Periodic Safety Update ReportsBy

Prof. Satish Sharma, Dean, School of Pharmacy

Introduction

• A ‘Periodic Safety Update Report’ (PSUR) is intended to provide an updateof the worldwide safety experience of a medicinal product to competentdrug regulatory authorities at defined time points post authorization.

• Marketing authorization holders (MAHs) are expected to provide a precisesummary information together with a critical evaluation of the risk-benefitbalance of the product in the light of new or changing information

• In India, it is the responsibility of pharmaceutical companies holding themarketing license

• MAHs should safeguard adequate pharmacovigilance obligation in thesystem to ensure the responsibility and liability of their marketed product.

Introduction

• Specifications of schedule Y of the Drugs and Cosmetics Rules 1945suggest the legislative requirement of pharmacovigilance in India.

• Reviewed and amended version of schedule Y dated 20th January2005 indicates the endless commitment of DCGI to ensure thatpharmaceutical companies are adequately complying with thepharmacovigilance obligations.

• The section under schedule Y entitled Post Marketing Surveillance(PMS) comprises of all the details related to PSURs submission,PSUR Cycle, PSUR templates and their timeline and condition ofreporting

Time line

• As mentioned under schedule Y for all new products, PSURs shouldbe submitted for the initial 2 years every 6 months and annually fornext two years thereafter

• In India many companies are not taking it seriously to report thePSURs in respective time frames.

• On 28th August 2012 an order from DCG(I) office has been passedto all the MAHs of newer drugs that they must adhere to the systemand report the PSURs as indicated in Schedule Y.

• Companies have been given additional 3 weeks period to submitprevious PSURs reports

PSUR in USA

• USFDA issued new guideline entitled providingpost-marketperiodic safety reports in the ICH E2C (R2) format: PeriodicBenefit-Risk Evaluation Report (PBRER)

• However, MAHs may seek waiver of PBRER and submit thePSUR in earlier format

• PBRER is in consistent with latest ICH requirements

• Reports are to be submitted quarterly for the first three yearsand annually thereafter

Need of PSUR

• In India around 294 Fixed Dose Combinations are in the market withoutconducting a local trial or without appropriate regulatory permissions

• In 2007 CDSCO called on state drug controllers to withdraw them frommarket but the manufacturers stayed the order in the madras high courtand the drugs were never withdrawn

• On 15th Jan 2013, CDSCO has given 18 months period to test drugs notapproved by India’s CDSCO for their efficacy and safety, to Indian drugmanufacturers otherwise they will be pulled from market

• Although, a serious matter which is related directly to patients is gettingdelayed and manufacturers are playing with life of patients and we don’thave stringent law in place to handle the situation.

• Over the past few years, a number of drugs have been withdrawnworldwide based on the post marketing surveillance data

Need of PSUR

• It is estimated that one third of the medicinal products werewithdrawn within two years of launch and half within five years

• The clinical trials in limited number of patients and in controlledcondition cannot detect all possible ADRs

• Many new ADRs are detected when drugs are used in realworld

Need of PSUR

• The above facts substantiate the need for such a surveillance system.

• PSURs submitted under post marketing surveillance of newly launcheddrugs have been whistleblowers towards the safety issues of drugs sold inthe market. For instance, in September, 2004 after studies showed thatVioxx (rofecoxib) increases the risk of myocardial infarction and stroke;Merck withdrew its anti-arthritis blockbuster drug.

• Due to safety concerns in the past few years, series of drugs have beenwithdrawn from market including some of blockbuster drugs e.g. lipid-lowering drug Lipobay (Baycol; cerivastatin), the anti-obesity drugsfenfluramine and dexfenfluramine, cisapride etc

• The latest data from the Indian drug regulatory authority CDSCO websiteindicates that around 90 drugs or their combinations were withdrawn fromthe market because of their low safety profile

PSUR and PBRER

PSUR PBRER

In November 1996, the ICH endorsed the ICH E2C Periodic Safety Update Report Guideline (ICH E2C(R1) guideline), which established the PSUR as a harmonized format for postmarketing periodic safety reports for approved drugs and biologic products, and described the format, content, and timing of PSUR submissions. FDA adopted that guideline and, in May 1997, published it as FDA guidance for industry E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs.5

On April 11, 2012, FDA announced the availability of a draft guidance for industry entitled E2C (R2) Periodic Benefit-Risk Evaluation Report,7 which reflected revisions by ICH and described the format, content, and timing of the updated version, the PBRER, as presented in the ICH EC2(R2)8 step 2 guideline.9 ICH subsequently endorsed a final version of that guideline on November 15, 2012, and published the ICH guideline Periodic Benefit-Risk Evaluation Report (PBRER) E2C(R2)10 (ICH E2C(R2) step 4 guideline).

Establishment of PSUR system in a hospital

• To provide necessary information and training to all health care professionals(Physicians, Nurses and Pharmacists etc.) on how to identify and reportsuspicious adverse drug reaction

• Preparation of drug information leaflets and circulation of drug information leaflets& ADR reporting form for the newer drug recommended by DCGI at each nursingstation of wards

• Identification and enrolment of the patients who are on the drugs recommendedby DCGI to follow. Either by accessing online drug dispensing database availableat chief pharmacist office or manual checks in the files of patients.

• Verbal/telephonic instructions to the respective department where these drugsare dispensed to keep these patients under observation and if any suspectedADR is found, then it should be reported through an ADR reporting form asmentioned or instructed.

Establishment of PSUR system in a hospital

• Reporting of ADRs through healthcare professionals on particulardrugs by using any suitable method.

• To take expert advice from safety review panel if any serious safetyissue is associated with the ADR.

• Collection of the data from each ward, nursing/pharmacy stationsand feeding of the relevant ADR data in the Case Record Form(CRF).

• Review and analysis of the reported ADRs in each month’s interval.

• Reporting of this processed Adverse Events (AEs) as a PSURperiodically to the DCGI, New Delhi, India.

Basic structure of a PSUR format

• Executive summary

• Introduction or scope of the report

• Worldwide marketing authorization status

• Action taken for safety reason

• Changes to core safety information

• Patient exposure data

• Individual case histories

Basic structure of a PSUR format

• Information from formal studies

• Overall safety evaluation

• Important information received after the data lock period

• Core safety information