Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 52

Aggregate reports are descriptions, or compilations and analyses, of a group of patients exposed to a drug (or sometimes more than one drug, e.g., combination products) and the AEs and other safety issues such as medication errors or quality problems. There are multiple standard formats, of which the Periodic Safety Update Reports (PSUR) is the main one. The US aggregate reports are called, sometimes confusingly, NDA Periodic Reports, Periodic Reports, and PADERs (Periodic Adverse Drug Experience Reports). To worsen the situation, PADERs is also occasionally used to refer to PSURs. And the FDA also accepts PSURs. Whatever they are called, companies are obliged to prepare them in a serious and careful manner and to submit them on time to concerned health authorities.

There are multiple biases and limitations involved in the quantitative analyses of spontaneous reported data that can result in case information and trends that do not truly represent the real safety profile of the drug. Two phenomena that act on spontaneously reported data are worth examining: (1) the Weber effect and (2) Secular effects, described below.

(1) Weber Effect: The Weber effect, also called the product life cycle effect, describes the phenomenon of increased voluntary reporting after the initial launch of a new drug. “Voluntary reporting of adverse events for a new drug within an established drug class does not proceed at a uniform rate and may be much higher in the first year or two of the drug’s introduction”.²

This means that for the period of time after launch (from 6 months to as long as 2 years), there will be a large number of spontaneously reported AEs/adverse drug reactions (ADRs) that taper down to steady-state levels after this effect is over. It is to be distinguished from secular effects. The Weber Effect has been seen in multiple other situations since the original report.³

However, newer information has thrown this phenomenon into question. A study published in 2014 looked at 62 drugs’ ADRs in FDA’s FAERS database. The reporting pattern for each was looked at over the 4 years after its FDA approval date. The results showed: “the general AE reporting pattern observed in this study appears to consist simply of increasing case counts over the first three quarters after approval followed by relatively constant counts thereafter.” Thus, there was not a spurt at the beginning followed by a drop. Rather, it was a rising volume over the first 4 years of reports. A few drugs did seem to show a Weber effect.

The authors conclude: “Our results suggest that most of the modern adverse event reporting into FAERS does not follow the pattern described by Weber. Factors that may have contributed to this finding include large increases in the volume of AE reports since the Weber effect was described, as well as a concerted effort by the FDA to increase awareness regarding the utility of post-marketing AE reporting.”⁴

Another study published in 2017 looked at 15 oncology drugs over 5 years after approval and also did not find evidence of the Weber effect here.⁵

In addition, safety data sourced from customer engagement programs, e.g., patient support programs, and disease management programs, etc., may have blunted the original effect.

So, to conclude, the Weber effect may now be less of a factor in pharmacovigilance than before, but is worth accounting for it’s potential effect when using spontaneous reported data in quantitative or numerical analyses.

(2): Secular effects are much less well documented in the literature. This refers to the use of media awareness, celebrity endorsements or critical comments or some other external event or media comment on a drug.

Drug safety officers live in dread of reports of celebrities or politicians using a particular product, especially if an AE is reported or if spectacular efficacy or harm is anecdotally reported. This phenomenon is also called temporal bias and reflects an increase in AE reporting for a drug or class of drugs after increased media attention or rumor, use of a medication by a celebrity, a warning from a health agency, social media comments, and so on. There are many multipliers of this effect, particularly if the event is widely reported or goes “viral” on social media. “Overall adverse drug reaction reporting rates can be increased several times by external factors such as a change in a reporting system or an increased level of publicity attending a given drug or adverse reaction”.⁶

The best known example of this is complicated and involves the still on-going (by some) discussion of vaccines increasing the risk for autism. Ultimately, it was concluded by the US CDC and others that there was no evidence to suggest a link between vaccines (in particular those containing thimerosal as preservative) and the risk of autism.

Wakefield and 10 of the original 12 authors retracted the interpretation of the original data. According to the retraction, “no causal link was established between MMR vaccine and autism as the data were insufficient”. Also, Wakefield did not disclose certain financial conflicts, i.e., he was funded by lawyers suing vaccine companies.⁷ The medical and media reports and comments on this are extensive. A good place to start is the comment by the CDC “Vaccines Do Not Cause Autism” (https://www.cdc.gov/vaccinesafety/concerns/autism.html).