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European Pharmaceutical Contractor

Observational Studies: Regulatory Considerations

Non-interventional studies provide an effective way of gathering real-world evidence. Following the latest regulatory guidelines indicates the key factors to consider when setting up an NIS.

The progression of evidence requirements from key stakeholders, such as regulatory agencies and payers, has moved in a direction where real-world evidence is becoming central to decision making when used in conjunction with clinical trials. Non-interventional studies (NIS) are a key method in gathering this type of evidence. They are generally naturalistic in nature, can be either prospective or retrospective, and allow for an unbiased view of real-world outcomes. These types of studies are hypothesis-generating as opposed to hypothesis-confirming: as they have limited inclusion/exclusion criteria, there is less control of assessments. NIS studies generally take place in a heterogeneous population of patients and are conducted over a long term. For example, disease registries can be used to look at disease progression over a long period of time or pregnancy registries can be established to follow women who have been exposed to a specific products during pregnancy.

Not surprisingly, like most studies, there are benefits and limitations with NIS. Benefits include: the ability to evaluate large numbers of patients/ consumers; a lower cost than clinical trials; the ability to establish and increase market leadership in a therapeutic area; the ability to heighten disease awareness; and the support of research and scientific inquiry. The limitations of the observational nature of NIS, however, can result in methodological challenges in attributing causality to outcomes selection bias (that is, no randomisation of treatment), enrolment bias, and challenges in conducting global NIS due to different stages of the life cycle in different countries. And finally, NIS can supplement, but not substitute for, randomised clinical trial (RCT) data to support changes to product labelling.

The European Commission Q&A document provides a decision tree to help determine if a study is a clinical trial or a non-interventional trial. The answers to the following questions found in the guidance document must always be ‘yes’ to qualify as an NIS:

  • Is this a study of one or more medicinal products, which has a marketing authorisation in the Member State concerned?
  • Are the products prescribed in the usual manner in accordance with the terms of the authorisation?
  • Does the assignment of any patient involved in the study to a particular therapeutic strategy fall within current clinical practice and is not decided in advance by a clinical trial protocol?
  • Is the decision to prescribe a particular medicinal product clearly separated from the decision to include the patient in the study?
  • Will no diagnostic or monitoring procedures be applied to the patients included in the study, other than those which are applied in the course of current clinical practice? (The issue of diagnostic and monitoring procedures is often a topic of contention and really needs to be discussed with an ethics committee. However, it should be noted that Volume 9A provides clarification that interviews, questionnaires and blood sampling may be considered as normal clinical practice)
  • Will epidemiological methods be used for the analysis of data arising from the study?

Regulations for NIS Studies

The Clinical Trials Directive (2001/20/EC) does not apply to NIS. The purpose for excluding these trials from the scope of Directive 2001/20/EC is that these trials are typically lower risk than interventional clinical trials. Moreover, this restriction ensures that medical activities which are normal clinical practice, and as such part of the general medical surveillance of patients, are excluded from the scope of the directive. Also, according to Section 1 of Chapter 1.7 of the Eudralex Volume 9A, the guidance of Good Clinical Practice does not apply to non-interventional post-authorisation studies. So what regulations do apply?

The overarching guidances that apply are from the World Medical Association Declaration of Helsinki and the ICH Guidance E2E for Pharmacovigilance Planning, but there are also guidances that focus on international, European and countryspecific perspectives. The key guidances frequently referred to in the EU are Regulation EC/726/2004 (as amended) and Directive 2001/83/EC (as amended) concerning medicinal products authorised through the centralised, national, decentralised and mutual recognition procedures. In addition, Pharmacovigilance for Medicinal Products, the EFPIA code of Marketing Practices and the European Data Privacy Act are also relevant guidances. It is important to remember that these regulations are not harmonised in the EU, so it is critical when considering EU-wide studies that all 27 member states are taken into account. Each member state has its own adaptation of the medicinal products act, the data protection act and the EFPIA code, so it is important to keep at least these three regulations in mind.

