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International Clinical Trials
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Once largely considered too costly to produce – given the limited number
of patients affected by a particular disease – new technology and
breakthroughs in biopharma have changed the orphan drug landscape,
allowing more of these drugs to be produced than ever before, and thus
saving countless lives that would otherwise be lost.
Bringing an
orphan drug to market, however, has its own unique set of obstacles and
considerations that must be overcome, many due to the narrow scope of
use for which the medicine is intended. Meeting these challenges, while
endeavouring to produce a needed drug as quickly as possible, requires
the cooperation of clinical trial investigators, drug manufacturers,
local and national governments and more.
Where to Start?
“Typically,
the demand for an orphan drug is recognised by a doctor needing a
specific drug in order to treat a rare disease,” says Robert Smith,
former Global Head of Quality for the Clinical Pharmacy Research Service
at Genzyme. “At this point, the doctor may apply for a research grant
through one of many funding services, including the National Institute
for Health, various philanthropic concerns or private industry.
Alternatively, the need may be raised by a disease advocacy group,
spotlighting a certain ailment that needs attention.” This was the case,
for example, with the Muscular Dystrophy Association (MDA), who began
advocating for cures for various neuromuscular diseases in 1950. Since
its founding, MDA has funded research and clinical trials for a number
of rare diseases, including Emery-Dreifuss muscular dystrophy,
Zaspopathy-related myopathy and Walker-Warburg syndrome.
“The
next step in the process is finding a drug manufacturer interested in
producing the needed drug,” claims Smith. “Due to their limited audience
and small production runs, orphan drugs can be very expensive to
produce, and there is a very real possibility that the manufacturer may
never break even on their investment. In the case of life-saving drugs,
it is not uncommon for manufacturers to provide the approved medications
through charitable access, or patient assistance programmes, often at
no charge for those that need it. On the other hand, the cost of
clinical trials can be significantly lower than those investigating
better-known diseases, as the study samples are necessarily smaller and
there is a lack of competing medications.”
Smith continues: “The
health versus economic benefits must be weighed when one contemplates
taking on a treatment for a rare disease. These treatments can be very
expensive, and the ramifications of such an investment must be
considered. Someone, somewhere has to make an objective decision about
whether or not to move forward. Sadly, we live in a world in which there
are very real restrictions. Consequently, we may have the ability, but
not the resources, to cure everyone.”
Second Life
Of
course, there is always the possibility that a drug intended to treat a
rare disease may be found to have a secondary, more profitable use, as
in the case of botox. Derived from botulinium toxin, it was originally
developed to treat spasms and dystonias due to its ability to weaken
muscle function. More recently, it has been used in cosmetic treatments
by paralysing muscles and preventing the development of wrinkles.
In
2012, more than six million botox injections were administered in the
US at an average cost of $570 each, with a total cost of more than $3.42
billion. Naturally, when a drug is found to have a second purpose, it
must still go through trials for efficacy, even though safety has
already been proven.
Trials and Tribulations
The
next step in the process is the execution of clinical trials. “Like all
clinical trials, the main purpose here is to prove the safety and
efficacy of the drug in question,” Smith states, “although, due to the
small patient sample size, some compromises must be made. While clinical
trials for a drug to treat diabetes, for example, might require a
sample size of several hundred, or even several thousand patients, the
required sample size for a drug to treat a rare disease might, by
necessity, number fewer than 20. In some instances, historical consults –
case histories of patients suffering from the disease – are used to
supplement the actual live patient sample.”
“I was involved with
a clinical trial for a rare disease that included 17 patients in the
study sample,” Smith recalls. “The question that we asked to prove the
drug’s efficacy was, simply, whether or not our sample population made
it to their first birthday.”
“Being such a particular niche
market,” Smith says, “with such a small number of patients in the study
population, there is much more personal interaction with doctors,
nurses, researchers and subjects. This means that the researchers really
get to know the people in their study, and losing one through failure
to come up with an effective treatment can be devastating.”
Ethical and Practical Considerations
“Another
consideration unique to studies of rare, lifethreatening diseases,”
Smith continues, “is whether or not it is ethical to give certain
patients a placebo, as is regularly done in ordinary drug trials. That
is a hard question to answer when you are trying to determine how much
good a drug actually does. By providing certain patients with a placebo,
are you sentencing them to death? And do you, as a researcher, have a
right to do that in service of a greater good? That is a terrible
question to answer.”
In cases like these, lower safety standards
may actually apply. “Again, due to the small sample sizes, studies may
accept a higher degree of toxicity in the study drug,” Smith claims, “as
doctors are better able to treat the results of the toxicity, than they
are able to treat the effects of the underlying disease. One has to
consider the risk/benefit ratio, especially in the case of
life-threatening diseases.”
“Another difference between trials
of orphan and non-orphan drugs,” Smith adds, “is the amount of follow-up
that is done. In a typical non-orphan situation, follow-ups are usually
part of the trial, examining the effects of the drug after a certain
period of time. With orphan drugs, or with drugs that need to be moved
to market quickly, additional surveillance of patients is allowed to be
done after the trial, to facilitate getting the drugs out there in a
timely fashion.”
Cold, Hard Facts
Aside from the
challenges that occur due to the small number of patients suffering from
a rare disease, logistics can also be an issue. “Particularly in the
early stages of development,” Smith states, “many rare disease or orphan
drugs tend to require cold chain logistics of one form or another,
especially when going through regions in which temperature control can
be a challenge. When dealing with drugs produced in such small
quantities, any degree of damage or spoilage can be a major issue. In
the case of life-saving drugs, the consequences may be severe. These
days, some researchers might choose to have a quantity of study
medications stored at the patient’s home, to reduce the risk of damage
in transit and to make administering the drugs easier. Practical
solutions are available, for example a radio frequency identification
refrigerator solution like MyCubixx from ASD Healthcare, which monitors
when the unit is open, what drugs are removed or replaced, and even
keeps track of expiration dates. Even with all that, however, it’s
critically important to have a shipper that intimately understands cold
chain and temperature-controlled logistics – otherwise all your efforts
may be for naught.”
“There is enormous pressure to get
everything right in doing this kind of work,” Smith continues. “The
difference between 95% right, which may be the case in non-orphan
trials, and 99.5% right, in the case of rare disease trials, is
enormous. This is why having good systems in place, as well as solid
contingency plans, is absolutely critical.”
In many cases,
paperwork can take up a huge amount of time as, after the trial is over,
the licensing process starts. “Although orphan and non-orphan drugs go
through the same licensing process,” Smith explains, “those in the
pipeline clearly recognise the need for life-saving drugs and go the
extra mile to make things happen quickly and efficiently. This greatly
streamlines the process wherever possible, meaning that the drug can be
released faster than it would otherwise.”
Once the licensing
portion of the journey is complete, the drug is taken to market. It is
common in the case of rare diseases for key opinion leaders and patient
advocacy groups to spread the word about a new treatment, supplementing
the manufacturer’s own marketing plan. At that point, the drug is out in
the world, working to both improve and save lives. While many of these
drugs are expensive, it is not unknown for drug companies to have
charitable programmes in place, where the drug can be made available to
patients without charge or at a substantially reduced cost.
A Matter of Time
For
those suffering from a rare disease, for which there is no current
treatment, Smith offers these words of encouragement: “Never give up
hope,” he says. “There are people all over the world looking for the
next great cure, and someone, somewhere is probably looking into your
disease right now. It may just be a matter of time.”
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