When does Bad Pharma Become Good Pharma Publishing phase I studies

Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson MO.
Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis. Clin Pharmacokinet. 2017. doi: 10.1007/s40262-017-0516-6. [Epub ahead of print]

PURPOSE:The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.
METHODS:This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.
RESULTS:The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance.
CONCLUSIONS:Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135.

We have been complaining about Eli Lilly not releasing their data from a trial (please sign our petition).


But in reality Merck does not smell of roses. 

Furthermore, I have to say to ProfG....."Kettle and Black" Spring to mind too.


The CLARITY trial of oral cladribine was published in 2010 meaning the trial finished in about 2009 and only now data is beginning to surface.

The extension study of CLARITY was completed many years ago and abstrasts presented but where is the data? 

You may say that is not as bad as not reporting a trial at all...where's the Charcot Project? :-)
Anyway back to the bad boys and in his study we are not talking about hiding data for 6-7 years, we are more likely talking ten or more years.

The trials reported in this study are unlikely to be only NCT00213135, as that is a phase CLARITY phase III. This study also reports on the Phase I study and therefore likely have to been completed well before 2005 before CLARITY started.
However, because the marketing machinery is beginning to turn as Merck hope that the regulators see favourably on their new application to get oral cladribine licenced we are seeing old data surface. 

Only about 40% of oral cladribine reaches the blood, if you use generic subcutaneous caldribine 100% reaches the blood. This study reports what happens to cladribine, after it is injected

In the three-compartmental modeling, three compartments describe the fate of a drug once administered: the central compartment, which represents the plasma; the highly perfused compartment, which represents the organs and tissues highly perfused by the blood; and the scarcely perfused compartment, which represents the organs and tissues scarcely perfused by blood (e.g.bone or fat).

However, this does make a point about how you all publish trials? 

Phase I trials are safety studies and they are dull as dishwater if all goes well and are boring as boring can be. 

Yes, this is important safety data that people should be aware of but generally there is an investigators brochure, given to clinical people within the trial so they can see that would carry this information. 

But should this be published within a year of completion as suggested by Ben Goldarce.

Companies wait until it is to their advantage (e.g. for marketing purposes) or until they are no longer interested beforwe they publish...However, if the data show worsening perhaps that should be criminal bnot to report it instantly, as it is negligent. 

Do we publish all trials within one year... No in fact 

Hands up M'Lud...guilty as charged, we have yet to publish our phase I trial and it has been over a year...It is on its way, but it is so boring I have put it all in supplementary data.