Learn more about the Drug Discovery Process

We've all been touched by the miracles of modern medicine. But few people understand how medicines are made, and the immense effort required to get them to market and into our hands.

Discovery Partnerships gives you the change to share costs, developments and challenges along the way.

Efficient drug discovery is still the key for the pharmaceutical industry to survive. With pharmaceutical companies worrying strongly about how to fasten time-to-market, effective drug discovery and enhanced prognosis become more important than ever. Therefore, many pharmaceutical companies are looking for long-term alliances and innovative ways of partnering to speed up development time and share risks.

IQPC's annual congress "Discovery Partnerships" is back. The only European event covering Early Discovery and Pre-clinical Partnerships! Be prepared for 2012 and beyond. Join the 3rd International Congress DISCOVERY PARTNERSHIPS from the 13 - 14 December 2011 in Düsseldorf, Germany.

Dieser in Englisch abgehaltene Fachkongress wird für die Fach- und Führungskräfte von pharmazeutischen Unternehmen, CROs sowie Biotechs initiiert. – Wie können erfolgreiche Partnerschaften etabliert werden? Welche Balance zwischen Risikostreuung und Kostenteilung ist vor allem bei einer Partnerschaft von KMUs und CROs optimal? Welche Vorteile bringen "2.0 Kommunikationskanäle" mit sich? – Diese und weitere Fragestellungen bilden den Rahmen des "3rd International Congress Discovery Partnerships".

Optimizing drug discovery through microdosing

Defining a microdose
The EMEA Position Paper defines the human microdose as the 1/100th of the dose calculated to yield a pharmacological effect of the compound based on primary pharmacodynamic data obtained from animal and in vitro models. According to the EMEA guidelines, the total amount of drug compound(s) being tested and administered in a human microdosing study must not exceed 100 micro grams.

Microdosing in optimizing drug discovery
Advances in areas of combinational chemistry, molecular and cell biology, high throughput technology and strong economic forces have lead to greater competition and rapid changes in nonclinical drug development. Patients, physicians and pharmaceutical sponsors alike are looking for more effective and safer medicines to be developed faster and also have improved costeffectiveness (Lesko et al., 2000).

Reigner et al. (1996) have explained that predictive power of preclinical drug metabolism has advanced due to a considerable betterment in the  understanding of the relationships between in vitro, animal and human pharmacokinetics. They further emphasize that focussed application of pharmacokinetics and pharmacodynamics has improved the efficacy of the drug development process in the pharmaceutical industry. Microdosing  has proven to be an effective method to understand the pharmacokinetic and pharmacodynamic  behaviour of new drugs in humans.

Microdosing has hastened the pharmaceutical preclinical to clinical translation involved in the drug development process. Pang, Rodrigues and Peter (2009, p. 363) elucidate that microdosing has not been developed to determine the safety or efficacy of test compounds when administered to humans. The main purpose of human microdosing studies is to determine key pharmacokinetic parameters in reaction to very small doses of a new drug being tested.

Advent of microdosing
Drug discovery is a long drawn process that involves preclinical pharmacological testing and clinical application in animals and then humans, before drugs can be certified for normal dosage and prescription. Considering the fact that microdoses help decipher the pharmacokinetics in humans for varied newly developed pharmaceutical compounds, large amount of resources in the form of time, energy and money need not be invested into a new drug candidate that is unsuccessful at this level itself.

As a matter of fact, around 40% of the newly developed drugs are withdrawn after phase 1 clinical trial because of undesirable pharmacokinetic properties (Lappin and Garner, 2003). Accordingly, a phase 0 testing has been introduced before the traditionally followed phase 1 clinical trial in humans. Through this, microdosing can be performed in human volunteers in phase 0 following minimal trials in animals. Based on the performance and pharmacokinetic behaviour during this stage, failure drugs can be easily identified and eliminated at the earlier stages without wasting much of time and energy in further drug development and testing, On the other hand, microdosing also helps identify the more promising drug compounds from a pool that could be further explored and developed to achieve desired clinical results in humans when they are tested at later stages of drug development. Sarapa (2003) highlights that two of the most important positive outcomes of performing phase 0 studies by administering microdoses to humans are the reduction in time  and resources wasted in prolonged further testing and reduced attrition during drug testing.

Concentration of microdoses
A microdose is usually 100 times less concentrated than the medication that would be administered once tested and verified. This way the concentration of the newly developed drug entering the human system would be well less than 1/100 concentration of the drug. This is less liable to produce any harm to the human volunteers during testing.

