An overview of managing safety concerns in the DSURs, RMPs and PBRERs

What are safe­ty concerns?

ICH defines safe­ty con­cern as an impor­tant iden­ti­fied risk, impor­tant poten­tial risk or miss­ing infor­ma­tion (GVP Annex IV, ICH-E2C(R2) Guideline).
An impor­tant iden­ti­fied and poten­tial risk could have an impact on the risk-ben­e­fit bal­ance of the prod­uct or have impli­ca­tions for pub­lic health. What con­sti­tutes an impor­tant risk will depend upon sev­er­al fac­tors, includ­ing the impact on the indi­vid­ual, the seri­ous­ness of the risk and the impact on pub­lic health. Nor­mal­ly, any risk that is like­ly to be includ­ed in the con­traindi­ca­tions or warn­ings and pre­cau­tions sec­tion of the prod­uct infor­ma­tion should be con­sid­ered important.

What con­sti­tutes an iden­ti­fied and poten­tial risk?

An unto­ward occur­rence for which there is ade­quate evi­dence of an asso­ci­a­tion with the med­i­c­i­nal prod­uct of inter­est is an iden­ti­fied risk. Evi­dence may include the following:

  • an adverse reac­tion ade­quate­ly demon­strat­ed in non-clin­i­cal stud­ies and con­firmed by clin­i­cal data,
  • an adverse reac­tion observed in well-designed clin­i­cal tri­als or epi­demi­o­log­i­cal stud­ies for which the mag­ni­tude of the dif­fer­ence, com­pared with the com­para­tor group on a para­me­ter of inter­est sug­gests a causal relationship,
  • an adverse reac­tion sug­gest­ed by a num­ber of well-doc­u­ment­ed spon­ta­neous reports where causal­i­ty is strong­ly sup­port­ed by tem­po­ral rela­tion­ship and bio­log­i­cal plau­si­bil­i­ty, such as ana­phy­lac­tic reac­tions or appli­ca­tion site reactions

An unto­ward occur­rence for which there is some basis for sus­pi­cion of an asso­ci­a­tion with the med­i­c­i­nal prod­uct of inter­est but where this asso­ci­a­tion has not been con­firmed (ICH-E2F Guide­line) con­sti­tutes a poten­tial risk. Evi­dence may include the following:

  • non-clin­i­cal tox­i­co­log­i­cal find­ings that have not been observed or resolved in clin­i­cal studies;
  • adverse events observed in clin­i­cal tri­als or epi­demi­o­log­i­cal stud­ies for which the mag­ni­tude of the dif­fer­ence, com­pared with the com­para­tor group (place­bo or active sub­stance, or unex­posed group), on the para­me­ter of inter­est rais­es a sus­pi­cion of, but is not large enough to sug­gest, a causal relationship;
  • a sig­nal aris­ing from a spon­ta­neous adverse reac­tion report­ing system
  • an event known to be asso­ci­at­ed with oth­er active sub­stances with­in the same class or which could be expect­ed to occur based on the prop­er­ties of the med­i­c­i­nal prod­uct (based on ICH-E2F Guideline)

Gaps in knowl­edge about a med­i­c­i­nal prod­uct, relat­ed to safe­ty or use in par­tic­u­lar patient pop­u­la­tions, which could be clin­i­cal­ly sig­nif­i­cant con­sti­tutes miss­ing information.

How are safe­ty con­cerns pre­sent­ed in phar­ma­covig­i­lance documents?

After the first sub­ject is exposed to the inves­ti­ga­tion­al drug, safe­ty con­cerns are intro­duced in a Devel­op­ment Safe­ty Update report (DSUR). As more sub­jects par­tic­i­pate in clin­i­cal tri­als, safe­ty data is accu­mu­lat­ed. The safe­ty pro­file of the inves­ti­ga­tion­al drug becomes clear­er and the safe­ty con­cerns for the drug may be defined. Thus, dur­ing the drug devel­op­ment and much before the approval of the drug, more knowl­edge on the impor­tant iden­ti­fied and poten­tial risks for the drug may become evi­dent through the annu­al DSURs.

