Many patients, families and donors may be wondering how the research process works, why drugs take so long to develop, and why some pharmaceutical companies focus on drugs for common diseases or cancers.
To help everyone understand this process a little more, the following article has been written by Clemens Brechtelsbauer, father of a Ewing’s sufferer and Principal Teaching Fellow in Chemical Engineering at Imperial College London.
Compound to Cure – The Drug Development Process
Any cure for any disease needs a medicine – a biochemically active compound that selectively targets the cause of the illness without harming the rest of the body too much.
The journey from a prospective target molecule to an approved pharmaceutical drug is long, risky and expensive. It takes about 10 to 12 years, several clinical trials with thousands of volunteers, and in the region of £1 billion to develop a drug.
During this period it can fail tests for safety and efficacy at any time – one adverse event can be enough to terminate a project. In parallel, a massive technical development programme ensures the drug can be produced in ever increasing quantities and at reduced cost for testing and product launch: a drug that were only available in milligrams to a select few for a fortune is not a medicine. The last hurdle is regulatory review, where a government authority reviews all filed information and either approves or rejects the new medicine: any drug has side-effects, and the benefits must outweigh the drawbacks.
Of approximately every 10,000 new compounds discovered, only 1 will make it into a commercial product which will help patients, and generate a return on investment.
This one drug also has to fund the remaining research and development portfolio – including those drug candidates that didn’t make it.
Major pharmaceutical companies spend in the region of £2 billion annually on research and development.
The generated value of a successful product is higher the larger the market and the more pressing the unmet medical need. Being first to market counts a great deal and goes a long way towards achieving the coveted ‘gold standard’ status. The window of exclusivity to recover costs, however, is small, as the patent clock of 20 years starts ticking as soon as the potential drug is first registered for testing. Once a patent has expired, generic drug producers can copy successful medicines based on the inventors’ hard-won information at knockdown prices, as they literally have no research and development outlay up front.
Cimetidine, the first H2 receptor antagonist to treat excessive gastric acid secretion, exemplifies this issue well. It was not only a drug with a revolutionary acting mechanism, under the trade-name Tagamet, it was also the first blockbuster, generating above US$1 billion sales per year. From the late seventies, it inaugurated a new golden era in pharmaceutical research and development, where the Holy Grail was very much to find a way of designing a blockbuster. Every investment was geared towards finding the next winner – and for a time, it all looked promising. Blockbuster drugs, which seemed to pop up like mushrooms, allowed huge profits and investment into more research and development. New chemical manufacturing methods were pioneered that still benefit projects today. To sustain these efforts, much faith was placed in the human genome project which, as was widely hoped, would allow identification of genetic causes for diseases and targeted design of new drugs by the turn of the century.
Unfortunately, this much sought after breakthrough has not quite happened yet. While a great deal of knowledge has been gained from the genome, it is still a big step from decrypting a language to launching a bestseller.
The major factor in achieving blockbuster status still appears to be the one thing nobody can control – serendipity. Many drugs end up as treatment for a condition that they were not designed for but instead discovered as a side-effect during clinical trials. Several conventional cancer drugs started their life as antibiotics but were found to be too aggressive.
In the cardiovascular field, Sildenafil originally failed tests to treat hypertension and angina, before it became as Viagra one of the most well known and successful lifestyle drugs of our time.
Relying on blockbusters as a financial model is risky business, as Cimetidine also illustrates. Once its patent expired in the early nineties its market dominance and revenue generating potential literally melted away overnight. Without the next money-spinner geared up, a blockbuster-reliant pharmaceutical company is left very vulnerable. Unfortunately, all experience so far indicates that blockbusters still cannot be designed from scratch.
The demise of the blockbuster business model from the beginning of the 21st century has led the industry to look for better and more sustainable alternatives. Increased emphasis is now placed on a balanced portfolio that seeks to reconcile risk with security of investment.
In-licensing and partnering at a stage where a drug candidate already shows promise keeps development costs low. If a blockbuster happens, then that is a great windfall, but companies do not rely on it any more. While this led to painful restructuring in the pharmaceutical industry, for patients it is mostly good news: there is a higher chance now that medicines for more and rarer diseases get discovered more quickly. This almost harks back to the days of Zidovudine in the nineteen eighties: the first antiretroviral drug came out of a collaboration between the US government and a company that focused on the treatments of what was then a fairly obscure disease – AIDS. Unmet medical need is still a powerful motivator which also opens fast tracks to review and approval by regulatory agencies. The downside is that rare and obscure diseases do not necessarily represent great commercial opportunity to recover development costs and make profit: a pharmaceutical company as a business needs to generate income to remain a viable investment for shareholders.
Where does that leave us with regard to a cure for cancer, and specifically, Ewing’s sarcoma?
Established treatment plans exist, which rely heavily on chemotherapy. One of the distinguishing features of cancer cells is that they replicate faster than normal cells, which leads to growth of tumours. The drugs used in conventional chemotherapy are essentially poisonous for all fast dividing cells – they are cytotoxic. Unfortunately, this means that other fast dividing cells in the body which are not cancerous (like hair follicles, the bone marrow, and cells in the digestive system) get also attacked resulting in significant negative side-effects. It is often these side-effects during treatment that are most distressing to deal with rather than the actual treatment itself. Traditional chemotherapy as such does not actually selectively cure cancer; it simply kills indiscriminately all fast-dividing cells in the body and then relies on the self-healing capacity of the body to repair the damage. Healthy cells can recover, while cancer cells cannot – provided the treatment works and the body holds out.
While this approach is somewhat successful, it is neither very pleasant nor a panacea. Different cancers need different drugs, and individual tumours of the same type respond differently to the same treatment.
Modern cancer drugs try to selectively target a weak link in the replication chain of cancer cells to break them down without affecting healthy cells. Despite scientists’ best efforts, however, the ‘magic bullet’ for cancer, including Ewing’s sarcoma, has yet to be found.
Many experts believe that at least one intermediate step would be to convert cancer from a terminal to a chronic disease, where, with the right medication, it is kept under control and does not interfere with quality of life. Whatever the approach to finding a cure, it is obvious that much more research, more development, and more trials are needed before cancer is finally defeated. We must also never forget that all research work and funding considerations aside, any progress in this area eventually relies on very brave clinical trial volunteers who are already in harm’s way.
The war against cancer is hard and relentless, fought at great cost with many unsung heroes, veterans and casualties. But, it is a war worth fighting – the spoils of victory will be for all of us to share.
Clemens Brechtelsbauer holds a degree in industrial chemistry and a doctorate in chemical engineering. He worked for 13 years in pharmaceutical process development and now teaches on the subject at Imperial College London.
Norvell Jefferson, From Molecule to Medicine, 2008