Microdosing procedure
Selecting candidates for human microdosingPharmacological activity is first studies in animal models. Based on this demonstration and minimal animal testing, it is decided whether or not to proceed with clinical trials in humans. Accordingly, candidates for the human microdosing study are selected.

>> Read more on:

• Microdose synthesis
• Administration of Human microdose
• Bio analysis post microdosing
• Advantages of Microdosing
• Limitations of Microdosing
• Microdosing in drug development
• Regulations for microdosing
• Conclusion

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Modified ecstasy 'attacks blood cancers'

By James Gallagher Health reporter, BBC News

Modified ecstasy could one day have a role to play in fighting some blood cancers, according to scientists.

Ecstasy is known to kill some cancer cells, but scientists have increased its effectiveness 100-fold, they said in Investigational New Drugs journal.

Their early study showed all leukaemia, lymphoma and myeloma cells could be killed in a test tube, but any treatment would be a decade away.

A charity said the findings were a "significant step forward".

In 2006, a research team at the University of Birmingham showed that ecstasy and anti-depressants such as Prozac had the potential to stop cancers growing.

The problem was that it needed doses so high they would have been fatal if given to people.

The researchers, in collaboration with the University of Western Australia, have chemically re-engineered ecstasy by taking some atoms away and putting new ones in their place.

One variant increased cancer-fighting effectiveness 100-fold. It means that if 100g of un-modified ecstasy was needed to get the desired effect, only 1g of the modified ecstasy would be needed to have the same effect.
Scientists say this also reduced the toxic effect on the brain.

Lead researcher Professor John Gordon, from the University of Birmingham, told the BBC: "Against the cancers, particularly the leukaemia, the lymphoma and the myeloma, where we've tested these new compounds we can wipe out 100% of the cancer cells in some cases.

"We would really need to pinpoint which are the most sensitive cases, but it has the potential to wipe out all the cancer cells in those examples.

"This is in the test tube, it could be different in the patient, but for now it's quite exciting."

'Soapy' cells
 
It is believed that the drug is attracted to the fat in the membranes of the cancerous cells.

Researchers think it makes the cells "a bit more soapy", which can break down the membrane and kill the cell.
They said cancerous cells were more susceptible than normal, healthy ones.

However, doctors are not going to start prescribing modified ecstasy to cancer patients in the near future.
The research has been demonstrated only in samples in a test tube. Animals studies and clinical trials would be needed before prescribing a drug could be considered.

First, however, chemists in the UK and Australia are going to try to tweak the modified ecstasy even further as they think it can be made even more potent.

'Genuinely exciting'
 
If everything is successful, a drug is still at least a decade away.

Dr David Grant, scientific director of the charity Leukaemia and Lymphoma Research, said: "The prospect of being able to target blood cancer with a drug derived from ecstasy is a genuinely exciting proposition.

"Many types of lymphoma remain hard to treat and non-toxic drugs which are both effective and have few side effects are desperately needed.

"Further work is required but this research is a significant step forward in developing a potential new cancer drug."

The shrinking of the knowledge base – what is the impact of this on the speed and security of drug development?

an Editorial by Paul Branthwaite, TranScrip Partners LLP, United Kingdom

We have all seen the litany of redundancy as blockbusters go generic and mainstream pharma reduces its cost base and/or merges with other struggling groups to compensate and/or restructures to move into new therapeutic areas of strategic importance. Not all announcements in the last few years have been negative but overall, big pharma shrank in size and continues doing so, particularly in the Western world. Part of that is accelerating outsourcing of manufacturing activities to Asia and Eastern Europe but actual slicing into corporate size is also the case. Astra Zeneca said this year that it was cutting 15% of its 66,000-strong workforce. 

Pfizer announced that it would close its drug manufacturing plant at Sandwich in Kent, UK and the ramifications of its merger with Wyeth have yet to become wholly clear. Many companies have undertaken similar substantial reorganizations throughout 2008 and 2009. Much of that was initially aimed at sales and marketing (reflecting imminent or actual patent losses) and manufacturing plants but the move to condense  R&D groups also took hold and reports across the sector shows this is likely to accelerate. In previous decades R&D departments were protected but new realities are now reaching into all aspects of development. You can see why, when US spending on R&D alone  reached close to $63 billion in 2008, topping $1.2bn in real costs per drug licensed that year, with similar showings in Europe. As a consequence, overall, in-house R&D cost-cutting by pharma is expected to gather pace in 2010, before slackening off from 2011 onwards, although some groups continue to buck the trend and have flagged markedly increased R&D spending; Novartis and Schering-Plough to name two.

