companies tend to fall into two business models, Innovative or
Research Oriented companies and Generic companies. In recent years there has been
a blurring of the line with the formation of hybrid models, either where innovator
companies have their own generics division or larger Generics companies that have
developed innovative products.
There is however an area of innovation which is well within the competencies of both
Innovative and Generic companies but has received little attention from the latter.
This is the area of “supergenerics”, sometimes referred to as “value-added” generics.
The term “supergenerics” has been used somewhat indiscriminately but most simply
describes a dosage form of a patent expired drug substance that has been improved by
reformulation, often in a new delivery system, or combination of a patent-expired
drug substances. As such, the off patent molecule is re-introduced to the market as a
product which is differentiated from and, presumably, better than original. If launched
by a generics company it is called a "supergeneric"; if by the originator it is called life
cycle management or "brand extension”.

2. In fact the market is full of products that fall within the broad category of
“supergenerics” but are often not recognized as such because the vast majority of
these products are developed by innovator companies as part of their life cycle
management strategies. Since the onset of the innovator pipeline crisis the majority of
“new” products have actually been line extensions of this type.
In many cases the actual development of a “supergeneric” is well within the capability
of a modern, medium sized Generic company. There is no need to look for specialist
drug delivery systems when simple procedures may well suffice. For example, the
production of rapidly dissolving tablets can be performed on the simplest of tablet
presses with the many new excipients that are available today. Taste masking
techniques require knowledge and experience rather than high level technical
solutions.
Various techniques that can be used such as controlled or extended release
formulations of existing therapies, developing alternative delivery routes, such as oral
as opposed to injectable treatments, or enhancing purity of the original product to
reduce dosing and to limit side effects have been reviewed (Hansen N and Tunnah P,
J. Gen Med (2003) 121 (16):6-12) and it is claimed that the major driver for success is
in improving patient compliance.
Some possibilities for “supergeneric” products.
1. Combination products
Fixed-Dose Combinations products (FDCs) are defined in 21 CFR 300.50 as “Two or
more drugs may be combined in a single dosage form when each component makes a
contribution to the claimed effects.”
1.1 Products showing therapeutic differentiation from the monotherapies.
There are occasional instances where such combinations are developed to improve
pharmacotherapies by exhibiting synergy/additivity which may show reduced
effective dosages to those needed in monotherapies or reduced side effects/toxicities.
These would potentially require considerable acquisition of clinical data.
Vivus Inc. a company specialising in “next generation” obesity products provides us
with an example of this class with the experimental weight-loss drug Qnexa®, which
combines two generic drugs phentermine and topiramate. Vivus mounted two late-
stage, 56-week trials, tracking the percentage of subjects who lost five percent of
body weight. They hit their primary endpoints, providing the data, the company says
it needs, to win regulatory approval.

3. 1.2 Products providing improved patient compliance
The main reason for combination product development is patient compliance giving a
simplified dosage regimen in a convenient dosage form, or in other terms, simple life
cycle management. Such combinations may require clinical data of quite limited
nature, frequently simply a trial of A+B versus the AB combination product. In
certain cases where the regulatory authority has determined that the combination is
safe and effective these trials may be limited to minimal bridging studies for the
combinations if PK/safety profile of the two remains unchanged. This is not much
more than proof of bioequivalence, something that is well within the experience and
financial resources of many Generic companies. Many such products already exist
including ACE inhibitors with the diuretic, hydrochlorothiazide, or metformin with
glyburide, glipizide, pioglitazone, rosiglitazone, sitagliptin etc. but there are still
several frequently co-prescribed products that are not available in combination.
2. New dosage forms of off-patent drug substances
The use of off-patent drug substances dramatically reduces the development costs in
terms of toxicology, safety and efficacy testing and is a much lower risk.
2.1 The directed approach
Examination of the pharmacokinetics and therapeutics of existing formulations can
reveal the possibilities of improved delivery systems. We shall review some of the
possibilities that have been realized already or could be developed.
2.1.1 Onset and duration of action-alteration of pharmacokinetic profiles
Zolpidem
Zolpidem (Ambien®/Stilnox® Sanofi-Aventis) is a hypnotic used to promote sleep. It
is conventionally formulated as a simple 5 or 10mg tablet.
The originator product had been shown to have a relatively short action, lasting for
between 3 and 5 hours. It would be obvious to any formulator skilled in solid dose
formulations that any one of a range of modified release excipients could be
incorporated into the IR formulation to give a prolonged release and consequently a
longer activity. However, although within the capability of Generic companies the
development was conducted by the originator who simply adopted a bilayer tablet
formulation giving rapid onset and prolongation of sleep. The actual clinical data
required would, in principle, be relatively simple although the innovator reported a
considerable investment in clinical data.
Several small companies adopted an alternative approach to formulating simple
“supergenerics” of the same molecule. These products were developed on the basis
that a large number of insomniacs have a problem of sleep onset rather than sleep
duration and therefore an improved formulation would be one with more rapid onset.