Eudralex Volume 9A states, “for noninterventional post-authorisation safety studies, the marketing authorisation holder and investigator should follow relevant national legislation in those member states where they exist.” The highest possible standards of professional conduct and confidentiality must always be maintained, and legislation and data protection always followed. The patient’s right to confidentiality is paramount; the their personal identifiers should be replaced by a code in the study documents and only authorised persons should access the identified personal data for data verification procedures. The responsibility of retrieval for information of personal records lies with the healthcare professional responsible for the patient’s care. Such information from medical records should be provided to the marketing authorisation holder who is thereafter responsible for handling this information.

The next set of guidelines that is important is the marketing and advertising code of practice, or the European Federation of Pharmaceutical Industries and Associations (EFPIA) code of conduct which provides guidance for non-interventional studies. According to the EFPIA code, the study needs to be conducted for a scientific purpose, should always follow a protocol, and contracts between the study sponsor and healthcare professional or institution must be written. Any remuneration provided has to be reasonable and reflect fair market value. The study protocol should be submitted for review in those countries where the ethics committees are prepared to review the document. Local data privacy laws, rules and guidelines must be respected. A company’s medical affairs or medical information department must approve the study protocol and supervise the conduct of the study. Companies should also publicly disclose the summary details and results of NIS in a manner consistent with parallel obligations to clinical trials.

The data protection act outlines the core principles of data protection. Information collected must be: fairly and lawfully processed for a specific purpose; adequate, relevant and not excessive; kept only as long as necessary; processed in line with individual rights; and must be secured and not transferred outside the European economic area without adequate protection.

With regards to registering the study on a publicly listed database, many companies publish their studies on; however, there are other options. The UK Clinical Research Network allows the results of NIS to be published on their website. The new European Network of Centres for Pharmacoepidemiology and Pharmacovigilance ENCePP registry, has been developed by the European Medicines Agency (EMA) to allow the registration of post-authorisation safety studies (PASS). With EMA’s new commitment to PASS, this website is an important global resource.

EMA has a commitment to PASS and three main aims for 2015, including meeting public health needs, improving access to medicines, and optimising their safe use. As a coordinating body, it plans to take a more proactive approach to public health threats when medicines are involved. EMA plans to address the high attrition rates during drug development and to improve the evidence base and post-authorisation phase to better regulate decision making and take into account the patient experience. However, there are dilemmas from the regulator’s point of view, and there is a balancing act with regard to early market access of new drugs. An interesting article by Eichler et al demonstrates this well by outlining opposing conundrums (1). Industry requires favourable conditions for innovation of new drugs, but payers/health technology assessment organisations are requesting comparative efficacy and effectiveness data. Patient groups demand early access to drugs, whereas the media and scientific community demand stricter and safer assessments after a series of market withdrawals. There is, of course, the unmet medical need versus overmedication, and also there is a demand for shorter timelines for access to medication. This all confirms that strategic discussions need to be held with key stakeholders early in the process.

Key factors to consider when setting up an NIS include:

  • The new pharmacovigilance regulations and the recent changes in the definition of a past study or a postauthorisation safety study
  • The legal basis of safety and efficacy studies
  • The process required to approve past studies; safety in real-life
  • EMA’s commitment to PASS, including efficacy studies (PAES), retrospective or prospective data collection methods that can be used to quantify safety and risk
  • The design of observational comparative effectiveness studies; natural history of disease registry and disease progression
  • Retrospective chart review studies looking at epidemiology and outcomes research
  • Value dossiers for reimbursement mandates, looking at health economics, cost of care and quality of life impact
  • Assessment of patient-reported and economic outcomes
  • Market access, evidence of value and proof of additional benefit


The regulations and guidelines for non-interventional studies are rapidly changing and are far from being harmonised in Europe. While reasonable efforts have been made to show the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities or ethics committees before starting any non-interventional study in Europe.

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Rohini Chari has worked in the pharmaceutical industry for 10 years with experience in number of multinational CROs. She has submitted clinical trial applications to various competent authorities in countries within Europe as well as the Asia Pacific region. In her role as a Regulatory Affairs professional she has compiled applications for multinational projects for early and late phase clinical trials in the fields of neurology, oncology, respiratory medicine, and various biologicals. Rohini has a PhD in Neuropharmacology from the Royal Melbourne Institute of Technology and a BSc from Monash University.
Rohini Chari
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