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However, many R&D cost-cutting efforts will be ultimately counter-productive if they reduce current expenditure but endanger the future drug pipeline that is the raison d’eˆtre of the company. This is the elephant in the room. Slashing R&D staff numbers will not provide sufficient savings in itself, especially if it cuts into the competencies that are critical to ensure that there will be a drug at the end of the process. In the longer term,  there must be consequences to all this cost-cutting activity and shift of emphases, particularly in loss of direct control over programmes, loss of expertise in-house to ensure reliable and positive deliverables, in the medical governance of programmes and the loss of senior mentors and role models for the next generations of drug developers.

At present, current and planned cuts in staffing may already be impacting the capabilities of major groups to process their pipelines, and will definitely do so in the future as juniors lose their mentors. Mainstream pharma ‘Old Hands’, who normally make the judgement calls, are taking advantage of generous redundancy packages, leaving behind teams of relatively junior medics and scientists to make critical operational and even strategic decisions. Furthermore, the senior staff remaining are handling ever-increasing workloads and are spread too thinly, placing the future of a vibrant pharma industry at risk. The critical question is whether the major CROs, consultants and interims realistically and effectively fill this void?

Outsourcing any knowledge-based element, large or small, on grounds of cost, without fully understanding what that actually means when you hand influence on critical issues over to an outside organization can be a risky endeavour. Drug development strategy, design and decision-making require disease area knowledge, experience, judgement and ‘feel’. When you put that in context of whole development programmes, multiplied by the number of pharma companies trying to develop their pipelines differently, and it becomes abundantly clear that the CROs on their own, as currently comprised, collectively cannot compensate for the lack of in-house knowledge in pharma; structurally they are not set up to do so, especially on the scale that might be necessary in the context of the changes taking place in big pharma. Nor are the CROs natural homes for those same ‘Old Hands’, who have no wish to be spread even more thinly, or used as business development bait whilst spending half their life in aircraft doing it. No matter how large, how experienced or how competent they are at processing and operations, CROs rarely have enough talent in their senior teams to compensate for those critical competencies that may be needed by the client.

If all of these things are true, what can be done to address the short and long-term needs; knowledge now and knowledge later? Assemblies of competencies, whether as loose alliances or tight companies are coalescing outside the regular CROs, although some larger CROs, alert to the issue, are trying to create clusters within their organizations, with variable success. Companies too are beginning to respond differently and despite the issues described, realising that outsourcing and drug development alliances will become a more dominant component of their resourcing strategy in the future, are seeking to utilise external resources to best effect while still cutting R&D costs/drug overall. 

Expertise outsourcing and partnerships will multiply, simply because the work still has to be done somewhere, not only in the traditional areas such as the use of chemists in India and China, or in the wholesale outsourcing of bits of clinical programmes to others but more importantly in the augmentation of the remaining inhouse expertise by outside competencies. Some estimates suggest a tenfold increase in this type of activity over the next five years. Accessing competencies have to balance Productivity against Efficiency and Speed against Security and Patient Safety. What tests should apply?:

• Value for money this does not necessarily imply the cheapest. Knowledge and expertise is less of a commodity than data management or clinical operations, which have tried and tested standards and measurable outcomes. As such, accessing through the same supply and tendering departments that negotiate with CROs may not work to best advantage.
• Security of the data – the data being the single most valuable element of the process chain, does your independent ‘consultant’/‘expert’ have secure IT systems? Security of access to the expertise – are there back-ups in case of accident or illness? Single experts cannot supply any of this, which is another reason driving the rise of the expert group. Single experts can also run into conflicts of interest if specialised in certain areas, where rival companies are operating. 
• Patient/volunteer safety – although the external knowledge requirement may seem to be tightly defined, without therapeutic context assessment and review by other critical eyes within the external ‘team’, mistakes can occur that endanger lives (as we have seen).
• Speed of access – although good planning can offset some issues around access to expertise, those heavy-hitters are in constant demand. The problem arises when those planning programmes do not foresee the need because of their own lack of experience. Knowing where to go has become a critical element. Much valuable time can be wasted in finding the right source. In addressing the training of the next generation of Industry physicians and scientists, assuming the trend on downsizing continues, what options are there? If we look at what big pharma used to supply in developing its in-house talent, one of the biggest positive elements in addition to formal training was working alongside exemplars of the professions. Both medics and scientists have structured access to mentors, diverse projects and functional groups that taught them much of what was required to develop drugs. These mentors are leaving, the projects are fewer and many of the tasks that functional groups did are outsourced. 

