cr.appliance- integrated concepts in drug development
cr.appliance has been offering scientific and strategic concepts and consulting in clinical drug development and approval since 2003. The company was established by the husband and wife team, Karen Grave-Hermann and Dr. Robert Hermann. Both partners have wide-ranging clinical, scientific and industrial experience in drug development. The two specialists talked to us about current developments and trends in their field and about the development of the German biotech sector.
Dr. Hermann (RH), your activities require you to constantly update your knowledge on new regulations. Where do you get the information on new regulations from?
RH: Drug development and drug approval has always been very dynamic; however, the speed with which new laws and regulations are published has increased considerably over the last few years. We obtain the information we need from many sources, for example expert conferences, workshops, scientific literature and the regular screening of official notes and papers published on the Internet sites of national and international regulatory authorities. In addition, we also benefit from personal contacts with people who are part of the same interdisciplinary network as us, as well as discussions with our clients. Mrs. Grave-Hermann (KH), what role does contacts, working cooperations and networks play in your activities?
KH: Interdisciplinary cooperations and networks are key in our activities. Of particular importance are our contacts with research organisations, authorities and contract research institutes, as well as contacts with clinical investigators and clinical researchers at universities and trial centres. In many cases, research-based companies tend to neglect the perspective of doctors and patients. But it is worth noting that clinical investigators are usually the first to take on board the perspective of patients.
Which are the main types of drugs that are currently most likely to gain approval, both in Germany and worldwide?
RH: At present, there are some remarkable trends. First, the big research-based pharmaceutical companies are currently withdrawing from the medical areas where they previously had the biggest medical and commercial successes. These include drugs for the treatment of acid-related gastrointestinal diseases (stomach and duodenal ulcers, reflux/oesophagitis), but also drugs for the treatment of fat metabolism disorders and hypertension, including complications such as cardiac infarction and stroke. In addition, for quite some time there has been a tendency in big pharmaceutical companies to reduce the research risk associated with smaller “niche products” by establishing smaller research-intensive spin-offs. Over the last few years, numerous pharmaceutical companies have spun off their antibiotics/anti-infective drug areas, despite the problem of growing resistances which make innovations truly necessary. Despite the huge demand for innovation, big pharmaceutical companies tend to see the anti-infective drug area through critical eyes, because genuine innovations, which could be used for example as “stand-by antibiotics” for problematic cases, still run the risk of remaining small fry, economically speaking, where sales are unlikely to cover drug development costs.
How has clinical drug development changed over the last few years?
KH: The pharmaceutical sector is characterised by movements in different, sometimes completely opposite directions. For example, a trend towards consolidation can be observed in the German and international pharmaceutical sector; this comes through company acquisitions and mergers, resulting in a smaller number of fully integrated research-based pharmaceutical companies. Only recently, two important publicly listed pharmaceutical companies, Schering and Schwarz Pharma, have disappeared from the stock exchange. In contrast, the German biotech sector is slowly gaining ground and numerous companies have been spun off from traditional pharmaceutical companies. The few remaining fully integrated big pharmaceutical companies have increasingly been assessing clinical development from the angle of process optimisation. They have concentrated on optimising partial processes of clinical trials on a technological and operative level and have neglected the further development of scientific and contextual study concepts.
Do you expect there to be a rethink resulting in companies going off in new directions?
RH: Top international companies have recognised the aforementioned difficulties and taken the necessary steps. In Germany, there are, unfortunately, huge insufficiencies and the companies do not appear to be very keen to learn from others. Many biotech companies and pharmaceutical spin-offs only have a limited knowledge of clinical development. This is due to the investors’ and/or management’s lack of understanding of the complexity and requirements of clinical drug development. On the other hand, new smaller companies in Germany find it very difficult to recruit people with qualified clinical development know-how, especially if the company only has one drug candidate in clinical development. Overall, as a result of these developments, the majority of pharmaceutical and biotech companies no longer have the necessary know-how and resources for the planning and execution of state-of-the-art clinical development processes. This results in a need for such companies to partner up with contract research organisations (CROs). However, in many cases, not even the minimum resources required for the management and the proactive cooperation with external CRO networks are set aside. Such a philosophy of course hardly enables the time-optimised development of clinical projects and hence there is no optimal value creation.
