Comment on Femme Fibroid Trial UK Clinical Trial comparing Myomectomy with Embolisation & Fertility

Femme Study

UK Clinical randomised trial of treating fibroids with either embolisation or myomectomy to measure the effect on quality of life among women wishing to avoid hysterectomy (womb removal) (the FEMME study)

The Trial was to compare the outcomes of Myomectomy vs Embolization to find which treatment has the best effect on women’s quality of life & if desired, pregnancy outcomes. This Trial is complete but it has now become apparent that the now recalled drug, Esmya, Ulipristal Acetate (From Gedeon Richter) was used in this Trial

The FEMME trial  primary outcome was to monitor the quality of life women with symptomatic uterine fibroids experience two years after they have been treated with either UAE (Uterine Artery Embolisation to shrink fibroids) or myomectomy (fibroid removal) , as measured by the disease-specific Uterine Fibroid Symptom Quality-of-Life (UFS-QoL) questionnaire. The Protocol also said, it would monitor pregnancy outcomes.

It was somewhat surprising that Esmya was added to the Femme Trial in light of this Trial Published in 2014. Which found more miscarriages & 1 pregnancy with a fetal abnormality in women who took Ulipristal Acetate standalone for Fibroids.

It was also surprising that despite failure of this treatment & known pregnancy outcome issues, this Esmya Product, went on to become a main treatment for Heavy Menstrual Bleeding following a guideline update c 2016. It is not clear whether the knowledge gained from failures from this Trial was communicated to the NICE Guideline Panel & Public. An investigator from the Femme Trial declares 1 Conflict of Interest in the NEJM publication , of being paid to represent Gedeon Richter as an expert witness (Pharmaceutical company responsible for Esmya Ulipristal Acetate in the UK). It’s not clear if a defence or concerns raised, re Esmya failure In the Femme Trial & pregnancy outcomes was made . It’s not clear if the Pregnancy Outcome Trial was highlighted. That trial found 90.5% of women who took Ulipristal Acetate, Prior to attempting to conceive, still needed Myomectomy after use. And 60% had 5 or more fibroids after use, which is a clear failure to cure the condition, contradicting much of the marketing claims that it would help women to avoid surgery.

It now appears that there was another intervention, used in the trial that was not in the original protocol. This was the use of a drug called Esmya Ulipristal Acetate (also known as Fibristal in the USA). This information was not made clear until an article was published in the NEJM Journal.  Title Uterine -Artery Embolization or Myomectomy for Uterine Fibroids

This Drug had been under severe restrictions, for a number of years in Europe,  due to many reports of Liver Damage & Liver failure. “

In May 2018, the European Medicines Agency (EMA) recommended additional measures to minimise the risk of serious liver injury with Esmya which included: 
  • not prescribing the drug to women with known liver problems;
  • liver tests before, during and after stopping treatment;
  • a card for patients to inform them about the need for liver monitoring;
  • a recommendation that patients contact their doctor should they develop symptoms of liver injury.

French Authorities found that the Risks did not outweigh the benefits.  The Authors of the Trial now say was a surgery following failed medication Trial.

Pregnancy outcomes were lower , than found in comparative surgical trials. It us unclear why an experimental drug of this nature was used in a Trial which also reviewed pregnancy outcomes. 

It is not clear whether the Trial Investigators gave specific written Informed Consent for the use of Ulipristal Acetate to Trial Participants. It was not in the original Trial Protocols. The government regulator MHRA made public safety warnings about this drug. It also stated that a Patient Safety Card be given to any patients who were taking it, to warn them of symptoms of liver damage & patients should be regularly monitored for liver issues. A complaint about the conduct of this Trial was made to the HTA. They state that if patients have any issues , they should take it up with the relevant hospital. 

The Results of the Trial contrast starkly with other trials that had more pregnancy outcomes ie “ Comparison of Long-Term Fertility and Bleeding Outcomes after Robotic-Assisted, Laparoscopic, and Abdominal Myomectomy “  http://dx.doi.org/10.1155/2016/2789201

We hope that for the final HTA the data from the Femme Trial, is clearly laid out in a similar way to this Trial. http://dx.doi.org/10.1155/2016/2789201 . Clearly laying out the separate types of Myomectomy & Embolization , together with any pharmatherapy used ie drugs used Pre, during  & post surgery. It also details any further surgery, including numbers of reoperations , IUD , HRT, GNRHa, NSAID, Opiod, Mesh use, ie further hysteroscopies, laparoscopic surgeries, and endometrial ablation & hysterectomy, and any operations related to complications with open morcellation, which we now understand is a common practice in the UK & warnings re Risks & Benefits should have been given.

Patient Safety Alerts

Where was the Trial? At Hospital centres across UK. Birmingham was the main co-ordinating centre. Clinical Trial Registry http://www.isrctn.com/ISRCTN70772394

Heart of England Hospital Published a study on Esmya  Ulipristal Acetate. “ acetate for uterine fibroids: 2 years of real world experience in a UK hospital. “ The study states “134 patients received UPA, 20 women (15%) received a second course. “ . Over 80% after 1 x 3 month course. Many Trial Participants went on to have a Hysterectomy, in this Trial. The Trial Results were described online.

It is  not clear whether the Femme Trial was part of the follow on from this trial. Some patients increased an increase in fibroid size. Many had no improvement. 

Esmya drug, was finally recalled in the UK in March 2020 due to further reports of Liver Damage. ”

Contact patients currently taking Esmya for uterine fibroids as soon as possible and advise them to stop their treatment. The licence for Esmya has been suspended to protect public health while a safety review is conducted following a further case of liver injury requiring transplant.” 18 March 2020. A firm of Solicitors called Leigh Day explained the issues in a Press Release 

MHRA issued a Drug Recall to Pharmacists. The drug has also now been withdrawn from use in Canada

All registered Clinical Trials should be covered by some form of Trial Insurance. The Trial Investigators should have exercised their Duty of candour , informing all of the Trial Participants as the issues arose & Liver monitoring patients exposed to the Ulipristal Acetate. Any side effects should be fully detailed in the Health & Technology Assessment that has not been published yet. This should provide the detail on surgeries, that is missing from the NEJM publication.

If you have suffered any side effects from drugs or surgical devices in this Trial you can make a written/ emailed  complaint to :

The hospital/GP practice or Private Dr who prescribed the drug.

You can Report all Side Effects (If any) to the MHRA using the yellow card scheme online . There are no time limits on reporting side effects at https://yellowcard.mhra.gov.uk

You can obtain legal advice if you have been harmed &/or you suspect it may have led to a less than favorable pregnancy outcome (if any).

You can write to the Trial regulators/ Ombudsman or by any method you feel is appropriate for your circumstances.

There is no Patient Safety Commissioner in place despite a report published this year called First Do No Harm, made recommendations that a Patient Safety Commisioner was necessary to protect women harmed whilst seeking health care.  Women find it difficult to know where to turn to when issues arise. 

There have been many women in UK patient groups who had poor outcomes with Esmya, Ulipristal Acetate. Many say that their symptoms ie heavy bleeding got worse, after using Esmya , then it was before they used it in the 1st place. We are also aware that many women had issues getting surgery without having to take part in a medication trial 1st, in many parts of the UK,  which delayed their access to surgery. 

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