EU requirements to provide results for authorised clinical trials – EC, EMA, MHA

Call for all sponsors to publish clinical trial results in EU database (joint letter by the European Commission, EMA and HMA)


The European Commission (EC), the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) have co-signed a letter reminding all sponsors of clinical trials conducted in the European Union of their obligation to make summaries of results of concluded trials publicly available in the EU Clinical Trials Database (EudraCT).

Transparency and public access to clinical trial results, whether positive or negative, are fundamental for the protection and promotion of public health. It assures trial subjects that their voluntary participation in clinical trials is useful and that the results have been collated and reported for the benefit of all. In addition, for those medicines which are placed on the market or used in further clinical trials, it allows patients and healthcare professionals, or any other citizen, to find out more information about medicines they might be taking or prescribing. Transparency also enhances scientific knowledge and helps to advance clinical research and support more efficient medicine development programmes.

It is the responsibility of sponsors to ensure that the protocol information and results of all clinical trials is submitted in EudraCT; this information is publicly available through the EU Clinical Trials Register (EU CTR). Since July 2014, sponsors are required to post results within one year after the end of a clinical trial (or six months for a paediatric trial). This information is also shared with the World Health Organization’s (WHO) International Clinical Trials Registry Platform (ICTRP) of which EU CTR is a primary registry.

As of April 2019, the EudraCT database included 57,687 clinical trials in total, out of which 27,093 were completed. Out of these completed trials, 18,432 should have had results posted; sponsors were in compliance with the publication requirements for 68.2% (12,577) of the trials, however results were still lacking for 31.8% of them (5,855).

The reporting compliance of non-commercial sponsors (e.g. academia) was much lower than for commercial sponsors (i.e. companies), with 23.6% of results posted for non-commercial sponsors vs 77.2% for commercial sponsors. Academic sponsors or smaller companies often lack awareness or incentives to post clinical results, therefore EU authorities are taking various steps to ensure sponsors are aware of their obligations and can act on them.

One of these initiatives is the “letter to stakeholders regarding the requirements to provide results for authorised clinical trials in EudraCT”, co-signed by Anne Bucher, Director General of the EC’s DG Health and Food Safety, Guido Rasi, Executive Director of EMA, and Thomas Senderovitz, Chair of the HMA Management Group. It will be disseminated to various stakeholder groups, with a goal in particular to reach academic sponsors. This should help to spread the word about the importance of making clinical trial results publicly available.

Amongst other initiatives conducted at EU level, EMA has since September 2018 been identifying trials with missing results on a monthly basis and sending reminders to the sponsors of those trials to ensure compliance with the transparency rules and their follow up on their results reporting obligations.


Sodium Valproate Review : Who knew What and When ?

Cumulative meta-analysis gives extra insights

2018 Abstract

Sodium valproate is licensed in the EU for treating generalised, partial or other forms of epilepsy. It has also been used to treat bipolar disorder and to prevent migraine. In February of this year, the European Medicines Agency recommended that sodium valproate should not be used during pregnancy unless no other effective treatment is available, and that it must not be used in women able to have children, unless the conditions of a pregnancy prevention programme are met. These measures to protect women and their children are welcome, but we argue that they should have been instituted several years ago, as the evidence was clear as far back as 1990 that there were risks of congenital malformations in women exposed to valproate.

Our analysis shows the value of cumulative meta-analysis, which, in our view, should be performed as standard in systematic reviews when any concerns about harms arise during the use of medications. …

…, we consider that drug companies, journal editors, prescribers and systematic reviewers have all acted too late. We, therefore, consider that from 1990 individuals should have been offered the opportunity to switch to treatments with lower risks, where they existed, and given minimum effective doses of valproate if alternative treatments were not available or advisable. In the intervening years, many women’s children will have been harmed. Manufacturers and regulators should be responsible for ensuring that cumulative analyses are carried out as part of postmarketing risk management plans.

Reporting side effects of medicines

EU Medicines Agency‏ survey on safety of medications and reporting of adverse drug reactions

This EU Medicines Agency survey, will take approximately 5 to 10 minutes of your time to complete. It will help understand the awareness of patients/consumers and healthcare professionals regarding the need and the way they can report adverse drug reactions (side effects). The results will be analysed by the European Medicines Agency and a report containing summary information will be provided to the European Commission (DG SANTE) and will be further disseminated publicly.

EMA launches survey to assess whether patients and doctors are aware of the arrangements for reporting of side effects – European Medicines Agency, the European Union agency responsible for the evaluation and supervision of medicinesEMA_News/status/905720311445893120, 7 sept. 2017.

European Medicines Agency started reviewing HPV vaccines safety

EMA confirmed evidence does not support that HPV vaccines cause CRPS or POTS… but the Nordic Cochrane Center said their report is flawed…

image of hpv-vaccine
Concerned by reports of serious adverse effects in young women receiving human papillomavirus (HPV) vaccines, the European Medicines Agency started a safety review. Three HPV vaccines are currently licensed in Europe: Gardasil/Silgard, Gardasil 9, and Cervarix, all of which are approved in the U.S. as well.

July 2015

The European Medicines Agency (EMA) started a review of HPV vaccines to further clarify aspects of their safety profile.

