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Let's help the EMA: Open PRAC question about risks associated with radium-223

Researchers
#1

Community:

@Rijnbeek, @jon_duke, @Christian_Reich, @j_vanderlei and others are participating this week in a EMA workshop on Common Data Models (this was subject of a community meeting a couple weeks ago). During yesterday’s session, it was highlighted by Dr. June Raine that there are currently several outstanding safety issues with substantial uncertainty that require better evidence to support regulatory decision-making. One recent example she mentioned was the potential risk of fractures and mortality associated with Radium-223 in patients with prostate cancer. The PRAC announcement is here: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Xofigo/human_referral_prac_000071.jsp&mid=WC0b01ac05805c516f

The questions that Dr. Raine mentioned in her talk:
-clinical characterization (treatment utilization): how many patients are exposed to Radium-223? what are the baseline characteristics of these patients? what proportion of abiraterone users have concomitant radium-223?

-clinical characterization (incidence rate): what is the rate of fractures in patients exposed to Radium-223?

-population-level effect estimation: what is the drug-attributable risk of fractures for radium-223 concomitant with abiraterone vs. abiraterone alone?

Dr. Stephen Evans closed the first day of the EMA workshop but reminding everyone that, while this meeting is about common data models, we mustn’t lose sight of our shared objective, which is to generate evidence that is sufficiently reliable to support regulatory decisions and improve public health. He argued that we also mustn’t let the perfect be the enemy of the good, as an approximate answer quickly is much more powerful than no information at all. He went back to Dr. Raine’s example, saying that if someone can shed light on the use of Radium-223 and it’s potential effects, then that would be an important contribution to the EMA. It sounded to me like a direct call-to-action to the OHDSI community!

To heed that call, I have created the following two cohort definitions:

  1. Help the EMA 1: New users of radium-223: http://www.ohdsi.org/web/atlas/#/cohortdefinition/1662807

This cohort identifies the persons who have a drug record or device record for radium-223. I ran this cohort internally on my data, and found that I have several hundred patients exposed in various US databases, but didn’t have any exposures outside US - I suspect that has to do with the intravenous injection codes outside-of-US and how they may be getting mapped. I used the new ATLAS feature to ‘Generate with features’ on the larger cohorts I produced, and that allowed me to confirm that indeed, >98% of patients on radium-223 have a prior diagnosis of prostate cancer, and also identify that ~35% have prior exposure to abiraterone, including ~15% concomitantly.

  1. Help the EMA 2: New users of abiraterone, with use of Radium-223
    http://www.ohdsi.org/web/atlas/#/cohortdefinition/1662808

This cohort starts with new users of abiraterone who started after May2013 (FDA approval date for radium-223), and then using the attrition feature, identifies the subset of those patients with exposure to Radium-223. To keep this broad initially, I’ve looked for any radium-223 exposure, prior to or after abiraterone exposure. Across 4 US claims databases, I’m seeing about its about 5-8% of new users of abiraterone have exposure to radium-223.

(I also created a cohort, ‘Help the EMA: New fractures’ and provide a template for how you can use the Incidence Rate tool to summarize the rate of fractures in the new users of radium-223 here: http://www.ohdsi.org/web/atlas/#/iranalysis/1662810)

I’d be keen to hear if others in the OHDSI community have access to exposures on Radium-223, and if so, what types of patterns you are observing? If together as a community, we have sufficient data, perhaps we can collaborate on a OHDSI network study to get Dr. Raine, Dr. Evans, the PRAC, and all the patients who are waiting, the reliable evidence they deserve.

#3

@Patrick_Ryan
Xofigo (Radium) was covered by Korean national insurance from 2014.
I just tried to find Radium treatment in Ajou university hospital by using Achilles, but I couldn’t find it.(Until now, we converted hospital data until 2015 and insurance data until 2013). I’ll figure out whether the problem is caused by mapping issue or we just don’t have a patient using Radium treatment.

#4

Thanks @SCYou!! I really appreciate your prompt review.

#5

@Patrick_Ryan:

Radium-223 is a radio-pharmaceutical. They are not drugs by the definition that a drug is a chemical that has a biochemical affect on the organism. Alpha radiation does that only indirectly. However, RxNorm has it listed, against their own rules. So, we probably need to have the vocab team look at how it is treated in the non-US assets.

Got 337 patients in our commercial claims database.

Got 1569 patients with abiraterone, of which 144 (8.41%) are also exposed to the Radium.

#6

@Patrick_Ryan, Until when do you need this data?
We’ll upgrade our ETL and convert hospital data into CDM again next week (including hospital data until now).

#7

I expect our friends at EMA would like whatever information they could get
whenever they could get it. I’m sure they would be delighted to learn more
about what you have captured in the Korea hospital data when you have it
ready.

#8

We imported your cohort definitions in our ATLAS and created the cohorts in our Dutch GP database but could not find patients. This could be because this data is captured in freetext in letters of the specialists. This is something we could investigate further if needed.

#9

@Patrick_Ryan @Rijnbeek
We found that Korean source code for Xofigo (Radium) has not been mapped to RxNorm.
I’ll update mapping table. After next-week (after ETL again), we can see how many patients we have in our institution.

#10

From NYP-Columbia, I got 0 for radium. I will need to check later. For abireratone, I got 43 taking it but of course 0 on radium. George

#11

I found 31 patients since 2013 from radiation therapy administration notes indicating that they received radium 223.

George

#12

Indeed, we’ve treated radium as a device, as well as all other radio-pharmaceuticals. But since RxNorm has it and other vocabularies like HCPCS distinguish between therapeutical and diagnostic radio-pharmaceuticals, we should do the same.
So far: you can find radium in BDPM (concept_id 43236005 and 43236005) and GRR (41647859); Xofigo - BDPM (43251842) under Device domain. Therefore, it still can be found in device_source_concept_id in device_exposure.
Somehow Xofigo even made it into Drug domain in GRR (41763053 and 41785585) with mapping to RxNorm Extension.

BTW, HCPCS release with radium mapped to RxNorm is coming shortly.

#13

Currently the Korean mapping tables are not handled like all the rest of them in Pallas and Athena. Do you want to bring it in, so it’s all done with the same principles to be downloaded from the same place?

#14

@Christian_Reich . Soon, I’ll release the mapping table for measurement (This also can help measurement group of THEMIS). Because I don’t have the ownership of the mapping table, I cannot tell you that it would be released. But I think we’ll go to the way which you said ultimately.

#15

Great.

You mean the drug mapping, right? Who does have the ownership?

t