Drug research, medical devices and laboratory practice

A series of important rules are in place for the production of pharmaceuticals. First, we should mention OECD's Principles for Good Laboratory Practice (GLP). These have been approved by the EU and have been introduced in Sweden (SFS 1991:93). These principles apply primarily to pre-clinical and toxicological documentation. WHO also have issued Good Clinical Laboratory Practice (GCLP) which will allow clinical laboratories to ensure that safety and efficacy data is repeatable, reliable, auditable and easily reconstructed in a research setting. In 2004, the European Union issued Directive 2004/9/EC on the inspection and verification of good laboratory practice and Directive 2004/10/ECC on the harmonization of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances. To be approved, medicine must also meet the Swedish Medical Products Agency's regulations regarding Good Manufacturing Practice for medicine (GMP). The Swedish rules rests on a EU directive (Commission Directive 2003/94/EC of 8 October 2003). For more GMP-guidelines, see this collection

European Union

Naturally, the European Union's directives and ordinances regarding pharmaceutical production are essential. The Directive 2001/20/EC has now been replaced by a regulation No 536/2014 on clinical trials on medicinal products for human use. It relates to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products. EMA has started work on implementing ethical standards for clinical trials done in third world countries, and presented a paper: Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted in third countries and submitted in marketing authorisation applications to the EMA.

Sweden, GCP & EMA

In Sweden, review in connection with clinical trials of medicine and inspection of medical devices is performed by the Medical Products Agency. However, international projects will, according to the new EU regulation, only be reviewed in one of the countries participating.

According to the fundamental ordinance LVFS 2011:19, clinical trials must be performed in agreement with the latest versions of Good Clinical Practice (GCP) and The Declaration of Helsinki. GCP addresses virtually all aspects of experimental work, and is especially focussed on the procedure of application to ethics committees. What is a clinical trial? GCP says;

"Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous."

The publisher of GCP, the International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use (ICH), has also issued a series of supplementary guidelines concerning aspects of pharmaceutical quality control, security and the performing of clinical medicine studies. In Europe, the main responsibility lies with the European Medicines Agency (EMA). A collection of guidelines from EMA can be found here, notably the Guideline for good clinical practice.

In order to harmonize the use of GCP between varous countries, both the International Standardization Organization and the Global Harmonization Task Force have worked with standardization of requirements. Also the European Forum for Good Clinical Practice issues GCP guidelines, for example on "Medical research for and with older people in Europe".

All medicine and medical devices must be approved for use by the Medical Products Agency in Sweden, or through EMA in London. For more information, see LVFS 2006:11. The safety and effect of a medicine is always to be based on clinical trials performed by the responsible medicine company. The exceptions to this rule are naturopathic and homeopathic preparations that can refer to reliable experience. Certain medicines can also be approved by licence, that is, for a limited time and for specified groups; for example, amphetamine for the treatment of children diagnosed with DAMP. So called Advanced-therapy medicinal products (based on gene therapy, somatic-cell therapy or tissue engineering) must be approved by the European medical products agency, EMA.

Medicines containing or consisting of genetically modified organisms must be assessed from the perspective of environmental risk, according to EU Directive 2001/18/EG. The ordinance ("Förordning" SFS 2002:1086) comprises the Swedish application of Directive 2001/18/EG. The Swedish Medical Products Agency's has issued regulations and general advice on deliberate release during clinical testing of such medicines (LVFS 2004:10), that include additional demands on such trials when no special measures to contain the gm products are in place.

More on Swedish laws and regulations

Fundamental ordinances are Läkemedelslagen (The Pharmaceuticals Act, applies to both humans and animals), Läkemedelsförordningen (the ordinance on medicinal products), the National Board of Health and Welfare's regulations and general advice on the handling of medicines in health and medical services SOSFS 2000:1), and the law on medical devices (SFS 1993:584).

In-vitro diagnostic products intended for evaluation of performance are addressed in the special conditions in 4§2 of the Medical Products Agency's regulations (LVFS 2001:7) on in-vitro diagnostic products. From the Swedish Work Environment Authority we have regulations on microbiological work environment risks (AFS 2005:1) and risks in work environments involving chemicals (AFS 2014:43). For all regulations from the Swedish Board for Accreditation and Conformity Assessment (SWEDAC), including those concerning measurement imprecision and calibration, click here.

First human trials & Clinical Trials Registries

In 2006, a clinical trial in London of a drug, TGN1412, designed to stimulate the immune system instead led to multiple organ failure in the human volunteers, creating quite a stir. The severe negative effects observed in the six human volunteers have led EMA to issue a guideline on strategies to identify and mitigate risks for first-inhuman clinical trials with investigational medicinal products.

Recently, the World Health Organization (WHO) has urged research institutions and companies to register all medical studies that test treatments on human beings, including the earliest studies, whether they involve patients or healthy volunteers. As part of the International Clinical Trials Registry Platform, a major initiative aimed at standardizing the way information on medical studies is made available to the public through a process called registration, WHO is also recommending that 20 key details be disclosed at the time studies are begun. See also the Ottawa statement: Principles for international registration of protocol information and results from human trials of health related interventions. The Helsinki Declaration nowadays also demand that clinical trials be registred before recruitment of study subjects. Also the medical journals have established a requirement that all clinical trials be entered in a public registry before the onset of patient enrollment, as a condition of consideration for publication, for example at the webpage ClinicalTrials.gov.

EU now has issued such a registry platform. It is the national medicine regulatory authorities that are responsible for entering data into a database called EudraCT. Once entered, a sub-set of this information is displayed through the EU Clinical Trials Register website.

See also the recent WHO Statement on Public Disclosure of Clinical Trial Results.

In the US, the foremost bodies of regulations are the US Department of Health and Human Services' publication Regulations for the Protection of Human Subjects and the US Food and Drug Administrations' regulatory guidances.

Pharmacogenetics

A particular issue is pharmacogenetics, the study of how genetics relate to individual drug response. This subject falls under rules for research on human subjects and genetic research (including regulations concerning the use of biobanks), but there are also distinctive guidelines. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH started the work by issuing Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories, and EMA followed with a Note for guidance on definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories. EMA, the principal European authority, has also provided a Reflection paper on the use of pharmacogenetics in the pharmacokinetic evaluation of medicinal products and a Reflection Paper on Pharmacogenomic Samples, Testing and Data Handling.

To the many organisations that have presented their own statements you find the Human Genome Organisation (HUGO Statement on Pharmacogenomics (PGx): Solidarity, Equity and Governance). See also Elements of informed consent for pharmacogenetic research; perspective of the pharmacogenetics working group. PWG is a voluntary association of pharmaceutical companies involved in clinical drug trials and genotyping whose goal is to advance the understanding and development of pharmacogenetics by addressing non-competitive ethical, regulatory, and legal issues.

Last updated: 2019-09-12