Grad­u­al­ly, for the approval of the drug, a Risk Man­age­ment Plan (RMP) will have to be sub­mit­ted to the reg­u­la­to­ry agen­cies. By this stage, sub­stan­tial knowl­edge about the safe­ty con­cerns is avail­able from the pre-clin­i­cal and clin­i­cal devel­op­ment. In addi­tion to the impor­tant iden­ti­fied and poten­tial risks, the mar­ket­ing autho­riza­tion hold­er (MAH) might also include miss­ing infor­ma­tion backed by a sci­en­tif­ic ratio­nale. These safe­ty con­cerns are like­ly to have an impact on the ben­e­fit-risk bal­ance of the drug.
In addi­tion to defin­ing the safe­ty con­cerns as in the DSUR, an RMP must also include a plan on eval­u­a­tion of safe­ty con­cerns after approval of the drug, includ­ing the min­i­miza­tion mea­sures. RMPs are updat­ed as and when sub­stan­tial infor­ma­tion on the safe­ty con­cerns becomes available.

The safe­ty pro­file of a drug is cement­ed by the post-mar­ket­ing expe­ri­ence through the Peri­od­ic Ben­e­fit-Risk Eval­u­a­tion Report (PBRER). In the PBRER, the MAH eval­u­ates the safe­ty con­cerns in con­text to the ben­e­fit-risk analy­sis. For the drug to stay in the mar­ket, the ben­e­fits should always out-weigh the risks. This analy­sis of safe­ty con­cerns may be peri­od­ic and/or cumulative.

It is impor­tant to ensure that all safe­ty doc­u­ments are con­sis­tent and present sim­i­lar infor­ma­tion about the safe­ty concerns.

When a sig­nal aris­ing from a spon­ta­neous adverse reac­tion report­ing sys­tem indi­cates strong relationship/basis, or when clear evi­dence of a class effect appears, an impor­tant poten­tial risk may be char­ac­ter­ized as an impor­tant iden­ti­fied risk. On the con­trary, when the safe­ty pro­file is well char­ac­ter­ized for the drug and there is no fur­ther impact on the ben­e­fit-risk bal­ance, the risks may even be down­grad­ed and removed from the RMP alto­geth­er. How­ev­er, depend­ing on the report­ing inter­val of the report, the MAH can still retain the risk in the PBRER in the sum­ma­ry of safe­ty con­cerns but pro­pose a ratio­nale to delete the same in the sub­se­quent PBRER in the sec­tion on char­ac­ter­i­za­tion of that respec­tive risk. Thus, a PBRER is a piv­otal doc­u­ment to com­mu­ni­cate the changes in the safe­ty con­cerns of a drug.

Over the years, when there would be no trig­ger to update the RMP, the data pre­sent­ed in the RMP would almost always remain out­dat­ed. The PBRER con­tin­ues to present the peri­od­ic and cumu­la­tive up-to date eval­u­a­tions of the safe­ty con­cerns. An adden­dum to the Clin­i­cal Overview would lat­er com­mu­ni­cate the agreed com­pa­ny posi­tion of the safe­ty pro­file of the drug from the PBRER dur­ing sub­se­quent renew­al submissions.

DSUR = Devel­op­ment safe­ty update report
RMP = Risk Man­age­ment Plan
PBRER = Peri­od­ic Ben­e­fit-Risk Eval­u­a­tion Report

Hav­ing a glob­al sub­mis­sion strat­e­gy for RMPs and PSURs may be advan­ta­geous for MAHs as less resources may be need­ed even­tu­al­ly to man­age con­sis­ten­cy and com­pli­ance to com­mu­ni­cate the safe­ty con­cerns to health agen­cies. As long as there is an on-going patient in a clin­i­cal study, the DSURs are pre­pared and sub­mit­ted to the reg­u­la­to­ry agencies.

ICRC-Wey­er GmbH has exten­sive­ly sup­port­ed sev­er­al sub­mis­sions and chal­leng­ing projects across dif­fer­ent ther­a­peu­tic areas. ICRC-Wey­er GmbH spe­cial­izes in safe­ty doc­u­ments and has expe­ri­enced med­ical writ­ers han­dling dif­fer­ent types of safe­ty doc­u­ments. Reach out to us for more infor­ma­tion at:

Keerthi­ka Gogu­la, Senior Med­ical Writer