An expensive process
The process of developing new drugs is extremely expensive. It is one of the biggest research activities in the world, taking a long time, costing billions of pounds and involving thousands of scientists, doctors, researchers, statisticians … and patients.
Once a new drug is manufactured, usually for a clearly defined disease or condition, it has to be tested and then its value proved in clinical trials. There will be rigorous independent examination of all the data from these studies before the regulators will give it a licence. Giving it to patients outside that indication is not permitted.
However, the drug may be a valuable treatment for other conditions. The company may have identified some of them and seek further licences to treat them. But it may not be willing to accept the extra costs involved and, because it owns the drug, no-one else can do it until the patents on that drug runs out. That may be as long as 15 years.
One of the risks of the process is that a drug can be developed which fails to be as effective in treating the target disease as the makers hoped. Such a drug may get shelved, even if there are diseases where it could be effective. If the drug company is not interested in any other disease, the drug will disappear from sight.
Ignored drugs, or drugs which have disappeared from our clinics, may be re-purposed so that benefits can be realised for patients. Here are three striking stories.
Thalidomide was a new kind of drug, marketed over-the-counter without a prescription, in the late 1950s as a treatment for anxiety, sleeplessness and morning-sickness. It was taken by a lot of pregnant women. When an increasing number of birth deformities started occurring, a link with thalidomide was established. It was withdrawn from the market in 1961 in the UK. Worldwide over 10,000 children were born with life-challenging deformities.
Many scientists were determined that this innovative drug had value. There were tests and trials in a number of diseases and then in 1998 came the first regulatory approval, for thalidomide to treat multiple myeloma, a blood/bone marrow cancer. The drug is now off-patent and anyone can make it. The World Health Organization includes it on its list of medicines which every country should make available to patients. It does however carry warnings that those of child-bearing age who are taking it, male or female, should use contraception.
Dexamethasone has been generic for many years and is a more recent example of repurposing. The drug has been in clinics for over 60 years and is valuable but boring. Over 20 manufacturers supply it to the NHS. It is used to treat a range of conditions, for example as an anti-emetic with chemotherapy, for many inflammatory disorders and to help control post-surgical swelling. The drug can be given orally or via an injection. There are also creams for certain situations.
It then leapt out of its relative obscurity and into public prominence in 2020 when the Oxford University RECOVERY clinical trial demonstrated that it had a benefit for patients suffering from advanced Covid and requiring ventilation. The drug is cheap, readily available and the side effects are well managed. It was in widespread use around the world to treat Covid within days of the RECOVERY trial results being known – a stark contrast with treatments such as hydroxychloroquine, also tested, heavily promoted by President Trump, but which has no noticeable effect on Covid.
Finding new indications for more recent drugs is something big pharmaceutical companies are beginning to take seriously. They patent their drugs early in their development and such patents last for up to 15 years. There are circumstances in which they can be extended beyond that. The company with the patent controls that drug’s use and no other organisation can develop uses for it without their agreement, so the growing interest from big companies in extending their drugs’ uses is to be applauded.
For example, pembrolizumab (Keytruda) is manufactured by Merck, Sharp & Dohme. It is an immunotherapy initially licensed for treatment of multiple myeloma (a blood cancer), then it gained licences for nine further cancers (including the difficult to treat triple-negative breast cancer). A search of the international clinical trials registry revealed that pembrolizumab is currently in 837 trials worldwide across the whole range of cancers (including rare sarcomas).
The future of drug re-purposing
The UK’s medicines regulator the Medicines and Healthcare products Regulatory Agency has identified re-purposing as an important route to discovering new treatments. Its innovative licensing and access pathway specifically encourages early engagement with the regulators by companies, charities and academic teams exploring the re-use of drugs in this way.
Finding the ‘hidden’ benefits of drugs that have been in use for many years and are off-patent like dexamethasone is challenging. The financial returns are uncertain and a successful development project needs a major funder because clinical trials are expensive. We can expect academic clinical units to be looking at this area, and they may be able to meet the funding challenge by involving the National Institute for Health and Care Research which offers various opportunities using government research funding.
Drugs that have been shelved, like thalidomide, or have never been marketed, are a different problem. There are small biotechnology companies taking up the challenge of finding new indications for such treatments, entrepreneurially seeking agreements with the companies which shelved them in the first place or acquired them in mergers only to ignore them ever since. If the agile biotech company can access all the early test data they hope they can identify potential new uses, develop the drug and build fresh clinical evidence which demonstrates how they can help treat patients and incidentally, they could become quite profitable.
NHS spending on drugs is inexorably increasing. In 2020/21 the cost was £16.7bn, an increase of 4.56% from 2019/20 and of almost 30% since 2010. The role of the National Institute for Health and Care Excellence in controlling access to new drugs, thus controlling costs, is widely publicised and has been controversial. Some drugs do create savings elsewhere so the increasing spend should be seen in context and drugs are only approved on the basis of benefitting patients. What the NHS pays is also actively negotiated. This control will continue regardless of the increasing privatisation of the NHS. At the end of the day, the cost goes to the public purse. It would be political dynamite if drug costs were passed on to patients in the way they are in the USA where a course of pembrolizumab (noted above) will cost about $80,000.
In this context the rationale for re-purposing is clear – the aim is to try and prioritise the best use of what we have already got.
- Regulator MHRA Innovative Licensing initiative
- NHS England on repurposing drugs
- Charities’ research collaboration (AMRC)
Roger Wilson has been an active patient representative in clinical research for 20 years, working with UK and international researchers, regulatory bodies and funding organisations. He founded Sarcoma UK, which funds research in rare cancers, he is an author of research papers and writes for the medical press. He is an elected member of Cancer Research UK.