Signal prioritisation and serious medical events: reported rate of fatality as a prioritisation variable

F. Maignen15 December 2009

EV-EWG IME list

• Useful but purpose not always clear (early signal detection? Focus the detection? Signal prioritisation?)

• Based on expert’s judgment• Has not been formally “validated” / tested

(no standards)• Probably situation dependant

Concept of seriousness

• Grading in seriousness: death >> disability (permanent) >>> life-threatening >>> disability (temp.) >> prolongation hosp.

• Variable linked to fatal outcome = reported rate of fatality

• For each drug-event pair = No of reported fatal cases / total number of reported cases

• Computed for the intensively monitored products

Reported rate of fatality

• Some reactions may be consistently linked to a high reported mortality rate

• Some reactions are serious but do not lead to a fatal outcome

• Some reactions are situation dependent (the reported rate of fatality may be highly variable)– Mean, min., max., range: max. – min., SD

Methods

• Data from last year intensively monitored products

• Imported in ACCESS, computation of reported rate for each drug-event

• Computation of average, min, max, SD and range for each MedDRA PT

• Analysis in R using the ODBC connectivity

Reported rate of fatality

How does it relate to IMEs?RHS: IMEsLHS: non-IMEs

How does it relate to IMEs?

• Reported rate of fatality for IMEs > non-IMEs

• Number of events for which the reported rate is high which are non-IMEs

• Very high number of IMEs for which the reported rate of fatality is zero.

• IMEs useful for prioritisation?

How does it relate to SIMEs?

The figure displays the distr. of the average reported rate of fatality for non-IMEs (left)compared to IMEs (right) (red and blue line = mean rate for non-IMEs (red) vs IMEs (blue))

Mean / median

• Difference of the mean rate / median between non-IMEs and IMEs but not very important (approx. 10%)

• Confirmation that some non-IMEs are linked to a high reported rate of fatality

• And that some IMEs are associated to a very low rate

How does it relate to IMEs?

The figure displays the distr. of the minimum reported rate of fatality for non-IMEs (left)compared to IMEs (right)

How does it relate to IMEs?

The figure displays the distr. of the maximum reported rate of fatality for non-IMEs (left)compared to IMEs (right)

Min and max.

• Confirm that some non-IMEs have a high minimum rate

• The median of the max. reported rate of fatality is quite low.

• Can IMEs discriminate between serious / non-serious signals?

Range: Max. – Min.

The figure displays the distr. of the range (max. – min.) reported rate of fatality for non-IMEs (left)compared to IMEs (right)

Relation between the different variables?

Lattice of the descriptive variables for the reported rate of fatality

Relations between variables

• No apparent relation• Confirms that a significant number of

events are associated with a very low rate (zero)

• Some events are associated with a very high rate

• No clear relation (from the lattice)

Grading of the severity of reactions? Hepatic reactions ranked by Avg (mild)

PT SME Average Min Max SD Range

Hepatitis toxic -1 0.06 0 0.142857142857143

6.08702806292663E-02

0.142857142857143

Hepatitis -1 0.055 0 0.333333333333333

8.51155316743531E-02

0.333333333333333

Gamma-glutamyltransferase increased

0 0.053 0 0.75 0.1046362136683 0.75

Hepatic enzyme increased -1 0.037 0 0.134831460674157

0.045862805331455

0.134831460674157

Cytolytic hepatitis -1 0.032 0 0.222222222222222

0.051937909442713

0.222222222222222

Hepatitis acute -1 0.017 0 7.69230769230769E-02

3.17977540864653E-02

7.69230769230769E-02

Biopsy liver abnormal 0 0 0 0 0 0

Haemangioma of liver -1 0 0 0 0 0

Hepatic enzyme abnormal 0 0 0 0 0 0

Hepatocellular injury -1 0 0 0 0 0

Hyperbilirubinaemia neonatal -1 0 0 0 0

Hepatic pain 0 0 0 0 0 0

Hepatitis B DNA increased 0 0 0 0 0

Hepatic displacement 0 0 0 0 0

Grading of the severity of reactions? Hepatic reactions (severe)

PT SME Average Mon Max SD Range

Liver transplant 0 0.146 0 0.545454545454545

0.193380460774507 0.545454545454545

Hepatic fibrosis -1 0.13 0 0.25 0.106671401410068 0.25

Liver injury -1 0.125 0 0.5 0.209165006633519 0.5

Hepatic necrosis -1 0.107 0 0.222222222222222

8.04169243768715E-02

0.222222222222222

Hepatic steatosis -1 0.095 0 0.333333333333333

0.102385019533591 0.333333333333333

Liver function test abnormal -1 0.091 0 0.8 0.114251756138268 0.8

Hepatic function abnormal -1 0.085 0 0.258064516129032

6.28347319601348E-02

0.258064516129032

Hepatic cyst -1 0.074 0 0.25 8.43965101118951E-02

0.25

Blood bilirubin unconjugated increased

0 0.067 0 0.2 0.115470053837925 0.2

Hepatotoxicity -1 0.065 0 0.333333333333333

7.56695844471282E-02

0.333333333333333

Alanine aminotransferase increased 0 0.0647 0 0.25 6.21239207887621E-02

0.25

Bilirubin conjugated increased 0 0.0626 0 0.25 8.84174221327833E-02

0.25

Hepatitis viral -1 0.0625 0 0.25 0.125 0.25

Aspartate aminotransferase increased

0 0.062 0 0.375 6.50949239649052E-02

0.375

Grading of the severity of reactions? Hepatic reactions (high reported mortality)

