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Rescue of abandoned molecules

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The use of medicinal compounds to manage diseases and improve patients’ quality of life is increasing, as more effective and safer agents become available. Research to develop these agents is occurring in health system practice settings throughout the world. The credibility of this research and the protection of human subjects is a major responsibility of all health professionals involved. The year 1938 saw the foundation of the modern clinical trial process in the USA with the requirement that drug manufacturers prove drug safety prior to marketing.

The process starts in the laboratory, and promising data leads to testing in human subjects concentrating on developing the drug’s safety profile and determining how it is absorbed, distributed in the body, metabolised and excreted. The durations of the drug’s effects are also measured. If the safety of the compound is established then phase II testing follows, consisting of small, well-controlled experiments evaluating safety and assessing side-effects. Participants are patients with the disease or condition being targeted by the drug. The optimal dosage of the drug is established, as well as statistical endpoints representing the targeted favourable outcome of the study. The current standard of care for the medical condition is used as a benchmark in setting the endpoint. Phase III, tightly controlled, double-blinded studies verify the effectiveness of the drug against the condition that it targets, based on the established statistical endpoints. The safety profile of the molecule continues to be built up with the recording of possible side-effects and adverse reactions resulting from long-term use. Effectiveness at this stage means the trial is deemed successful. Ongoing evaluation of the drug’s safety during routine use continues after marketing.

The EU has issued their own guidelines for clinical trials – including trials in children, an issue that has recently received much attention. In some countries regulations determine that all clinical trial drugs must be under pharmacy supervision. Hospital pharmacists should play a pivotal role in the management of drugs used in clinical research with both approved and investigational drugs, either as a principal investigator or using their skills in drug storage, preparation and record keeping, in addition to critically reviewing the protocol.

When working as a hospital pharmacist some years ago I was involved in an EORT phase III trial evaluating a new molecule with a novel mode of action. This was the very first 5HT3 antagonist, batanopride. It was the first drug demonstrating high efficacy in preventing Cis-platinum-induced nausea and vomiting, with minimal side-effects. The trial was a double-blinded, multicentre study which was stopped quite suddenly, despite the heavy investment in the drug’s development, after two patients demonstrated a life-threatening drop in blood pressure. Drug development is time-consuming and expensive and can take in excess of 10 years at a cost of more than $1,000m. Thus, anything that does not look extremely promising is simply not developed. The world had to wait quite some before ondansetron, the first registered 5HT3 antagonist (antiemetic), became available.

This is one example of many new and promising drugs which fail to become registered for one reason or another. There are many reasons why budding treatments do not make it to the market. Making the leap from something that looks hopeful in the laboratory to testing it in patients is one of the most challenging steps in drug development, but science has progressed so rapidly in recent years that there are more compounds available than commercial resources to investigate them. I recalled that particular clinical trial after reading a report of a cancer charity which plans to revive research into drugs that showed potential but whose development has been shelved.

Cancer Research UK plans to carry out new clinical trials of anti-cancer agents whose development has not been pursued by the pharmaceutical industry. It is hoped the initiative will ultimately see effective new drugs reaching the market. Drug companies have a large pool of potential anti-cancer molecules but priority is given to the most promising. According to the spokesperson for the charity, there is a real potential to develop a raft of new anti-cancer drugs and thus avoid losing potentially effective treatments.

A clinical development partnership has been set up as a joint initiative with drug companies. The charity will “borrow” a drug from a company and conduct early clinical trials at no cost to the company. If the drug looks promising, the company will retain the option of developing and marketing the drug, with the charity receiving a share of any revenues. The charity has set an ambitious target: to double its drug development activity over the next five years, seeking out new treatments that might otherwise not get developed. According to Cancer Research UK, there are many potential treatments trapped in the pipeline and the charity has the expertise and capacity to release this potential. This partnership may allow investigation of new medicines, designed to tackle rarer cancers, which are lower down the priority list because they are less profitable. Companies will retain intellectual property rights over their original molecules and first option to view the trial data, so they should have no reservations about loaning these compounds for further investigation.

Commenting on the plan, the Association of the British Pharmaceutical Industry said: “This is a simple, rapid and cost-effective way in which pharmaceutical companies could boost their product lines.”

I couldn’t agree more, and wait with cautious optimism to see all of humanity reaps the fruits of this joint venture.



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