Pharmacovigilance of Medicines for Rare Diseases

Dr. Danica Cvetkovic looks at the issue of pharmacovigilance for orphan or rare diseases.  Many issues associated with the sector are challenged by the small patient population. This article looks at the commonly used strategies for evaluation of post-approval safety and the effectiveness of rare and orphan drugs.

What Is An Orphan or Rare Disease?

From a medicines regulatory point of view, in the USA and the European Union (EU) orphan or rare diseases are defined as those that affect less than 200,000 individuals (prevalence <650/million population) and less than 5/10,000 (500/million) respectively [1]. Most patients suffer from even rarer diseases affecting 1 person in 100,000 or more. Approximately 5,000-8,000 distinct rare diseases affect 6-8% of the EU population i.e. between 27 and 36 million people [2].

Although the regulatory framework for pharmacovigilance does not differentiate orphan drugs, the orphan drugs that have been approved in recent years present major outstanding challenges for pharmacovigilance departments. The pharmacovigilance of orphan drugs presents problems related to the small patient population, and this is further challenged by the fact that many of them are present in the paediatric population [3, 4].

Commonly Used Strategies

In the field of rare diseases, commonly used strategies for evaluation of post-approval safety and effectiveness, such as meta-analyses and review of spontaneous adverse event reports, may not be applicable. Real-world data sources, such as claims databases, electronic healthcare records, and disease and drug registers, show substantial promise in studying orphan drugs [5].

Long term data collection may be needed to better understand the safety profile in children and particularly to detect any long-term or delayed toxicities in the developing child. All elements and procedures of safety monitoring plans for orphan drugs for rare diseases have to be carefully evaluated and based upon information available about the drugs from all sources, including nonclinical toxicology information, and any data from previous human experience for other indications other than that in the rare diseases.

There are possibilities to increase the speed by which data in the post-marketing period can be generated by better use of data from ongoing formal clinical trials, by early planning of drug or disease registries, and networks to facilitate international research, specifically in rare diseases.

Talk To Us

We are working with several companies on pharmacovigilance projects related to orphan drugs.  If you would like to talk to us about your project, please contact us on 00353 52 61 76 706, email:, or complete the form below.

Further Clinical Reading from Acorn Regulatory

Update on EU Commission’s Rare & Orphan Drug Strategy – August 2020

On August 11th, 2020, the European Commission published the results of a multi-year evaluation of orphan and paediatric medicines regulations.  The results referenced in the published document will be used to guide future legislative changes and to shape EU pharmaceutical strategy.  You can read the European Commission’s document here.

Veterinary Clinical Trials: New EU Law & Global Approaches

Clinical studies are intended to advance animal health care by identifying the most effective therapies and practices for a given condition, or by advancing our basic understanding of the disease. Much like a clinical study in the human population, a veterinary clinical study involves research that gains information from animal patients.

Read more here.

Pharmacovigilance & Social Media in 2020

We have been tracking the role of social media in pharmacovigilance in social media since 2015.  We first wrote about it here.  5 years on, we are glad to say that the field has moved on substantially in terms of research into the practical applications of social media in Pharmacovigilance. Regulatory guidance for the industry, however, has yet to be updated.

Read the full article here.

Download Our Clinical Trials E-Book

Acorn Regulatory is a leading regulatory, pharmacovigilance and clinical consultancy company headquartered in Ireland.  Our Clinical & Medical team works with the largest and the leading companies in life sciences to assist them in bringing their products to market.  The team, led by Dr. Danica Cvetkovic, has written extensively on the issue.  In the latest e-book from Acorn Regulatory, we look at the best and most popular articles from our Clinical & Medical team.

Download the e-book here.

A Practical Approach to Risk Management Plans

Writing a risk management plan (RMP) for the first time can be a daunting task. The RMP is a legally binding regulatory document submitted to health authorities and is a mandatory commitment for all Marketing Authorisation Holders in the European Union. The goal of the RMP is to improve the benefit-risk balance of a medicinal product by combining risk assessment and risk minimisation. The RMP is a complex document, but with the revised RMP module (March 2017), comes the revised EU template for RMPs (rev 2 format) and the RMP is now structured in a clear manner with less repetition and with attention to detail.

Read more here.


1.Richter T, Nestler-Parr S, Babela R, et al. Rare disease terminology and definitions. A systematic global review: report of the ISPOR Rare Disease Special Interest Group. Value Health 2015;18:906–14.

  1. European Medicines Agency, Orphan designation. Available at accessed in May 2020
  2. Food and Drug Administration. Draft guidance. Rare Diseases: Common Issues in Drug Development. Guidance for Industry. January 2019. Available at:  accessed in May 2020

  1. Blin O, et al. Orphan drug clinical development. Therapie 2020;75(2):141-7.
  2. Crisafulli S, et al. Role of healthcare databases and registries for surveillance of orphan drugs in the real-world setting: the Italian case study. Expert Opin Drug Saf. 2019;18(6):497-509.