Editorial

Dormant therapies: hope for the

rare disease community

Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by 99.236.82.155 on 11/26/14

For personal use only.

D Wayne Taylor
1.

Drugs at the margin

The Cameron Institute, Cambridge, ON, Canada

2.

Unrealistic and imperfect

solutions

3.

Why all the fuss?

4.

Est tempus

At the margins of the orphan drug world are found what have become
known as dormant drugs or dormant therapies -- drugs that have been abandoned as they failed to meet designated clinical endpoints in their development and for whom patents have expired. There are also literally millions of
compounds disclosed in old patents that cannot be patented again and
were overlooked in favor of a few. If partial research and/or development
has been done on compounds and drugs, whether failed or not, then that
experience must be protected to incent firms to mine the wealth of science
already completed in the hopes of finding effective therapies for some of
the most debilitating and lethal diseases known.
Keywords: dormant therapies, drug re-purposing, intellectual property, market exclusivity, rare
diseases
Expert Opinion on Orphan Drugs [Early Online]

1.

Drugs at the margin

For years orphan drugs for rare diseases have been investigated, developed, and regulated at the margin of the pharmaceutical sector. This was to be expected given the
numbers involved but over the years, ever since the passing of the Orphan Drug Act
over 30 years ago by the US Congress [1], there has been established a credible niche
for these life-saving and life-improving drugs. But at the margins of the orphan drug
world are found what have become known as dormant drugs or dormant therapies.
Dormant therapies are often drugs that have been abandoned as they failed to
meet designated clinical endpoints in their development and for whom patents
have expired. Without adequate protection of their intellectual property, pharmaceutical manufacturers are loathe to re-open investigations even though promise
may have been shown. As potentially valuable drugs cannot be patented a second
time, potentially effective therapies -- either for their originally intended use or a
new use altogether -- may be overlooked as they are shelved. Firms may be incented
to re-investigate and/or re-purpose these failed drugs if their efforts and potential
rewards from those efforts were protected.
Some drugs take longer to develop than others and, in a typical new product
development gate-keeping exercise, many are screened out of development when
remaining effective patent life is inadequate for a firm to recoup its investment.
There are also literally millions of compounds disclosed in old patents that cannot
be patented again and were overlooked in favor of a few. In fact, pharmaceutical
firms patented 10 million compounds in drug-patent applications between
1976 and 2011, which produced only 700 new drugs [2]. Yet many of these compounds may provide therapeutic benefits if pursued further. Under current regulatory and patent regimes, re-designing old compounds to make a patentable product
is usually cost and time prohibitive.
Precision of definition is currently a challenge. It has been proposed in the US
that a dormant therapy be defined as either a small or large molecule drug that
meets an unmet medical need and has prospectively ineffective patent protection,
that is, 14 years from the date of approval [3]. In the European Union (EU) a
10.1517/21678707.2014.987125 2014 Informa UK, Ltd. e-ISSN 2167-8707
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D. W. Taylor

dormant product may also be a product, which has not been

marketed for a 12 months period and will not be for another
12 months. In this case a product may remain dormant for a
maximum of 5 years and can be re-activated anytime. If not
re-activated within 5 years approvals are withdrawn [4].

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2.

