Government must apologise to those affected by Primodos, valproate, and mesh, says review
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m2726 (Published 07 July 2020) Cite this as: BMJ 2020;370:m2726Linked Editorial
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Dear Editor
Primodos was nearly identical to the oral contraceptive Anovlar.
Primodos is norethisterone acetate 5 mg and ethinyl oestradiol 40 micrograms and nearly identical to the oral contraceptive (OC) Anovlar which had 4 mg of the same progestogen and 50 micrograms of the same oestrogen.1
The impression being given is that Primodos contained much bigger doses than oral contraceptives which is not the case.
In fact, there have been no basic changes in effects of OC or HRT progestogens and oestrogens over the past 55 years.
Combined formulations are predominantly progestogenic but can also have extra androgenic or estrogenic actions. Adverse effects relate to the prolongation and augmentation of physiological actions of these hormones.2
First generation progestogens included norethisterone acetate which has extra estrogenic activity and norgestrel extra androgenic activity and megestrol acetate.
Second generation progestogens included levonorgestrel which is the active isomer in norgestrel.
Third generation desogestrel and gestodene are more powerful substituted derivatives of norgestrel and therefore are given in lower doses. Etonorgestrel is an active metabolite of desogestrel. Norgestimate is converted in the body to norgestrel.
Structurally similar progestogens, cyproterone acetate, medroxyprogesterone acetate and megestrol acetate, formed DNA adducts in primary cultures of human hepatocytes signifying a genotoxic risk.3
The risk of teratogenesis and cancers is increased if DNA adducts block multiple tumour suppressor genes.4,5
In 2007 the International Agency for Research on Cancer (IARC) listed contraceptive or menopausal progestogens and estrogens as highest-level Group 1 carcinogens.6
The aim the report of the Independent Medicines and Medical Devices Safety Review. 8 Jul 2020 is to “First do no harm”. https://www.immdsreview.org.uk/Report.html which is very welcome.
1 Mears E, Grant ECG. Anovlar as an oral contraceptive. BMJ 1962 1962;2:75-79.
2 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998:8:789-91. DOI:10.1080/13590849862131
3 Werner S1, Kunz S, Beckurts T, Heidecke CD, Wolff T, Schwarz LR. Formation of DNA adducts by cyproterone acetate and some structural analogues in primary cultures of human hepatocytes. Mutat Res 1997 Dec 12;395(2-3):179-87.
4 Howard JM. The detection of DNA adducts (risk factors for DNA damage). A method for genomic DNA, the results and some effects of nutritional intervention, J Nutr Environ Med 2002;12:19-31.
5 Hemminki, K. DNA adducts, mutations and cancer. Carcinogenesis,1993 14,2007–2012.
6 IARC. Combined estrogen-progestogen contraceptives and combined
estrogen-progestogen menopausal therapy. IARC Monographs on the Evaluation
of Carcinogenic Risks to Humans 2007; Volume 91.
Competing interests: No competing interests
Dear Editor
If the mesh is the problem, how come the widely used mesh repairs of inguinal hernias have not come under the spotlight? Could the problems have something to do with the nature of the operations?
Competing interests: No competing interests
Dear Editor
The report of the Independent Medicines and Medical Devices Safety Review (the Cumberlege Review) documents the serious suffering caused by three treatments intended to help patients but which ended up injuring many. The lessons emphasised by the report include the establishment of better ways of allowing the patient’s voice to be heard, improved informed consent procedures and the implementation of remedies to help those who have suffered harm. As with all enquiries into failure, the most important of its several objectives is to ensure that reform occurs which will prevent the story from being repeated. In the case of vaginal mesh, the focus of attention must be on improving the systems for licensing, regulating and monitoring medical devices. Without better methods for ensuring that the safety and effectiveness of medical devices is evaluated thoroughly, further scandals of this type are sadly inevitable.
The IDEAL Collaboration has developed recommendations for scientific study of devices which provide an integrated evaluation pathway throughout their life cycles. This begins with maximum transparency about the device, its use and the outcomes from the very first case. We advocate a Total Product Life Cycle (TPLC) approach to evaluation and licensing, in which permission to market a device is widened in stages as more clinical evidence is provided. At each stage in the life cycle, sponsors should be required to conduct studies following a standardised template designed to provide the highest quality and most important evidence relevant to that stage. This is much more likely to identify safety issues early than current arrangements. The Cumberlege report references some of these important ideas, and makes recommendations for evidence development at both early stages (Para 5.52) and during longer term follow up (Para 1.48) aligned with IDEAL recommendations, which we very much welcome.
The report correctly points out the current opportunity for reform of device regulation in the UK in the wake of Brexit. The notified body system used in the EU drastically limits the power of national regulators to specify evaluation methods and to see the results of tests done for regulatory purposes. A new framework in which sponsors of new devices will be required by the MHRA to provide data from prospective ethically approved studies using standardised formats in return for progressive degrees of market access (and to contribute to the costs of maintaining a long term device registry) would make repetition of the mesh story much less likely. IDEAL provides an explicit framework for achieving this.
Prof Peter McCulloch,
Chair
IDEAL Collaboration on behalf of the IDEAL Council
Competing interests: No competing interests
Re: Government must apologise to those affected by Primodos, valproate, and mesh, says review
Dear Editor
I'm Jan, an implant survivor. I support many ladies here in the UK. Some have lost so much - homes, families, jobs. I lost 5 years from my life due to implants and failure to be listened to or be supported. We in the UK along with an apology would like the laws and rules to be changed to support people. This is so very real. Please help support people from being silenced. I hope you will share our petition. Thank you for reading.
https://petition.parliament.uk/petitions/548976
Competing interests: No competing interests