The problem of orphan drugsBMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c6456 (Published 17 November 2010) Cite this as: BMJ 2010;341:c6456
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One of the disappointments of patients suffering from rare diseases is the price charged for their medicines. These high prices lead to protracted discussions and unacceptable delays and in some countries to rejection of reimbursement. The industry suggests that these prices are the result of the drug's development cost which runs into billions but it's very doubtful whether this applies to orphan drugs. However, the question I ask myself is why a clinical study with fifteen patients (such as for Zolgensma for example) is being conducted by a commercial organization with one hundred and twenty six thousand people on the payroll? Why should these medicines for small groups of patients not be developed by an academic faculty or clinic that uses its resources in a much more effective and economical way? Anyone looking for cost-efficiency in the discovery and development of medicines will not find it in big pharma that uses thousands of procedures, carries an exorbitant indirect cost, pays countless expensive managers and still seeks out the academic world for solutions.
In my opinion, cost-effective drug development and the resulting price controls will succeed if the development of some drugs and treatments is brought back to where they are discovered: the academic world. Many drugs will be developed as orphan drugs in the future as a result of our increasing knowledge of the biomedical and biomolecular sciences. One of the ways to achieve socially acceptable development and pricing is through a new business model, that of the “orphan company”. Orphan companies are temporary micro-companies that develop medicines for small groups of patients and that remain the property of the university. They are run by the research center with representatives from the academic clinic, from the government and patient organizations, and by professional ethicists. They exist as long as the medicine or treatment remains on the market.
The various European governments, the European Commission, patient crowdfunding, ethical investors and private foundations manage a fund that allows these orphan companies to be supported and rewarded for the health impact of their new treatments. What the drug generates in quality-adjusted life years can be economically quantified and returned to the discoverers as a reward. The choice of new drug development is also better controlled by the government. It must decide in which therapeutic areas developments can and must take place. This way, she can manage and control the costs of medicines herself. The price that society will pay will then be the real cost and recognition for the discovery and development, stripped of that of marketing, lobbyism and managerial waste that are present in the current drug prices.
Competing interests: No competing interests
Why does someone within the DoH not put this product on the drug tariff and save the nhs a lot of money?
Competing interests: No competing interests
Having read the series of articles in the 20 November 2010 issue of
the BMJ, I thought it was a pity that none of them found it pertinent to
mention the many positive aspects of the orphan drug legislation.
Whilst it is true that some drugs receiving orphan designation have
already been available as unlicensed products for treating the same
condition, sometimes for many years, it should not be forgotten that
unlicensed products are officially of unproven value. Although they may
seem to be safe and effective, the medical literature is littered with
examples of drugs which were thought to be beneficial and which were later
found out to be unsafe or ineffective or both. The medical community is
continuously asking for more and better data on new drugs, in order to
prevent repeats of, for example, the rofecoxib story. Yet, for some
reason, when it comes to drugs for rare diseases, people are prepared to
accept little more than anecdotal evidence as a basis for treatment.
Having said that, the amifampridine story is clearly one which is
going to provoke an outcry because in this case the sponsor didn't have to
run clinical trials to demonstrate efficacy, basing the application on
published studies. But this is the exception rather than the rule and
usually it is necessary to run proper pivotal efficacy studies, even for
products which are already available.
In addition, the majority of off-patent drugs being developed for
orphan indications are currently licensed for unrelated conditions. In
fact, the FDA list (the Rare Disease Repurposing Database) mentioned by
the authors of the letter to David Cameron, is primarily a list of such
drugs. It is not a list of drugs for commercial exploitation of a
regulatory loophole. In order to develop such a drug for an orphan
indication, it is usually necessary to perform a full development program
demonstrating safety and efficacy, as one would expect.
Notwithstanding the above, which many may still find to be ethically
questionable, the really important potential benefits for patients with
rare diseases lie with the innovative new drugs which are being developed
by the biopharmaceutical industry. For most rare diseases, there
currently exists no treatment and for others there was no treatment until
very recently; many of these new treatments have only been possible in
recent years as the molecular mechanisms underlying the disease have been
elucidated. In some cases the treatment may be very specific for
particular mutations, so that it will only be effective in certain
subgroups of the broader disease population, and diagnostic gene
sequencing is required prior to treatment. This also applies to treatment
in clinical trials, adding to the complexity and cost of such studies.
Indeed, clinical trials in rare diseases are logistically much more
complex than clinical trials with common diseases. The patients are, by
definition, widely spread and so even a small trial may require several
countries. In addition, within each country, the patients may not be
grouped close together, so it may be extremely difficult to get them to
the study site for the trial procedures. And for many conditions, it is
not always easy to know who or where the patients are, although this has
begun to improve, due to the work of patient organisations and the setting
up of registries. A considerable number of patients remain undiagnosed
due to lack of expert knowledge of the rare disease and this is why many
countries are setting up National Plans for rare diseases and creating
Centres of Excellence.
Finally, I would like to deal with the point about why the
development requirements for orphan drugs are considered to be less than
for drugs for treating common diseases. It should be obvious that, for a
rare disease, the availability of patients will be much less than for a
common disease. It would be pointless to require large-scale studies
where the world population may be only a thousand or less, so a pragmatic
approach is required if the development is not to stall at the outset.
Furthermore, to demonstrate efficacy it is often not necessary to run a
large trial, since the treatment effect can be extremely large in patients
where there is no available therapy. The medical need is high and it is
important to get such a drug on the market without unnecessary delays.
Therefore, an orphan drug may get a marketing authorisation on the basis
of clinical trial data on a very small number of patients (by "normal"
standards) with a requirement to continue collecting information post-
Therefore, anyone who thinks that the orphan legislation is a simple
and easy road to riches is mistaken. Despite the few exceptions, the
incentives of the orphan drug legislation are necessary and are
responsible for facilitating the development of elegant and sophisticated
treatments for patients with real unmet needs.
Competing interests: My company is a clinical services provider specialising in orphan drugs. We help in the development of orphan drugs but have no commercial interest in the price the sponsor obtains for the product after authorisation.
I fully agree with the authors on their analysis. And I am merely adding
that the Dutch situation is exactly the same. Just adding one more example
to the examples given by Ferner and Hughes: Zincsulfate has been used in
The Netherlands for years in treating Wilson's disease (copper excretion
problem). Zincsulfate liquid was prepared by pharmacists for a price of
approximately ?100 a year (including preparation fee and ingredients). An
orphan drug company registered zinc-acetate capsules completely based on
literature studies that frequently involved other zinc salts than zinc
acetate. The registration of an orphan drug that costs ? 1750 a year
implies that pharmacists would not be allowed to compound the very cost
effective alternative anymore.
Competing interests: community pharmacist, member of committee on appreciation of the therapeutic value of pharmaceuticals in the Netherlands (CFH)