Birgit Fischer: Research, development, manufacture, marketing – How a pharmaceutical is created

The journey from researching an active ingredient to producing a marketable drug is a long road full of challenges. For a substance to work as an active ingredient, it needs an extraordinary combination of properties.

 

Medication has improved Germans’ life expectancy and quality of life considerably. Yet new medicines are urgently needed all the time, as there are still no appropriate treatments for many patients. In addi­tion, the status of the population’s health is extremely important for productivity – especially in an ageing society. The export of pharmaceutical products is a crucial economic factor all around the world. Producing effective pharmaceuticals means creating value. In the knowledge society, expertise in pharmaceuticals and patient care is Germany’s raw material in international competition. Developing a new drug is a complex project with no guarantee of success and, even if things run smoothly, one that rarely takes less than 13 years. Contributions are needed from specialists with very different fields of expertise – medicine, chemistry, pharmacy, engineering, information technology, patent law, etc.

Germany remains one of the leading countries when it comes to discovering new drugs, thanks to the research and development institutions of both German and foreign companies. To­­day, however, no drug is developed in a single country. Those that are fully developed are always intended for the world market right away.

There are various questions to be asked before the start of any pharmaceutical project: Which illnesses present an urgent need for new drugs? Have there been any new findings in fundamental research that show where it might be possible to intervene in the course of the disease more effectively than before? Could a drug be found that has fewer side effects than the current ones? Would health insurance provid­ers or patients pay for a drug like this if it were successful?

If the answers are positive, a process with many hundreds of individual steps begins. At the heart of every drug is its active ingredient. This may be a substance that the patient is lacking – such as a clotting factor in haemophilia patients. In most cases, however, pharmaceutical researchers first have to find a point in the incidence of the disease where an active ingredient could intervene. Companies usu­­ally find indications of this in the research literature. In other cases, groups of researchers they cooperate with may report such findings to them. This goes to show the enormous importance of an environment with academic research at a world-class level for com­­panies. Germany has a lot to offer here, too.
Once a useful point of attack has been found, an active ingredient able to have an effect needs to be created. This kind of thing cannot be done on a draw­ing board, but pharmaceutical researchers have other ways to achieve their goal. For example, they can take a large collection of chemical and natural subst­ances and find those that display at least a small effect. Using these as a starting point, the research teams then develop the exact active ingredient they need by repeatedly adding or taking away atoms.

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In contrast, pharmaceutical researchers usually de­­velop genetic active ingredients by starting with a human protein, which they then modify in a medically appropriate way. For manufacture, a gene is then ultimately implanted into cells that multiply well in large steel tanks, where the active ingredient is man­­ufactured in bulk.

The final active ingredient not only has to intervene at the right point in the course of the illness, it must also have other good properties. As far as possible, it should act only on the desired location in the body and not impact on many other molecules. If it is to be taken as a tablet, it needs to be able to travel from the intestine to the location at which it is meant to work without damage.

If a potential active ingredient looks promising, a pat­­ent application is submitted. Before it can be tested on people, however, it still has to pass through a rigorous programme of tests, focused on inves­­tigating whether the new substance is toxic, carcinogenic or otherwise harmful. This is done using tests in test tubes, with cell cultures and on animals. Only potential active ingredients that prove themselves here can be considered for further test­ing; the others are all discarded.

Testing on humans, known as clinical development, is divided into three stages: trials with a few healthy people (phase I), trials with a few ill people (phase II) and trials with a large number of ill people (phase III). Clinical development is the most complex and expensive part of drug development, sometimes involving tens of thousands of patients in many hundreds of hospitals all over the world. German hospitals play a big role in this: in fact, Germany is the world‘s sec­­ond most active country after the USA when it comes to involvement in industry-initiated clinical studies.

If all studies and trials are successful, the company can apply to the European Medicines Agency (EMA) and other pharmaceutical regulatory bodies around the world for the drug to be licensed.

Once it has been licensed in the EU, the company has the right to launch its new drug on the market in Germany straight away, so that it is available to doctors and patients. However, this is only possible if the high-tech systems required for mass production were completed even while clinical trials were still ongoing, and if the company has established a sophisti­cated logistics network to bring the drug from their production facility to the patients around the world. Germany has been able to assert itself against other coun­­tries in internal company com­­petition as a production location for innovations many times over the last few years; including for genetic drugs and innovative synthetic anticoagulants. However, competition between locations is fierce, espe­­cially from toll manufacturers in emerging economies, who are also improving their technical equipment continuously. Following the market launch, the company and health insurance providers negotiate the amount the health insurance providers reimburse for the drug (based on the results of a benefit assessment for the drug, among other things). Throughout all the years the drug was being development, it has cost more and more. It is only once it has been launched on the market that the company can regain these costs, at least until the patent protection expires and copycat companies are able to bring out their own versions of the drug.

The author has been Director General of the Association of Research-Based Phar­ma­ceutical Companies (vfa) since May 2011. She was Minister for Women, Youth, Family and Health for the state of North Rhine-Westphalia from 1998 to 2002, and the state’s Minister for Health, Social Affairs, Women and Family from 2002 to­ 2005. In addition, Birgit Fischer was CEO of Barmer GEK from 2010 to April 2011.