Pharmaceutical companies must be free to determine their own research priorities: Lessons from Alzheimer’s Disease

Guest blog post from Barbara Arzymanow, Independent Healthcare Consultant 

Sir David Jack (1924-2011), one of history’s greatest pharmaceutical R&D directors under whom many important drugs were discovered, once told me that neither governments nor companies should overrule senior R&D management. If a company lacks confidence in an R&D director, he should be sacked. It is the duty of an R&D director to pursue a programme appropriate to the needs of his company.

If asked what he would most like to discover David Jack would say a drug for dementia, particularly Alzheimer’s Disease. He would quickly add that his reason was a personal fear of this affliction in old age. Alzheimer’s Disease was not in fact a major area of R&D focus for him because he did not have any relevant scientific ideas with a sufficient chance of success.

Drugs are not discovered by everyone having the same opinions. Original research leading to major breakthroughs often occurs by thinking outside the box and frequently involves a degree of luck. Major discoveries can generally not be foreseen in advance and may well relate to illnesses where breakthroughs had not been widely anticipated.

One company, Neurochem based in Montreal, chose to bet its future heavily on a drug candidate for Alzheimer’s Disease. The condition is strongly associated with a build-up of a waxy substance called “amyloid plaque” in the brain. It was widely believed that the damage resulting from the presence of the plaque may be the major cause of the disease. Neurochem had found a drug that interfered with plaque formation and hypothesised that the product could stop or slow down the progression of Alzheimer’s Disease.  In my view it was right that the drug should be properly tested in clinical trials, a process that would have eventually cost hundreds of millions of pounds if the drug had made it through all stages of testing. The company pursued the drug at its own financial risk without a development partner. The initial results looked promising but unfortunately the final stage of testing revealed that the drug was not effective enough to justify commercial marketing as a prescription pharmaceutical. The share price of Neurochem fell from an equivalent peak of over a thousand Canadian dollars in April 2004 to just 32 cents at the time of writing. Shareholders have therefore lost 99.97% of their money over the past 9 ½ years corresponding to a loss of around one billion Canadian dollars in total. Losses on this scale happen in pharmaceutical and biotechnology companies that back unsuccessful products.   The most disturbing example in the UK was provided by British Biotech, the first biotechnology company to be floated on the London Stock Exchange. The shares rose strongly in the first few years on the London Stock Exchange, partly because the company came to believe with good reason that it may have discovered a major breakthrough in cancer. Like Neurochem with Alzheimer’s Disease British Biotech largely funded the testing of what appeared to be a potentially exciting new drug, marimastat for cancer. British Biotech nearly got into the top hundred British companies (all industries) as measured by the FT-SE 100 index before marimastat failed to be of benefit to patients in the final stage of testing.  The shares collapsed.

Pharmaceutical and biotechnology companies do not in deliberately invest heavily in R&D projects that fail. Unfortunately most drugs R&D do fail owing to unexpected side effects, the drug not reaching the required parts of the body for long enough in the necessary concentration, resistance developing to the product or the drug simply not working as expected.  R&D departments are constantly looking for ideas that can form a basis for R&D programmes with a commercially acceptable potential market and a reasonable chance of fulfilling an unmet medical need. Any concept that the Government, civil servants, doctors or healthcare consultants should try to steer companies towards specific areas of research is seriously flawed. The idea that there are politicians better able to judge what to research than experienced R&D directors is absurd. Furthermore, the UK represents only about 3% of the world pharmaceutical market. Companies should clearly focus R&D on global medical needs rather than any non-representative   opinions emanating from individual countries.

The main Alzheimer drugs that are available commercially and that are proven to benefit patients are known as “acetylcholinesterase inhibitors” (“C1-inhs”). The brains of people with Alzheimer’s Disease show a loss of nerve cells that use a chemical called acetylcholine as a chemical messenger. The loss of these nerve cells is related to the severity of symptoms that people experience. C1-inhs inhibit a substance known as acetylcholinesterase from breaking down acetylcholine in the brain. Increased concentrations of acetylcholine lead to increased communication between the nerve cells that use acetylcholine as a chemical messenger, which may in turn temporarily improve or stabilise the symptoms of Alzheimer’s disease. In broad terms C1-infs lead to a short-term improvement in Alzheimer patients but within about 6 to 12 months they are in a similar position to when they began treatment with C1-infs. After a 6 to 12 month period of better health than at the outset patents resume deterioration at a similar rate to that applying before C1-inf treatment began. The effect of C1-inf therapy is therefore essentially to delay progression of Alzheimer’s Disease patients by 6 to 12 months.

When a drug is being medically as opposed to financially approved for a particular use it is generally right and proper that the burden of proof should be high. We do not want drugs with the potential for unacceptable side effects or poor efficacy to slip through the net. The pharmaceutical industry is well aware of the standards expected, which vary according to the circumstances but typically involve testing in humans for around six years and over a thousand patients. The training of doctors emphasises the caution with which medical data on drugs in R&D should be interpreted. However, the same burden of proof should not apply to purely financial matters. The public interest in the areas of economics and financial matters is best served by making the best educated estimates of what the position will turn out to be. Declining to give an opinion because full evidence is not yet available is unheipful, because it could result in withholding medically approved drugs from patients. NICE’s original restrictions on the use of C1-inhs, later retracted,  arose because NICE was unwilling to take a view  on what experts would expect future trials to show.

Apart from C1-inhs the only class of Alzheimer drug to have a representative on the market is “NMDA antagonists”, which helps to prevent excessive levels of the brain chemical “glutamate”, which can cause brain damage. The aim of treatment is to slow down deterioration, particularly in the later stages of the condition.

Many other types of drug are being tested in Alzheimer’s Disease but none of these is yet proven to work. More than 1,200 clinical trials in patients are in progress or awaiting results around the world. Many of these trials concern experimental new drugs although some relate to other aspects of patient care, for example techniques for diagnosis. Amongst the many people researching Alzheimer’s Disease there will be some who passionately believe that success is just around the corner. Unfortunately holding a scientific opinion with conviction does not guarantee success in tests. Nobody can predict how far away a cure or major advance (i.e. slowing down progression by decades rather than months) will turn out to be.

What can governments do to help?

1. Adopt a drug pricing scheme and tax measures that encourage R&D.
2. Maintain a drug pricing scheme that helps companies during barren or unlucky periods in R&D.
3. Support academic excellence in relevant subjects
4. Encourage life science hubs and parks.
5. Highlight the contribution of the industry to mankind, science and the economy.
6. Aim to have more scientists, engineers, mathematicians and doctors in Parliament.
7. Support cooperation between the industry, NHS and academia and make it easier.
8. Encourage funding of medical charities that undertake important research that is uncommercial for drug companies and beyond the budget affordable by governments. 

What should governments avoid?

1. Drug pricing systems that are controversial or arbitrary,
2. Pricing that overpays for block-busters that will do well anyway.
3. Second guessing where future discoveries will be made or creating shopping lists of desired breakthroughs.