4. It is well known that the sublingual administration route leads to more rapid drug
absorption and Meda Pharmaceuticals Inc. recently obtained FDA approval for an
extremely simple sublingual tablet formulation. Edluar® sub-lingual tablets are
bioequivalent to Ambien® tablets (Sanofi-Aventis) with respect to Cmax and AUC,
however they have a pharmacokinetic profile characterized by more rapid absorption.
The significant success factor of this product may be the structure of Meda which is a
Swedish based speciality pharmaceutical sales and marketing organisation that
concentrates on marketing and market-adapted product development. Acquisitions
and long-term partnerships are fundamental factors that drive the company’s strategy.
It acquires “supergeneric” type products from small companies and moves them
through the regulatory process and into the market place.
Another version of a “supergeneric” zolpidem is Zolpimist®, a metered oral spray
using Novadel’s NovaMist™ proprietary oral spray technology for systemic delivery.
The companies developing these were required to provide relatively limited clinical
data.
ACE-Inhibitors-a change in Tmax
If we look at the prescribing information for certain ACE inhibitors we find that a
minor change in the pharmacokinetics could well produce an improved product. The
prescriber information for Accupril® (Pfizer) states the following:
“Most patients have required dosages of 20, 40, or 80 mg/day, given as a single dose
or in two equally divided doses. In some patients treated once daily, the
antihypertensive effect may diminish toward the end of the dosing interval. In such
patients an increase in dosage or twice daily administration may be warranted. In
general, doses of 40–80 mg and divided doses give a somewhat greater effect at the
end of the dosing interval.”
If we analyse this dosing regime it would appear that the product is barely a once a
day product with the critical period being at the end of the 24 hour period. This was
actually pointed out by one FDA reviewer in the Summary Basis of Approval. The
product recommendation is to give the product twice a day or a higher dose.
A reformulation to a modified release product is a simple matter and at least an initial
proof of concept might simply be to carry out steady state studies against the IR
product taking twice daily. There are several improvements possible and yet this
block buster drug is only available as the instant release product.

5. Old drugs revitalised
Such modifications can even breathe life into old and almost dead products.
Cyclobenzaprine, for example, has been on the market as an instant release product
for over thirty years and there are currently no less than ten generics for the instant
release product approved by the FDA. One of the major disadvantages of this product
is that fluctuations in blood levels are quite large and the product is associated with
drowsiness. Cyclobenzaprine ER®, an extended release formulation using Eurand’s
Diffucaps multiparticulate bead technology and licensed by Cephalon extends the
release period and reduces fluctuations in plasma levels that are associated with
drowsiness. This old product is seeing a resurgence of interest as Amrix® approved in
the USA in 2007. Cephalon has succeeded not only in marketing an improved product
but also in differentiating its product from the other generic companies (several of
whom have already filed ANDA’s with paragraph IV claims and have been taken to
court by Cephalon and Eurand).
2.1.2 Bioavailability and dose reduction
Itraconazole is an oral antifungal agent (Sporanox®-Janssen). The absolute oral
bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.
Itraconazole is a class II compound in the Biopharmaceutical Classification and
therefore improvement of either solubililty or permeability will likely improve
bioavailability and allow a reduction in dose.
HalcyGen acquired an oral formulation of itraconazole with greatly improved
bioavailability. In Australia the company demonstrated similar pharmacokinetics of
their reduced dose to that of the brand. The FDA did not accept a simple
pharmacokinetic approach but responded positively to the proposed development of a
“half-dose” form of itraconazole and required that the company undertake a simple
Phase III study geared towards demonstrating the safety/improved safety of
formulation in comparison to the brand product. It is possible that in some countries
the company may be able to get approval based on pharmacokinetic studies alone.
2.2 Serendipitous approach
Sometimes a generic company when developing a generic product may fail a
biostudy. The main criteria involved in evaluating the bioequivalence data are Cmax
and AUC with Tmax as a secondary consideration. In some countries even
acetaminophen requires a biostudy and on one occasion a simple formulation of this
product failed a biostudy because it released faster than the reference product. The
“failed” formulation has a Tmax approximately 30% faster. The company, as most
companies would, redeveloped the product. With a supergeneric mindset one might
ask if this could not have been a “supergeneric” in the making. After all what is
wrong with curing a headache ten minutes sooner?

