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Pharmacology Research & Perspectives

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Cover image for Vol. 4 Issue 6

Editors: Darrell R. Abernethy & Andrew J. Lawrence

Online ISSN: 2052-1707

Associated Title(s): British Journal of Clinical Pharmacology, British Journal of Pharmacology

Call for papers on Target validation

Call for papers on Target validation: publication of negative findings

Historically, ‘negative’ findings have tended to remain unpublished. Indeed, journal referees often reject papers on the grounds that the findings are negative.

We consider that this is not appropriate. Those who ignore history are condemned to repeat the mistakes of the past. When there is no record of history then it is inevitable that others will waste time and resources in unwitting replication of failed programmes. Indeed, increasingly, disclosure of ‘negative’ findings at the clinical trial end of research is likely to become a requirement in most countries.

PR&P is offering the pharmacology community an opportunity to publish studies with negative findings. We seek preclinical papers that show a hypothesis to be incorrect. Separately we seek papers on drugs that have failed in early clinical development. We have been given guidance from the British Pharmacological Society on the latter.

1. Call for preclinical papers that show a hypothesis is incorrect

Submit a paper

Background and purpose

There are numerous types of hypothesis testing in pharmacology. When the outcome is clearly negative this may indicate that the molecular target (whether it be a receptor, a sub cellular organelle, a cell type, or a process such as apoptosis) is not a valid target for that disease or it may be that the target is not drugable. Likewise, it may be that a drug type in preclinical development is found to have a pharmacophore for an off-target action, making it a flawed class. We would like to motivate the community to submit for publication such findings to allow a distinction to be made between these different potential interpretations.

Preparation and submission of manuscripts

Standard journal instructions apply. Additionally the title should take the form “Target Validation: remainder of title text“. The abstract and the introduction should indicate succinctly the hypothesis under test. The discussion is expected to be brief, but it should explain how the data show the hypothesis to be false, and draw attention to any caveats. Please submit the work as a regular article.

2. Call for papers on drugs that have failed in early clinical development

Submit a paper

Background and purpose

Failure in clinical ‘proof-of-concept’ studies is known to be a major factor contributing to high attrition rates in drug development, either from lack of efficacy or side-effects. These failures reflect the fact that preclinical ‘target validation’ studies do not always translate into man, where ultimate target validation must reside. Data from such clinical studies could therefore provide invaluable information on molecular target validation. Only a trustworthy and comprehensive data base will serve the community. PR&P intends to generate such a data base by publishing papers on early negative clinical studies that could contribute to the overall knowledge base on ‘target validation’. Because we recognise that if projects are terminated it may be difficult to justify significant resource to write up negative data, we would encourage authors to use such resources as are available e.g. information from the Clinical Investigator’s Brochure or published data. In addition, because our primary goal is to inform ‘target validation’ we would encourage publication of the data required to address the issue as to whether the negative result is likely to be a failure of the compound, the study design or the molecular target in that disease.

Preparation and submission of manuscripts

Standard journal instructions apply with respect to layout, bibliography, ethics statements, and acknowledgements etc. In order to encourage and facilitate submission, please note the following.

  • The Introduction may be sparse, but please provide a brief explanation why the compound/molecular target was considered in the chosen indication/patient population.
  • Previously published methodological detail or results should not be included, but the sources should be cited.
  • Please include (or cite) key animal model data as it is relevant to the target validation. Please include basic pharmacokinetic data in relevant species, including man, and basic pharmacology data like potency and selectivity ( eg IC50, pKi and PA2 values), particularly at the human receptor. This may go in the Introduction (as citation links) if prior published, or in Methods and results if unpublished.
  • Please include human and animal safety data where it may be relevant to assessment of therapeutic index
  • Please describe the study population with inclusion and exclusion criteria, primary outcome and secondary outcome measures
  • Please describe the protocol
  • It is particularly important to provide clinical data to justify that the molecular target has been engaged in man at the dose used in the clinical study; this could be biomarker studies, measurement of receptor occupancy at the site of action, or PK/PD modelling.
  • Full disclosure is encouraged, meaning there is no specific limit on extent, numbers of tables/figures etc. Please include primary outcomes data, including tables, graphs and statistics, and secondary outcome data.
  • The discussion should be brief, and should focus on whether the hypothesis (about a target) has been disproven or not.

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