PT SME Average Min Max SD Range

Hepatic haemorrhage -1 0.33 0.333333333333333 0.333333333333333 0

Hepatitis C RNA positive 0 0.33 0.333333333333333 0.333333333333333 0

Cytomegalovirus hepatitis -1 0.328 0.25 0.416666666666667 5.73958290801377E-02 0.166666666666667

Hepatitis C -1 0.301 0.2 0.35 0.046725479075312 0.15

Hepatitis cholestatic -1 0.288 0 0.5 0.196517954829488 0.5

Hepatosplenomegaly -1 0.266 0.2 0.333333333333333 9.42809041582064E-02 0.133333333333333

Liver transplant rejection -1 0.257 0.166666666666667 0.333333333333333 6.22824202822112E-02 0.166666666666667

Autoimmune hepatitis -1 0.254 0 0.6 0.215915745393141 0.6

Ischaemic hepatitis -1 0.25 0.25 0.25 0

Hepatic encephalopathy -1 0.248 0 0.75 0.228080784714652 0.75

Hepatomegaly -1 0.240 0.157894736842105 0.5 0.093057582329235 0.342105263157895

Liver disorder -1 0.189 0 0.62962962962963 0.228267036935107 0.62962962962963

Hyperbilirubinaemia 0 0.187 0 0.75 0.236614554462323 0.75

Blood bilirubin increased 0 0.162 0 1 0.152288707976078 1

Cancers (low rate)PT_new SME AvgFatal MinFatal MaxFatal StDevFatal MaxMinusMinFatal

Thyroid cancer 1 0 0 0 0 0

Adenosquamous carcinoma of the cervix 1 0 0 0 0 0

Testis cancer 1 0 0 0 0 0

Breast cancer in situ 1 0 0 0 0

Breast cancer stage I 1 0 0 0 0 0

Breast cancer stage II 1 0 0 0 0 0

Salivary gland cancer 1 0 0 0 0

Cervix carcinoma stage 0 1 0 0 0 0 0

Metastases to peritoneum 1 0 0 0 0

Mucoepidermoid carcinoma 1 0 0 0 0 0

Lip and/or oral cavity cancer 1 0 0 0 0 0

Recurrent cancer 1 0 0 0 0 0

Lung squamous cell carcinoma stage unspecified 1 0 0 0 0 0

Rectal cancer 1 0 0 0 0

Carcinoma in situ 1 0 0 0 0 0

Cancer (highest rates)PT SME Average Min Max SD Range

Rectal cancer recurrent 1 1 1 1 0

Oesophageal carcinoma 1 1 1 1 0 0

Lymphangiosis carcinomatosa 1 1 1 1 0 0

Gastric cancer 1 1 1 1 0 0

Colorectal cancer 1 1 1 1 0

Lung cancer metastatic 1 0.990610328638498

0.985915492957747

1 8.13169393224786E-03

1.40845070422535E-02

Prostate cancer metastatic 1 0.874369636211742

0.833333333333333

1 6.24720744883884E-02

0.166666666666667

Metastases to bone marrow 1 0.8 0.8 0.8 1.53898531047798E-08

0

Leiomyosarcoma 1 0.733333333333333

0.666666666666667

0.8 9.42809041582055E-02

0.133333333333333

Non-small cell lung cancer 1 0.722444800569801

0.461538461538462

1 0.266745732595527 0.538461538461538

Breast cancer metastatic 1 0.679331245932365

0.58 1 0.125781468817772 0.42

Metastases to meninges 1 0.678571428571429

0.428571428571429

0.75 0.133630620956212 0.321428571428571

Metastases to pleura 1 0.666666666666667

0.666666666666667

0.666666666666667

0 0

Small cell lung cancer stage unspecified

1 0.666666666666667

0.666666666666667

0.666666666666667

0

Liver injuries / cancers

• Reported rate # seriousness of injury• Some iconsistencies (bilirubin or skin

cancers)• Unclear concepts (liver disorders) linked to

a fairly high reported rate

Data reduction (PCA)

• Principal components analysis• Performed on Average, Min, Max, Range• 99% of variability explained by first two

PCs +++• First two PC closely associated to Max

and Average

PCA

Biplot

1st Principal component / Max.

Sum 1+2 PC / Avg

Discussion

• Reported rate of fatality can be useful for signal prioritisation

• Needs to be considered with caution (events with rate of zero include e.g. Torsade de pointes, autism, Breast cancer in situ, Breast cancer stage I, Dermatitis exfoliative)

• Death is not the only criterion which could be used

• EudraVigilance = only serious reactions

Conclusion

• Reported rate of fatality could be useful for signal prioritisation but not the only variable

• Some events are consistently associated either with low rate or conversely with very high rate

• Other events = depend on the context