6. Par Pharmaceuticals was the first company in the US to develop and get approval for
a generic form of Megace® suspension (megestrol acetate 40mg/ml and a dose of
20ml). Through their early development work they came to realize that there was a
possibility for a higher concentration and better bioavailabiity and now market
Megace ES® which contains 125mg/ml with the advantage of being a teaspoon dose
having minimal food effects. As a product indicated for the treatment of appetite loss,
severe malnutrition, or unexplained, significant weight loss in AIDS patients, the
lower dose and lack of food effects is of considerable advantage.
3. Reformulation for patient compliance.
Patient acceptability is another route for generic companies to enter the
“supergeneric” field. Rapidly dissolving and chewable tablets are, with the advent of
new excipients, all within the range of generic companies and there are generic
companies that are exploring such directions.
In 1999 Par Pharmaceuticals got FDA approval for a generic version of hydroxyurea
capsules. This product was actually also a “supergeneric” in that the formulation was
much simpler than the originator product and was formulated as a capsule two sizes
smaller than Hydrea®, the Bristol Meyers brand product, thus being very much easier
to swallow. In such cases there are no regulatory restrictions, the product is
administered by the same route and is required only to demonstrate bioequivalence. It
is significant to note that the advantages of the Par product were not accompanied by
increased sales or market share of the generic.
One specific area that might have been anticipated to attract far more attention is the
development of paediatric dosage forms. There are various paediatric initiatives that
should encourage companies to look at this area and whereas one might understand
the innovator company not dedicating its resources to what may be under 5% of the
market of a particular product, that same percent is a highly attractive figure for a
generic company. In the US there is the Best Pharmaceutical for Children Act and a
Paediatric Formulation Initiative Group. In the European Union there are several
paediatric initiatives including TEDDY (Task Force in Europe for Drug Development
for the Young) a Network of Excellence funded under the Sixth EU Framework
Programme for Research and Technological Development. However most of the
emphasis has been on safety issues related to paediatric use of adult formulations.
Whereas this aspect has been quite successful, the formulation demands for the
younger patient have been largely ignored with the default being to either formulate
as solution or suspension (one of the more inaccurate delivery systems) or with such
instructions as-
“The capsule can be swallowed whole, but it also can be opened and the contents
sprinkled onto a teaspoon of soft food such as applesauce, custard, ice cream,
oatmeal, pudding, or yogurt. The contents on the spoon should be swallowed right
away without chewing. Drinking a little water or juice may help to ensure that all the
medication is swallowed. The package insert includes diagrams for patients to
follow.”
Such formulations basically limit the paediatric population to only instant release
formulations as suspensions and crushable tablets that are not easily formulated as
controlled release forms.

