On September 16th, The Department of Health and Human Services (HHS) released a final regulation about clinical trials submitted to the FDA, and the National Institute of Health (NIH)issued a new policy regarding the same subject. These are the basics:
The HHS regulation, also called the "Final Rule", states that a responsible party, such as a pharmaceutical company submitting a phase 2, 3, or 4 clinical trial for review by the FDA, with the purpose of getting a new drug approved, or a new indication for an existing drug, must register the trial at clinicaltrials.gov within 21 days of enrolling the first participant. Registration involves providing, "1) descriptive information, 2) recruitment information, 3) location and contact information, and 4) administrative information."
In addition, "The Final Rule requires a responsible party to submit summary results information to ClinicalTrials.gov for any applicable clinical trial that is required to be registered, regardless of whether the drug, biological, or device products under study have been approved, licensed, or cleared for marketing by the FDA."
The, "...results information must be submitted no later than one year after...the date that the final subject was examined or received an intervention for the purpose of collecting the data for the primary outcome measure. Results information submission may be delayed for as long as two additional years...," for a few complicated reasons we won't get into here.
Results need to include, "1) participant flow information, 2) demographics and baseline characteristics of the enrolled participants, 3) primary and secondary outcomes, including results of any scientifically appropriate statistical tests, and 4) adverse events."
Importantly, "The Final Rule also adds a requirement to submit the clinical trial protocol and statistical analysis plan at the time of results information submission."
Information needs to be updated on clinicaltrials.gov at least once a year. And any errors, deficiencies, or inconsistencies that the NIH (which runs clinicaltrials.gov) identifies need to be addressed by the responsible party.
That's the HHS final rule. Trials need to be registered on clinicaltrials.gov, information needs to be kept relatively current, and results have to be posted.
The NIH policy broadens the scope of which trials they consider subject to these requirements.
These are good things for trial transparency and honesty. We'll get to the catches in a bit.
Let me backtrack and try to explain why I'm writing about this. Currently, pharmaceutical companies submit drug trials to the FDA, to get approval. They're supposed to register these trials on clincialtrials.gov, but they often don't, it's not policed, and the data they do submit isn't checked. Note that clincialtrials.gov is run by the NIH, not the FDA, so there's a built in disconnect right from the start.
While a study is being reviewed by the FDA, the pharmaceutical company can publish anything they want about that study in peer reviewed journals. They can do this even if the drug ends up not being approved. They often mis-report data and results. And there is no way of knowing if they are staying true to their original study protocol, or if they're messing around with the stats in ways that benefit them. The journals have no way of knowing what's true and what isn't. The whole "peer review" part is also a sham, because the "peers" are given whatever information the pharmaceutical company feels like giving them.
And the FDA does nothing to prevent any of this from happening.
This is not me being paranoid. Here's an article that describes a disturbing example:
The citalopram CIT-MD-18 pediatric
depression trial: Deconstruction of medical
ghostwriting, data mischaracterisation and
academic malfeasance
Jureidini, et al.
Abstract.
OBJECTIVE: Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.
METHODS: Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-(NMG) were deconstructed.
RESULTS: The published article contained efficacy and safety data inconsistent with the protocol criteria. Procedural deviations went unreported imparting statistical significance to the primary outcome, and an implausible effect size was claimed; positive post hoc measures were introduced and negative secondary outcomes were not reported; and adverse events were misleadingly analysed. Manuscript drafts were prepared by company employees and outside ghostwriters with academic
researchers solicited as ‘authors’.
CONCLUSION: Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram wassafe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.
International Journal of Risk & Safety in Medicine 28 (2016) 33–43
DOI 10.3233/JRS-160671
And this is the abstract from the original article, for comparison:
A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents.
Wagner KD1, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.
Abstract
OBJECTIVE:
Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression.
METHOD:
An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children (ages 7-11) and adolescents (ages 12-17) with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients (N=174) were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children's Depression Rating Scale-Revised; the response criterion was defined as a score of < or =28.
RESULTS:
The overall mean citalopram dose was approximately 24 mg/day. Mean Children's Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study (effect size=2.9). The difference in response rate at week 8 between placebo (24%) and citalopram (36%) also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively). Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.
CONCLUSIONS:
In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.
Am J Psych. 2004;161(6):1079-83
In the end, the FDA did not approve citalopram for use in children. But the study has been cited over 160 times, putting it in the top 5% of cited articles in medicine from 2004. Between 2005 and 2010, nearly 160,000 children under age 12 received escitalopram, despite the FDA's lack of approval. (There was a switch at some point from off-patent citalopram to on-patent escitalopram, in this time period.) It's hard not to conclude that the published study had impact on prescribing practices.
There's a much fuller description of this here, by Bernard Carroll. And a lot more about this whole topic on 1BoringOldMan.com.
Getting back to the Final Rule, there are some problematic loopholes. There are allowances for delays in reporting. There is also the crazy idea that the study protocol doesn't have to be reported until the results are submitted. This leaves room for dinking around with the protocol, changing outcome measures after the trial has started, etc.
Here's what you can do. Take a look at this petition, and if you're on board, sign it. It's entitled, "Stop False Reporting of Drug Benefits & Harms by Making FDA & NIH Work Together". The main point is this:
We now petition Congress to require the FDA and NIH to coordinate their monitoring and sharing of key information through ClinicalTrials.gov. Working together, the two agencies could enable stakeholders to verify whether purported scientific claims are faithful to the a priori protocols and plans of analysis originally registered with the FDA. Publication of analyses for which such fidelity cannot be verified shall be prohibited unless the deviations are positively identified (as in openly declared unplanned, secondary analyses). This prohibition shall include scientific claims for on-label or off-label uses made in medical journals, archival conference abstracts, continuing education materials, brochures distributed by sales representatives, direct-to-consumer advertising, and press releases issued by companies or their academic partners. It shall extend to FDA Phase 2, Phase 3, and Phase 4 clinical trials. By acting on this petition, Congress will create a mechanism for stakeholders independently to verify whether inferences about clinical use suggested by the unregulated corporate statistical analyses can be trusted.
Please think about it. Thanks.