The review looked at available data with a focus on rare reports of two conditions:

  • complex regional pain syndrome (CRPS)
    a chronic pain condition affecting the limbs,
  • postural orthostatic tachycardia syndrome (POTS)
    a condition where the heart rate increases abnormally after sitting or standing up, causing symptoms such as dizziness and fainting, as well as headache, chest pain and weakness.

In its review the agency’s Pharmacovigilance Risk Assessment Committee (PRAC) considered the latest scientific knowledge, including any research that could help clarify the frequency of CRPS and POTS following vaccination or identify any causal link. Based on this review, the Committee decided whether to recommend any changes to product information to better inform patients and healthcare professionals.

November 2015

EMA concluded this review : HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS.

Summer 2016

An official complaint has been filed by the Nordic Cochrane Center against the European Medicines Agency (EMA) over its handling of safety issues concerning human papillomavirus (HPV) vaccines.

In the complaint, which runs to 19 pages, the Nordic group says that the official EMA report is flawed.

  • Complaint to the European Medicines Agency (EMA) over maladministration at the EM, Nordic Cochrane Centre, 26 May 2016.
  • Complaint Filed Over EMA’s Handling of HPV Vaccine Safety Issues, Medscape Medical News, July 05, 2016.

EMA is wrong to recommend Mysimba drug (weight management in adults)

Prescrire denounces the unacceptable decision of the European Medicines Agency (EMA) to recommend that marketing authorisation be granted for the dangerous combination naltrexone + amfebutamone (Mysimba/Contrave)

Impending approval of a dangerous amphetamine drug for use in weight control? An unacceptable EMA recommendation that must be overturned.

Prescrire logo
Prescrire denounces the unacceptable decision of the European Medicines Agency (EMA) to recommend that marketing authorisation be granted for the dangerous combination naltrexone + amfebutamone (Mysimba/Contrave).

PRESS RELEASE – Paris, 19 December 2014.

” Today, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has announced its decision to recommend that marketing authorisation be granted for the combination naltrexone + amfebutamone (also known as bupropion) for use in weight control (MYSIMBA in the EU / CONTRAVE in other parts of the world), despite “uncertainties with regard to cardiovascular outcomes in the longer term”.

A major regression for European patients’ safety. Amfebutamone is an amphetamine drug, as is amfepramone. In 2000, the EMA withdrew the marketing authorisation of several appetite suppressants with a similar mechanism of action to that of amfepramone (clobenzorex, dexfenfluramine, fenfluramine, fenproporex, etc.), in order to protect public health (2). In 2009, sibutramine (Sibutral), an appetite suppressant structurally related to amphetamines, was also withdrawn by the EMA due to disproportionate and serious adverse drug reactions. And benfluorex (Mediator) was also withdrawn from the whole European Union market in 2010.

In addition, in 2013, the EMA rightly refused to authorise the dangerous fixed-dose combination phentermine + topiramate on safety grounds, and the application for the drug lorcaserin (Belviq) was withdrawn by the company following the CHMP’s “provisional opinion that Belviq could not have been approved for weight control in obese and overweight patients”. How is it possible that the CHMP now takes an incongruent decision on the fixed-dose weight-control combination naltrexone + amfebutamone (also known as bupropion) (CONTRAVE/MYSIMBA)?

Health authorities should learn from past public health disasters. A weight loss of a few kilograms achieved through drug therapy cannot in itself justify exposing obese or simply overweight patients to a disproportionate risk of adverse drug reactions, especially since the weight lost is very often regained within months of discontinuing treatment.

Health authorities should learn the lessons from past public health disasters, notably those due to several appetite suppressants subsequently withdrawn from the EU market for disproportionate and serious adverse drug reactions (sibutramine (Sibutral), benfluorex (Mediator), rimonabant (Acomplia)).

Prescrire urges national Drug Regulatory Agencies’ representatives with a seat at the CHMP and who voted against the recommendation on naltrexone + amfebutamone (CONTRAVE/MYSIMBA) to insist that patients’ safety be defended. Member States opposing the recommendation still can and should require arbitration by the European Commission and convene a standing Committee meeting. The EU Commission, as last gatekeeper, also has the possibility of deciding not to follow the CHMP’s  recommendation.

In 2015, weight-control medicines that do more harm than good should no longer be authorised in the European Union. ”

Sources and more information
  • Impending approval of a dangerous amphetamine drug for use in weight control? An unacceptable EMA recommendation that must be overturned, prescrire, 19 December 2014. See also the press release PDF.
  • Mysimba recommended for approval in weight management in adults, EMA, 19/12/2014. See also the press release PDF.
  • FDA approves weight-management drug Contrave, FDA news, September 10, 2014.

PRAC recommends strengthening the restrictions on the use of valproate in women and girls

Women to be better informed of the risks of valproate use during pregnancy

The European Medicines Agency (EMA)’s Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended strengthening the restrictions on the use of valproate medicines due to the risk of malformations and developmental problems in children exposed to valproate in the womb.

More information
  • Published on 12 Oct 2014 by APESAC channel. Website.
  • Valproate should not be used to treat epilepsy or bipolar disorder in girls and in women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated. Women for whom valproate is the only option after trying other treatments, should use effective contraception and treatment should be started and supervised by a doctor experienced in treating these conditions.” … continue reading EMA press release, 10/10/2014.
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