New insights into drug development: drug’s efficacy versus decision making?

Drug development is one of the largest industries of today. It is the process of bringing a drug from the last stages of drug discovery all the way to the market. In order for a drug to be marketable, it has to go through pre-clinical research involving microorganisms or animals in addition to clinical trials on humans. Often, however, even after years of work and millions of dollars, drugs will not make it through the last stages of clinical trials. Recent initiatives are trying to take advantage of this large investment already made in drugs that never made it to the market for one disease, but could be viable for another.

Pre-clinical trials consist of finding new chemical entities which show promising activity against a particular biological target. Physicochemical properties of these entities are also determined, such as chemical makeup, stability and solubility. However, in order to determine the safety, toxicity, pharmacokinetics and metabolism of these new chemical entities, tests are carried out with in vitro methods using isolated cells or animals. If chemical entities show promise, clinical trials on humans are conducted. Clinical trials involving new drugs are normally conducted in four phases. In the first phase researchers test an experimental drug on a small group of people to determine a safe dosage range and identify any side effects. The second phase establishes the testing protocol, where the experimental treatment is given to a larger group of people to test the drug’s effectiveness. The third phase consists in final testing to confirm the drug’s effectiveness and compare it to commonly used treatments. The fourth phase consists in post-approval and post-marketing studies.

Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. Most of the time, the information gathered from pre-clinical tests is submitted to regulatory authorities as an ‘Investigational New Drug’ application. If the application is approved, the drug is put forward to clinical phase. It is therefore interesting to point out that the path of the transformation of a new chemical entity into a functional drug is not only defined by its success at targeting its biological target, low toxicity and few side effects, but more from its validation by regulatory authorities. Therefore, regulatory authorities have the power to approve or reject new chemical entities into clinical phase. It follows that a lot of new chemical entities don’t make it through the clinical phase. This has raised the question as to whether ‘abandoned’ drugs can rise again.

A recent case has shown that old and archived drugs can be rescued. Progeria is a rare disease which causes children to age such that they can look like octogenarians when they are just ten years old. However, recently the drug lonafarnib, which was initially developed by Merck in the 1990s against head and neck cancer but failed to be effective enough, showed promise against Progeria as a therapeutic drug (1). After the resurrection of lonafarnib as a therapeutic agent, the director of the National Institutes of Health (NIH) Francis Collins proposed that the same could be done with sheltered drugs that passed only the initial stages of drug development. Indeed, roughly 30,000 drugs have been shelved by the pharmaceutical industry. Additionally, the UK Medical Research Council is about to announce a £10-million programme aimed at continuing the development of 22 stalled compounds of an AstraZeneca industry based in London (2). A similar program is also being put forward by the NIH’s National Centre for Advancing Translational Sciences, where researchers were invited to look at 58 compounds provided by eight big drug companies (3). All of these compounds passed pre-clinical trials and were brought to early human trials, where they were found to be safe. They were however abandoned when they were either deemed inefficient against their targets or unsuitable for business-related reasons. A total number of 160 pre-applications have been put forward for a maximum of eight awards, and the most promising compounds will be developed.

While the programs was received enthusiastically by some people, others argue the fact that these compounds have already been tested extensively against many targets could lead to a conflict of interests. More specifically, if the application for the renewal of a particular drug is successful, then companies would be obliged to carry on the development of the drug. This would mean that companies would have to share the intellectual property with the grant holders if they find new uses for a compound, where companies can then license it back to develop the drug. Alternatively, they could sell the agents to the academic partner, or have the the agents manufactured by a third party. This is however not always a simple decision to make. For example, the chemical structures of the 58 compounds provided by the english drug companies to researchers were not revealed. This has led to a wasted effort of chemists trying to understand any novel activities that the compounds might have. However, a positive outlook has to be maintained, as this drug renewal program could open doors to a new era of sharing compounds and data by the various industries, promoting a beneficial exchange of information.

(1) Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. Proc Natl Acad Sci U S A. 2012 109(41):16666-71.

(2) Drug repurposing programmes get lift off.Asher Mullard, Nature Reviews Drug Discovery 11:505-506

(3) http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/directory.html