tisdag 20 juli 2010

The new pharmacology

The challenge for the pharmaceutical industry is to create medicines that provide profits despite the enormous development costs, which to a large extent have been created by the steep requirements of the consumers and the authorities on security and documentation.

At the same time opportunities rise for new kinds of drugs through the ongoing breakthroughs in the biosciences. The irony is that these new opportunities may pose serious problems for the industry, health care systems and regulators.

If we are not careful we might end up in a situation where significant improvements of health and well-being exist, but are consigned to remain in the R&D lab rather than on the shelves of the pharmacy.

The first kind of advance in pharmacology is rational pharmacology. Using our new and deeper knowledge of cellular processes medicines can be designed rationally through switching specific signals in the cells on and off. This is a significant improvement compared to the old guesswork helped by trial and error. Simulation technology enables rapid digital testing of drugs before they are tested with animals, lowering costs. New understanding of immunology enables vaccinations that can be used not just preventively but also as medication against for instance cancer, autoimmune diseases as diabetes, and narcotics like cocaine.

But the most significant advance, and the one likely to cause problems, is pharmacogenomics. It has been known for a long time that different patients react differently to the same drug. Side effects, risks of overdose or lack of efficacy is a serious problem in most treatments. Pharmacogenetics, the study of how different individuals react to a specific medicine depending on their genome started to be developed quite a long time ago. The methods were slow and expensive, and since the body’s reactions to a medicine are dependent on several genes the interactions were often difficult to decipher or detect.

New opportunities have risen today through the combination of genetics and informatics, genomics. Instead of studying individual genes, large chunks (or soon the entirety) of an individual’s genome are studied. This enables the study of how genes influence complex diseases, how medicines affect them and how they affect the entire human body. This perspective has the object to describe how different systems affect each other, which does not only give a deeper understanding but also applicable therapies.

The present developments in genetic testing are dramatic, with sharply declining prices on previously highly advanced tests. Chips covered with a DNA layer that detect the presence of various genes are soon expected to become standard for many diagnoses. They enable laboratory test processes that previously required entire rooms of equipment to be performed with accessories that connect to a single computer. The trend points toward a proliferation of cheap genetic tests, not only of a specific gene at a time but whole groups.

The goal is to develop therapies consisting of the right medicine at the right dose to a specific patient. At an early stage the vision of individualised medicine was spread: maybe we will be able one day soon to go to a doctor, make a gene test, and get the medicine that is tailored to our own metabolism. More at hand is the opportunity to test a patient prior to the prescription of a medication in order to reduce the risk for side effects. This would in itself be a great progress, instead of the often-frustrating trial and error process of finding just the right dose. Drugs are repealed from the market when serious side effects are discovered, but if these are prominent in just a genetically well-defined group an otherwise efficient medicine can still be used.

Pharmacogenomics can also aid the development of new drugs through digital tests or as a supplement to pilot studies. A great cost reduction that shows if they are unsuitable before initiating large-scale trials. It is also easier to protect the trial subjects through testing for the presence of genetic sensibilities to the drug. Research is made more efficient when more homogenous trial subjects can be collected and clinical variations minimized. As fewer participants are needed, costs are reduced and medical developments are accelerated.

Many potential drugs that are efficient with a part of the participants are not developed as they show lower efficiency or side effects with some test subjects. Pharmacogenomics would facilitate the identification of such patient groups on which the drug has the best effect.

The pharmaceutical industry has the last decades seen an enormous acceleration in development costs and pharmacogenomics reduces them, but the development of more specific drugs risks segmenting the market. Drugs against common illnesses (blockbuster drugs) are extremely profitable and have been main income sources for many corporations, but the product lines that are intended for just a minor group of patients have a harder time motivating their development costs. Government regulation regarding the subsidising of drugs for rare diseases (orphan drugs) are decided on the basis of how many patients share the disease, not on the genotype that makes the drug useful. This could create many more patient groups that could be treated but do not receive help.

Certain genotypes are more common in certain ethnic groups than in others, which has led to controversies when some drugs have had different effects and efficiency. Today this is circumvented by ignoring ethniticity to a certain degree in favour of genotype - that a certain set of genes is more common in certain groups does not provide as much information as the exact testing of an individual’s specific set of genes. The problem remains though that certain genotypes may be described by outsiders as typically caucasian or typically mongoloid, and may make the development and application of certain new drugs very controversial indeed.

