Laws, Regulations, Guidances, Guidelines and Best Practices

Aug 22, 2017
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert


There is a fair amount of confusion in regard to the different drug safety (DS) and pharmacovigilance (PV) requirements in different regions of the world. This has produced issues for companies, especially those not in either the US or Europe, on what is and is not obligatory and what are “best practices.”

The focus here will be on the US and the European Union.


In most countries in the world there are legal requirements (obligations) on reporting most serious AEs (SAEs) and some non-serious AEs (NSAEs) from both clinical trials and post-marketing situations to the health authority. Similarly there are, in most countries, requirements for periodic aggregate reporting of summaries of SAEs, some NSAEs and some sort of analysis of the safety of the product.

At the most basic level, some legal requirements are broad and give little detail beyond requiring a company, sponsor, MA or IND or NDA or ANDA holder, etc. to submit individual case safety reports and aggregate reports. Some countries have very specific requirements on how the submitting company is to handle this. There is some harmonization in both clinical trial and post-marketing requirements; however, there are many differences from country to country and region to region even though the International Conference on Harmonisation has tried to harmonize requirements since 1989. Note that there is not even agreement in the English language on the spelling of the word harmonization (US) and harmonisation (UK).  If anything, there is a divergence away from harmonization now as more and more countries set up systems for DS and PV with their own local twists.

It is the obligation of the company to search out the requirements (as well as best practices) in every country and market where their products are marketed or studied. It may even be necessary to acquaint oneself with the requirements where the company uses a local licensing partner to market or study the drug as these may impact the company indirectly.


The United States

In the US, DS and PV are governed by laws, regulations and guidances.


A law is a written statute, requirement, ordinance, etc. passed by a legislature and signed into law by the executive (where required) at federal, state & local levels.

In the US, a federal law is passed by both houses (The Senate and The House of Representatives) of Congress and signed by the President. Investigational drugs (“New Drugs”) are primarily governed by Section 505(i) [21 U.S.C. 355] and marketed drugs by Section 505(k) of the Food Drug and Cosmetic Act. These laws are sometimes very detailed and sometimes only high level.


Many laws then charge other US government agencies to create and issue regulations which have the force of law (“regulatory law”). In the case of DS & PV, this duty falls upon the FDA. These regulations do not have to be approved by the Congress or signed by the President. A proposed new or amended regulation is published in the Federal Register and a time period is usually defined for the public to comment. After review, the final regulation is published by the FDA in the Federal Register and in the Code of Federal Regulations. The time period for review may be very long.  Sometimes a proposed regulation is withdrawn or never put into effect.


The FDA also is empowered to issue other documents which do not have the force of law and are not obligatory. The main document in this situation is the “Guidance”.  This represents FDA’s current thinking on the issue in question. It is not a law and is not obligatory. As the FDA states on the first page of every guidance:


Guidances may be issued as drafts for comment or directly as final guidances. FDA has no obligation to finalize a draft guidance and it may simply be left as a draft.

It is generally felt in the industry that following FDA guidances is a wise course of action.  However, a company is not obliged to follow a guidance and will not be cited in an FDA inspection as failing to follow a guidance. For example, the concept of Clinical Trial Data Monitoring Committees (DMCs) was issued as a guidance in March 2006 with an expiration date which has continually been extended and is now due to expire December 31, 2018. So DMCs are not obligations. In practice DMCs are very well accepted and their use is widespread. However, technically, they are not obligatory.

FDA may issue other documents such as FAQs (frequently asked questions), white papers, comments and presentations from the Commissioner or other senior FDA officials. These documents may give opinions on FDA’s thinking and thus are not obligatory unless they clearly reference laws or regulations. Careful attention must be paid.


The European Union

The EU is different and more complex compared to the US. The EU is 28 countries (Member States-MSs), soon to be 27 with the UK Brexit.  Some of the laws in the EU also apply to other countries in Europe, such as those in the European Economic Area (EEA): Iceland, Liechtenstein and Norway.


The EU has “primary legislation” which refers to treaties and agreements at a very high level amongst the MSs such as the Treaty of Rome, the Treaty of Maastricht, etc.

Then there is secondary legislation which derives from the primary legislation. Below this are directives and regulations.  The main legalities that deal with DS and PV are the directives and regulations.


Regulations are directly applicable and binding in all EU countries without any additional national legislation after approval by the governing EU bodies in Brussels. A regulation, as it is published, is word for word and immediately, the law in each MS. Note that this concept is different from the use of the word “regulation” in the United States. Regulations hold the force of law and must be obeyed in both the US and EU.


Directives are different. A directive binds MSs to the “objectives of the legislation within a certain time period (e.g. 2 or 3 years). In this situation each MS must take the contents of the directive and put it into local (national) law within that time frame. This often produces differences and inconsistencies amongst MSs. Some MSs do not do so and the EU must then take them to court or use other measures to force a non-compliant MS to put the directive into law. Sometimes the directive is adopted by MSs word for word (in the local language). Directives hold the force of law and must be obeyed.


Guidelines in the EU are different. They are not, in theory, legally binding. They are referred to as “soft law” but they are, in practice in DS and PV, obligatory. This is actually a complex issue and is evolving. See, for a discussion on soft law.

As noted, in practice, they are de facto obligatory in DS and PV. For example the EU Good Pharmacovigilance Practices is a guideline and includes 16 modules and many other documents.  The reality is that these must be obeyed and an EU/MS inspector or auditor will cite you if you are deficient in these modules.

Note that this is different from the US where guidances are not “soft law” and are not obligatory.


Best Practices

This is the area where things get even hazier and more difficult. There are no published “official” government best practices documents. Rather there are various publications, documents, books (including my own Manual of DS and PV 2nd edition) which explain how the real world works and what must be done, what should be done, what should not be done as well as areas where nothing is clear.

In practice, companies are expected to obey the obligatory laws and adhere to best practices (e.g. using Data Monitoring Committees). It is up to the company to pay attention (“regulatory intelligence”) to requirements and suggestions from health authorities and put in place reasonable operational systems to do good DS and PV.

A tricky example of this in the US now is the December 2015 FDA draft guidance on IND Safety Reporting. This draft guidance suggests major changes in the way safety reporting is done in clinical trials. It suggests setting up various thresholds for expedited reporting, setting up an unblinded Safety Assessment Committee, creating safety surveillance plans and more. This represents a very significant change in the way safety is/would be handled in clinical trials. Note that this is a draft guidance and is not obligatory. In fact, comments have been requested and are, presumably, under review. Yet many companies are attempting to set up some or all of the “suggestions” in this document.


In summary, being a good corporate citizen and following FDA, EU and other health agency requirements is a very tricky business. Sometimes there are no clear answers. Good luck!



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