Unrealistic and imperfect solutions

Changes to existing patent laws in the very near future to

better accommodate the needs of researchers, universities
and pharmaceutical manufacturers is highly unlikely. Intellectual property regimes remain to be harmonized globally.
Major sticking points in the negotiation of the Comprehensive Economic and Trade Agreement, providing for free trade
between Canada and the European Union, and similarly the
Trans-Pacific Partnership hinge around the differences in
intellectual property protection around the world. Change
in this is difficult and time-consuming to reach.
Some academics and social activists call for government
funding of the development of unpatentable drugs. In todays
global economic malaise along with the increasing entitlement
spending on an aging population in the industrialized world,
government funding of dormant drugs is highly unlikely given
the huge risk involved. Charitable funding is also an unlikely
alternative source of capital for dormant drugs given the high
uncertainty of success and the hundreds of millions required
for each successful candidate. Half of rare diseases do not
even have a charity to raise funds. Prize funding of research,
also suggested by some academics and non-government organizations, is based upon some limited success where discoveries
are commodities (as in the development of margarine) [5], or
where the science involved is applied (as in the development
of the canning of vegetables) [6] and not wet bench. There is
absolutely no evidence to support the notion that such funding
could work in the field of pharmaceuticals where serendipity is
as much at play as rational, linear processes [7].
Currently there are two regulatory tools available to help
incent the development of dormant therapies: patents and their
extension, and market or data exclusivity. Patents and exclusivity ultimately have the same effect but provide different
approaches to the same problem. Patents -- normally 20 years
-- are granted anywhere along the development timeline of a
drug by a patent and trademark authority and can be extended
for various reasons. Exclusivity for selling a product in a market
is granted by a drug approval authority, such as the Federal
Drug Administration in the US or the European Medicines
Agency, upon approval of a drug and can run concurrently or
not with a patent. Data exclusivity protects clinical trial data
and delays the entry of generics. Market exclusivity guarantees
non-competitive sales for a period of time in a marketplace,
which is more appropriate in the case of orphan drugs as
genericization is most unlikely given the market sizes and costs.
The existing 5 year data exclusivity in the US for small
molecule drugs, which protects only clinical trial data, is inadequate for the time, cost, and risk involved in investigating a
2

dormant therapy in a competitive marketplace. The EU provides 10 year data exclusivity for small molecule drugs and
12 years for biologics, which is somewhat better. In 2011,
building upon the market exclusivity given orphan drugs
(7 years in the USA and 10 years in the EU) the MODDERN
Cures Act was introduced in the US Congress. If passed, the
Act would allow a firm to apply for data exclusivity for a
drug or biologic, whose patent had expired, so as to reinvestigate a dormant therapy to determine if it can prevent,
slow the progression of, or cure a disease, meet an unmet
medical need, improve outcomes, or reduce risk compared
to existing therapy [8]. Under MODDERN, new drugs would
receive 15 years of market exclusivity if they contained no
active moiety previously approved by the FDA and
had < 14 years of patent life left. In exchange, firms would
waive their previous patent rights. As of the time of writing,
the bill was still before the House of Representatives.
Although a good beginning, MODDERN would still preclude the re-investigation of new uses for existing drugs,
which, of course, generally is not pursued by research-based
pharmaceutical companies as genericization lurks around the
corner of the patent cliff making a whole new round of clinical trials unprofitable. This is unfortunate as often there is
already early indication of efficacy for another treatment, the
drugs safety profile is already understood, and mass production has made the cost of raw materials for the potential
new trials inexpensive.
3.

Why all the fuss?

Two words: rare diseases -- diseases that affect very small populations, usually < 1 in 2000, many of which are life-threatening, seriously debilitating, or serious chronic conditions [9,10].
Rare diseases, their signs and symptoms are uncommon to
most primary care practitioners making diagnosis difficult
and often too late. Globally, ~ 6800 rare diseases and disorders have been identified affecting 300 million people
with > 80% of them being genetically based, which makes
the discovery of effective treatments very costly and complicated. Only 350 rare diseases account for ~ 80% of patient
cases making the remainder of rare diseases very rare indeed.
Over half of known rare diseases start in early childhood
with about one-third of children, affected by a rare disease,
dying before the age of five. Rare diseases account for 35%
of all deaths in the first year of life.
However, just over 400 orphan drugs designated to treat
rare diseases have come onto the American market over the
past 30 years. The low-hanging fruit has been plucked. The
search for new therapies for yet untreated rare diseases
(beyond just palliation) becomes ever more challenging both
intellectually and economically.
Given the very small patient population sizes in any one
country, which make a Phase III clinical trial of a 1000
patients to demonstrate efficacy very difficult if not impossible
to achieve, and the preponderance of rare diseases starting in

Expert Opinion on Orphan Drugs (2014) ()

Dormant therapies: hope for the rare disease community

early childhood where patient pathology is less understood

than in adult males, the hurdles in discovering usable orphan
drugs are huge. Traditional patents would expire long before
sufficient data was ever accumulated for approval. Anything
to help science overcome these hurdles would be most welcome by patients, their families and caregivers.

Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by 99.236.82.155 on 11/26/14

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4.

Est tempus

Discovery and commercialization of orphan drugs for rare

diseases is a very difficult challenge for the pharmaceutical
industry. If partial research and/or development has been
done on compounds and drugs, whether failed or not, then
that experience must be protected to incent firms to mine
the wealth of science already completed in the hopes of finding effective therapies for some of the most debilitating and
lethal diseases known.
Scientific discovery and the marketplace must drive the
development of new therapies, not arbitrary laws and regulations with no evidence to support them other than convention. Potential therapies that could save lives, or at least
provide better quality of lives, are currently not being developed or are being dropped by the wayside during research
and development due to intellectual property protection
designed for widgets and hairpins. But the patent system is
not irrelevant. Every drug on the market owes its success to
Bibliography
Papers of special note have been highlighted as
either of interest (!) or of considerable interest
(!!) to readers.
1.

2.

3.

An act to amend the federal food, drug,

and cosmetic act to facilitate the
development of drugs for rare diseases
and conditions, and for other purposes.
75th United States Congress,
Washington D.C; 1983. p. 97-414
Roin B. Dormant therapies. Harvard
Law School, Cambridge MA;
2014. Available from: http://petrieflom.
law.harvard.edu/assets/publications/
14.02.19_Roin_slides.pdf [Accessed
17 October 2014]
The MODDERN (Modernizing Our
Drug and Diagnostics Evaluation and
Regulatory Network) Cures Act was
introduced in the U.S. House of
Representatives on November 18, 2011
This is the next important step in
legislating improved access to therapies

the protection of intellectual property. Patents are an integral

part of markets working efficiently. It is in everyones interests
that antiquated, one-size-fits-all patent laws be revised and
augmented so that the proper incentives are created to incent
the development of dormant therapies for rare diseases. There
is a virtual treasure trove of orphan drugs for rare diseases to
be discovered amongst the millions of compounds relegated
to the shelf because of effective patent expiration. The social
benefit of the development of dormant therapies for rare diseases will outweigh the efforts needed to reform the patent
system.

Declaration of Interest
No funding was received from any source by any means to
write this article. The author is a retired professor from
McMaster University in Canada and currently works parttime as the Executive Director of The Cameron Institute, a
health policy think tank. The author has no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony, grants or patents
received or pending, or royalties.
new methods of funding research such
as prizes and patent pooling.

for patients with no current

treatment options.
4.

Annual updates and notifications of

changes. Available from: http://www.ema.
europa.eu/ema/ [Accessed 9 October
2014]

5.

Wolfe E, Clancy C, Jasper G, et al.

Science Power 9: Atlantic Canada
Edition. McGraw-Hill Ryerson Ltd;
Toronto: 2000

6.

Dagoon JD. Applied nutrition and food

technology. REX Printing Co. Ltd;
Quezon City PH: 1989

7.

Taylor DW. History, evidence and

reason: a review of proposals for and
innovative sources of funding to
stimulate R&D. The Cameron Institute;
Hamilton ON: 2009
This provides a brief overview of the
economic arguments against proposed

Expert Opinion on Orphan Drugs (2014) ()

8.

The MODDERN (Modernizing Our

Drug and Diagnostics Evaluation and
Regulatory Network) Cures Act

9.

Rare diseases. Available from: http://

www.siope.eu/activities/europeanadvocacy/rare-diseases/ [Accessed
16 October 2014]

10.

Rare Diseases: facts and statistics.

Available from: http://globalgenes.org/
rare-diseases-facts-statistics/ [Accessed
16 October 2014]

Affiliation
D Wayne Taylor PhD FCIM
Executive Director,
The Cameron Institute, 1539 King St E, PO Box
28043 (Preston), Cambridge, ON N3H 5N4,
Canada
Tel: +1 519 653 1555;
E-mail: dwaynetaylor@rogers.com