What is the effect of these developments on your work?
KH: These developments are the basis of our business model. We offer companies that are experiencing resource bottlenecks or unexpected problems, the necessary drug development know-how as well as the concrete resources that they need to accomplish their tasks. We develop solutions for individual project requirements in close cooperation with our clients and can also help clients to look for and find the CROs that are best suited to their needs.
What are the major complications associated with drug development and approval procedures?
KH: A major difficulty in the pharmaceutical industry is that phase III of clinical drug development is becoming complicated and too expensive. Normally, many phase III problems are the result of ineffective planning and execution of phase II clinical trials, in which, for example, the identified dose or dose regimen is often not optimal. As a result, top pharmaceutical companies nowadays tend to invest more time and money in phase II clinical drug development and there also tends to be more projects abandoned in this phase. Therefore, investment in phase III projects has a far greater and more predictable chance of success. Another frequent cause of complications are rare, unexpected side effects, which, due to their low incidence, are often only recognised in phase III or even after the launch of the product. Further problems and challenges are toxicological findings, which are obtained from experimental animal tests during the preclinical drug development phase. The results from animal experiments can only with difficulty be transferred to the situation in humans and are difficult to assess. In addition, further problems might be pharmaceutical development problems (e.g., the stability of the formulation), technological problems, cost and patent issues.
What are the most frequent reasons for the delay or failure of a drug approval procedure? What makes researchers, investors and company executives underestimate the requirements of clinical development?
RH: The major problem is most likely the systematic underestimation of the approval requirements in terms of a positive benefit-risk assessment of the new product. During the development of a drug or prior to approval, many companies tend to reject consulting help. R&D departments often depend on the influence and wishes of the marketing department. This causes companies to orient clinical development around unrealistic market requirements, rather than on the actual product properties and approval requirements. This may then lead to the approval failure of promising products, because they need to be administered twice a day rather than once daily as required by the marketing department. Another popular field of tension is that companies often find it difficult to clearly identify which patient groups will benefit from the product and which will not benefit at all. This would limit the potential application area of the product and reduce profits. However, the authorities are increasingly unwilling to approve drugs for which such information is unavailable. Experience also shows that unsuitable projects are often not abandoned because there are no suitable subsequent projects due to pipeline and portfolio management problems. Approximately 70 per cent of available R&D resources are still allocated to projects that will never reach market approval.
What is so special about the philosophy and activities of cr.appliance?
RH: I believe we are one of only a few service providers in Germany with a clinical, scientific and industrial background in drug development. In addition, we focus strongly on a 360-degree approach. Prerequisites for this approach are the experience-based anticipation of project-specific requirements and potential problems, long before they actually occur in the development process. Therefore, we are careful to ensure that our consultations and services give our clients more value, rather than simply giving answers to questions on individual scientific, technical, clinical or regulatory details. We strive to put in place holistic approaches to the development of solutions that are goal-oriented, custom-made and tailored to suit a market need. What distinguishes us from big operatively active CROs is that we do not have a goal conflict with our clients.
Dr. Robert Hermann has been a doctor and research associate in the field of anaesthesiology and clinical pharmacology for over eight years; he has also spent 17 years as clinical developer and manager in the pharmaceutical industry (amongst others ALTANA Pharma). Hermann is the chairman of the Fraunhofer ITEM Institute of Toxicology and Experimental Medicine board of trustees and member of the American College of Clinical Pharmacology.
Karen Grave-Hermann studied clinical development at the University of Tübingen and is a nurse specialised in anaesthesia and intensive care medicine. Prior to the foundation of cr.appliance, Grave-Hermann worked in the field of clinical drug development and pharmacology.