Pharmacogenomics is particularly cost efficient when there are serious clinical and economical consequences to avoid, when reactions are difficult to measure with present methods, when there is a well-established connection between genotype and clinical phenotype, and that genetic variations are reasonably common. But the most important part of pharmacogenomics’ success is the prevalence of increasingly cheaper, faster and easier gene tests, like the ones consisting of DNA chips connected to hand held computers. When they become ubiquitous they will enable quick tests at the bedside to test the patient’s receptiveness of a proposed medication. This would be particularly significant for chronic diseases where patients require long time care and side effects and correct dosage have great importance.

But the development costs for treatments in the present climate of regulation are very steep indeed, which could block or restrict the use. Currently the regulatory climate is uncertain, which makes companies nervous about how much to pursue drug and gene test packages. If regulatory agencies demand as much data about the test as the drug, the cost and delays might be prohibitive.

An increased use of pharmacogenomics will put huge informational demands on the medical staff. They will not only be required to be knowledgeable about the general effects of medicines, but also of how these can be influenced by genetics, and also be required to be able to execute gene tests. Patients are also searching more actively for information on the Internet, soon possibly with pharmacogenetic tests at home. This will put health care before the serious problem that patients could become more knowledgeable about their own state of health than the physician but lacking the deeper medical competence to make a well-balanced evaluation, especially if organisations and regulations impede the integration of pharmacogenomics in primary health care.

Designer drugs are the exact opposite of the present’s generic medicines. How will governments react to patient demands to gain access to medicines that have not been proven efficient for other patients with the same affliction? How will they balance egalitarianism with cures?

In the presents risk adverse system there is always a problem of making even small risks predictable. If a new drug is shown to have a serious side effect with a small genetically identifiable patient group, the choice for the administration is between approving its use and also demand gene tests (two new costs to the health care system) or not to allow its use (no new cost and no new risk). If an old drug is a risk for a small group, either a new test will have to be introduced (a cost) or the drug removed (no costs, no risk). The present medical administrations with cost minimization as their main goal will encounter problems in the future when new technology and patient demands collide.

Another area of potentially great clinical importance is neuropharmacology. The detailed knowledge of the signal paths in cells and the brain is very relevant in order to understand and influence the brain’s function. The economic and personal costs of mental diseases are enormous, making any advance in managing mental health a significant one. Medical treatment can also enhance therapy, and therapy-potentiating medications can certainly be a future synthesis. An example is professor Michael Davis’ research at Emory university on how the substance DCS can enhance the de-learning of phobias, stress syndromes, and panic anxiety. In experiments with person’s with fear of heights, a simultaneous treatment with DCS could give the same effect on two therapy sessions, instead of eight without DCS, and reduce the risk for relapses after treatment. It is possible that similar combinations of medications and therapy can be used more extensively in the future, making treatment shorter and more efficient.

The barrier between curing, preventing and enhancing medicine is being erased. A reason is the increased medicalisation of various states, for instance age related memory lapses. Such memory lapses are probably a natural part of ageing, caused by decreased neuromodulators, but it decreases life quality. Memory enhancing drugs are under development but can also be used with healthy, younger persons. Here the border between curing and enhancing is starting to blur.

In the same way "life style medications" such as Viagra and Xenical have crossed the barrier between curing/preventive medicine and enhancing. Often the term life style medications is used in a very negative way, insinuating that it is an unnecessary medication and thus really not needed. But an older group of these drugs are already well spread in society: birth control pills. The same argument could be used against these, but it is unlikely that any politician would like to ban or reduce access to birth control pills on the basis that they are unnecessary, costly for public health care, and do not cure or ameliorate a formal disease.

The market for enhancing drugs is probably huge (as indicated by the health food business, alternative medicine, and functional food), and at the present mainly undeveloped. Pharmaceutical corporations search for new blockbuster drugs with large patient groups and would probably like to exploit this market. But to make that possible changes must be enacted on the regulations regarding medicines, especially regarding the influence patients have on their treatment and its goals.

Here, the physicians’ and the patients’ attitudes play a huge role on what pressure will be applied on regulations. If working enhancing drugs are developed, but are made unavailable in Europe because of a restrictive stance it is probable that the black market for drugs will increase further.

Patients become more dissimilar, and medicine more individualized, with pharmacogenomics. This brings rising costs and administrative problems to the present’s health care systems, despite offering huge gains in health and future cost savings. The debate should hence be directed towards what health care systems should be adopted given the influence of rapid medical developments. The new pharmacology will be old news before long.

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