7. What distinguishes a life cycle management product from a “supergeneric”?
What we see is that it is not the technology that is a distinguishing factor. Both
innovative companies and generic companies are, in most cases, in possession of the
tools, the technologies and the qualified and experienced staff to undertake the
development of these products.
An obvious differentiation is that of marketing. A life cycle or line extension is a way
of preserving the investment in establishing a brand name or image whereas a
“supergeneric” has to establish its identity, and its superiority, in an uncharted
marketplace.
It is interesting to examine the possible reason for the different commercial outcomes
for the two “supergenerics” of Par Pharmaceuticals mentioned earlier.
At the time of the hydroxyurea product Par was a simple generic company and as
such had no significant sales force that was capable of promoting a specialist product.
With regards the megestrol suspension Par had already acquired the use of the brand
name Megace™ from the originator, Bristol Meyers Squib and had a dedicated sales
force which was capable of promoting and differentiating the new product. The
company split off its “supergeneric” efforts into a separate proprietary division,
Strateva which now has a second “supergeneric” approved and several more in late
stage development.
This demonstrates a key factor and possibly the key factor, in the success or failure of
generic company’s involvement in “supergenerics”, namely their ability to market it.
The Generic companies that are established in the commodity generic markets such as
the US or UK traditionally do not have a sales force that can detail the product to the
opinion leaders, nor do they have experience in launching branded products.
Therefore a company concentrating on the developed generics markets will be
unlikely to commercialise such products unless it adopts this as a clear marketing
strategy with the commitment to establish its own sales and marketing division which,
in turn, requires a critical mass of such products. The alternative is to develop such
products in partnership with an innovator but this is fraught with difficulties. To even
talk to the originator will firstly reveal the potential strategy and secondly, normally
receive the classic “not invented here”. Other Innovator companies will not want to
take a product which is a line extension of a major competitor so the possibilities are
limited.
There is one generics market where “supergenerics” could and should be extremely
attractive. This is in the branded generic markets as found in many of the Central and
Eastern European (CEE) countries and in Asia and the Far East. Generics in these
countries are sold under brand names, the companies have dedicated sales forces
promoting the generics and it is not infrequent for the branded generic in a specific
country to actually outsell the originator product. Historically many of these markets
had what might be termed “pseudo-supergenerics” because of less rigorous regulatory
requirements. It is not uncommon to find unique combination products or different
dosages on these markets although these are slowly disappearing from those CEE
countries that are now under the jurisdiction of the EMEA. However, the companies
in these markets are ideally situated to capitalize on the “supergeneric” option. The
development skills and knowledge in these companies is adequate for the task, the
GMP levels and understanding of the regulatory process is advancing rapidly and,
most importantly, the marketing organisations are in place. Most companies in the
branded generics markets are looking over their shoulders and dreading the day that

8. they will become commodity generic markets but, in terms of strategy, little is seen
outside of the conventional generic copy and low cost approach. The Indian generics
companies have shown themselves to be much more aware of the business
possibilities for “supergeneric” products and this is because they can justify the
development costs and clinical trials in India against the relative ease of getting
approval and the size of their local market.
CONCLUSION
For a generics company to move into the field of “supergenerics” it needs to become
an innovator, not in terms of knowledge or technology but in terms of strategic
thinking. It must abandon the overriding considerations of first to file/first to launch
and low cost or vertical integration. It must also look to its marketing strategy as a key
success factor. If it is in a branded generics market it will have its own sales force in
place but it is difficult to envisage the commercial success of a supergeneric which is
restricted to sales in only one or two countries, therefore whether a branded generic
company or a commodity generic company, the supergeneric strategy must include
the development of out-licensing and business development skills of a different order
of magnitude in order to negotiate with major international pharmaceutical
companies. Due to the current pipeline crisis in the innovator companies this may be
the best time for such changes.
And finally, as in all innovative initiatives, it requires a management that is capable of
lateral thinking. Over many years we have observed young formulators in the generics
industry being pushed away from innovative ideas (some good and some bad) and
forced into the traditional generic role of “don’t try to be clever-just copy the brand”.
Further reading
Espicom Healthcare Intelligence: Emerging Opportunities in Controlled-Release
Generic Drugs: Pub ID: ESPI2422516 (2009)
Dubey R, Seshasayana A, Reddi S P, Jayanthi S and Ross M: The combination drugs
debate. Pharmaceutical Technology Europe (2009) 21(9): 28-35
King J: Can a drug live for ever? R&D Directions (2003) 9(4): 1-11
Mitchell M and Bingham D: Rules to live and die by for life cycle management. PFQ
(2009) 11 (2): 20-23