Introduction
The practice of pharmacovigilance revolves around patient safety by improving the benefit-risk balance of a pharmaceutical product. This is done by alleviating the extent of the adverse reaction associated with it or by enhancing its benefit. Routine minimization measures such as specific dosing regimens, warnings & precautions communication through labeling , patient follow-ups, relevant testing etc tackle safety concerns that are associated with a pharmaceutical product. However, for certain important risks additional Risk Minimization Measures (aRMMs) may be required based on the frequency, seriousness, severity, effect of the risk on public health, and the preventability of the risk [1].
Additional Risk Minimization Measures
For medicinal products for which the Benefit-Risk ratio is smaller, risks posed by the product are potentially serious and routine RMMs are considered to be insufficient, additional RMMs are required for the safe and effective use of a medicine.
These include:
- Educational material i.e., Dear Dr. Letters, HCP brochures, Patient brochures, etc.
- HCP Counselling for pregnancy & contraception awareness
- Pregnancy programs i.e., pregnancy registration, detection, outcome, and follow up
- Controlled access programs, and
- other measures such as controlled distribution systems, direct healthcare professionals communication
These aRMMs are usually developed by qualified experts & professionals.
Pregnancy Prevention Program
Isotretinoin was licensed in the United States as a category X medication in 1982 which was associated with various fetal abnormalities [2]. The medicine was licensed in the European Union in 1984 along with a PPP that was implemented in 1988 [3]. It included guidance documents for physicians, patient information & contraception brochures, patient consent forms, and a checklist for prescribing the product to female patients. The PPP was updated to additionally include guidance documents for pharmacists and more informative education material for patients after the isotretinoin generic product entered the market in 2003. However, in-spite of the PPP being implemented in the EU, pregnancies were still reported in patients that were taking isotretinoin [4, 5] which led to the need for more efficacious PPPs.
These include:
- Use of Product labels i.e., SPC & PIL
- Risk information on packs
- HCP Counselling for pregnancy & contraception awareness
- Pregnancy programs i.e., pregnancy registration, detection, outcome, and follow up
In March 2022, the European Medicines Agency published a draft guidance on GVP guidelines for PPP that highlights the criteria for a PPP and risk minimization measures that constitute a PPP [6]. Indeed, the most recent scientific evidence for teratogenicity should form the basis of conducting a PPP.
The program integrates interventions with various tools that inform healthcare professionals and patients about any teratogenic risks associated with the product, ways to minimize the risks, ensure pregnancy tests are carried out before prescribing a product, limiting the prescription time period to a maximum of 30 days, and providing counseling in case of accidental pregnancy.
Implementation
Traditionally these aRMMs have been used in form of physical form or as email packs. However, over the last years, technology-based innovations have led to advances in risk minimization. Systems and web-based tools have gained traction for aRMMs that were once paper-based.
In order to successfully implement aRMMs contribution from all stakeholders such as MAHs, healthcare professionals, and patients is imperative. As per the Good Pharmacovigilance Practice (GVP) Module XVI guidelines, the following must be addressed in the risk minimization plan (RMP) with respect to aRMMs:
- Rationale
- Objectives & description of how the aRMM addresses the safety issue
- Description of the aRMM as well as tools that will be used
- Proposal for implementing the aRMM
- Plan for evaluating how effective the aRMM was with respect to the health outcome
Additional Risk Minimization support with DDReg
ICSR processing & reporting, medical & safety writing, and aggregate reports are some of the key components of the drug safety and pharmacovigilance portfolio at DDReg. As part of its risk management capabilities, the safety team evaluates product risks and developing & managing risk management plans (RMPs). Additionally, the team has experience in creating and implementing aRMMs including PPPs, product labels (SPCs & PLs), educational material, HCP counseling and more in accordance with competent authorities. Having worked & gained rich experience in drug safety & risk management, DDReg has automated its processes for Risk minimization with use of latest technology. DDReg now has capability of developing customized tech based aRMM programme.
References and Further Reading
[1] European Medicines Agency. Guideline on Good Pharmacovigilance Practices (GVP) Module XVI-Risk minimization measures: selection of tools and effectiveness indicators. 2012
[2] FDA. Labelling and prescription drug advertising: content and format for labelling for human prescription drugs. Fed Regist 1979; 44: 37434-67
[3] Abroms L, Maibach E, Lyon-Daniel K, et al. What is the best approach to reducing birth defects associated with isotretinoin? Plos Med 2006 Nov; 3: 1978-83
[4] Autret-Leca E, Kreft-Jais C, Elefant E, et al. Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France. Drug Saf 2010; 33: 659-65
[5] Schaefer C, Meister R, Weber-Schoendorfer C. Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. Arch Gynecol Obstet 2010; 281: 221-7
[6] European Medicines Agency. Guideline on Good Pharmacovigilance Practices (GVP) Module AVI Addendum III- Pregnancy prevention programme and other pregnancy-specific risk minimization measures. 2022