The questions are these:

• Companies – will they continue to fund the formal training of their staff? How will they diversify the experience of their staff when the silo-isation of departments is strengthening (e.g. medical affairs staffers do complain that they do little more than job-bagging)?
• Academic centres – Can they compensate for the lack of experience gained in companies? Does the Dip. Pharm. Med. and the scientific/regulatory equivalents need to be more ambitious in scope and do we need higher mandated levels of training?
• CROs – can they provide structured learning in similar vein to develop high-end expertise? Can they attract or afford to employ these people in a way that can be integrated with their financial model?
• Learned bodies – Can they do more? We sit at the start of an R&D revolution. Drug development is undergoing significant change to permanently re-shape its activities, with moves away from large budgets and research teams towards external resources. Because pricing pressures from patients, governments and insurance companies and rising cost hurdles to registering products, the drive to produce more effective, safer drugs, more cleverly and at lower development cost with less risk will continue. 

Choose your knowledge partners with care!!

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The shrinking of the knowledge base – what is the impact of this on the speed and security of drug development?
We have all seen the litany of redundancy as blockbusters go generic and mainstream pharma reduces its cost base and/or merges with other struggling groups to compensate and/or restructures to move into new therapeutic areas of strategic importance.

(c) Paul Branthwaite, TranScrip Partners LLP, United Kingdom

Drug transporters and their role in drug interactions and toxicity

Background

Drug transporters have gained prominent attention from almost everyone involved in drug development across the globe in the last two decades. Researchers now have a fair understanding of the vital role played by drug transporters in drug absorption, distribution, metabolism and excretion (ADME). Attention has been drawn towards their involvement in drug interactions and toxicity. Improvement in clinical translation of in vitro and preclinical transport studies and increased impact of regulatory authorities for better understanding of transport interactions (draft EMEA guidance and 2010 ITC whitepaper) are also stressed.

A range of various drug transporters is present in the human body. Most important of these include transporters expressed particularly in the endothelium of the blood–brain barrier and in the epithelia of the liver, intestine, and kidney during drug development. These drug transporters are specific to their substrates. However, the number of substrates specific to each transporter may vary. For example, a transporter may be specific for only one substrate while another may act as a transporter for three substrates. At a particular site,  distribution of each of these transporters varies, entailing the different physiological functions and sometimes the pathological reaction. Lack or absence of these transporters can result in numerous genetic disorders. The bioavailability of drugs with less permeability and absorption can be enhanced by the use of transporters involved in the absorption or else by restricting the transporters required for the efflux system.

Thanks to fresh developments in molecular biology in gene cloning and other techniques, molecular level characteristics and distribution of transporters can be studied. Over the years, the major cause of failure for late stage therapeutic entities during drug development has been drug-induced organ toxicity. In vitro screening of molecular compounds can be done to ascertain the effect of drugs on various pathways or mechanisms that might be linked to drug toxicity. However, very few negative in vivo outcomes can be predicted in this manner; as in the case for most of the models, the in vivo conditions cannot be replicated.

The two major conditions required to determine the organ specificity for toxicity are increasing the concentration and delivery of drugs to the target. Much progress has already been made in deducing the role of these drug transporters in drug safety and efficacy. For the human genome, over hundreds of transporters have been discovered. Examples include the two most important superfamilies, namely, the ATP binding cassette and the solute carrier (abbreviated as ABC and SLC, respectively).


Since a lot of research has been done with focus on interaction of drugs and their metabolites, scientists have simultaneously developed a huge range of literature on the topic. Several of these studies suggest the in vivo role of drug transporters in the drug’s disposition, efficacy and some negative responses. Models for in vivo demonstration of the role of drug transporters include a number of animal species, commonly knockout (KO) mice. In humans, loss-of-function genetic variants have also been used. The in vivo role of many ABC and SLC transporters has been elucidated using such studies. Many such studies have proved the role of  transporters along with several drug-metabolizing enzymes (DMEs) during ADME. Clinical pharmacokinetic drug-drug interaction studies also support genetic polymorphism of DMEs.

Read more about:

    Overview of drug transporters:

• P glycoprotein (P-gp)
• BCRP
• OCTs and OATs
• OATPs

1. Issues on Drug Development
2. Future Directions
3. Conclusion

Click here for the complimentary 5-page article: Drug Transporters.

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