Citizens should have access to medicinal products with proven effectiveness, quality and safety.
The entity responsible for admitting medicinal products to the market is the President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products. Supervision and control over the production and trade in medicinal products is exercised by the Chief Pharmaceutical Inspector.
The reason why NIK started this audit was a complaint related to URPL’s decision to add a new therapeutic indication for a medicine called Arechin (Chloroquini phosphas). The follow-up of the complaint audit results was the planned audit related to the registration and post-registration changes of medicinal products.
Overwhelming delays in registration procedure for medicinal products
Out of 279 marketing authorisations for medicinal products under the national procedure, only 23 proceedings were accomplished within the statutory period (in accordance with the Pharmaceutical Law the proceedings should not take longer than 210 days). The remaining 256 proceedings were finished with delays from 4 to 1021 days. Including the statutory period - it is over three years!
Giving consents to postpone deadlines to complete data or submit explanations as “consent upon request”
In the course of the registration procedure, responsible entities (e.g. pharmaceutical companies, manufacturers, distributors, importers) repeatedly requested URPL to postpone the deadline to complete data and submit explanations required by the Office. And the Office, without providing any legal basis, consented to its postponement. A consequence was that one of the audited registration proceedings took more than six years.
Assuming post-registration obligations – illegal procedure or something more?
As many as 114 unconditional marketing authorisations for medicinal products under the national procedure were issued after responsible entities submitted – as information – the so-called post-registration obligations, that is those entities’ commitment to take specific measures after a medicinal product is admitted to the market. That practice was not compliant with the law. As a result, URPL could not enforce the responsible entities to meet those obligations as they were not part of the marketing authorisations.
One of examples was related to autosyringes against chemical warfare agents (IZAS-05). The President of URPL granted an unconditional marketing authorisation for that medical product, in May 2020, after the responsible entity made a range of post-registration obligations, including to change the active ingredient provider immediately after receiving the licence. The URPL President granted the marketing authorisation for the product, although in April 2020 the said provider was issued the Statement of non-compliance with Good Manufacturing Practice (GMP). It was stated in the certificate that the manufacturer should not be granted authorisation in any new or pending procedures related to marketing authorisation or post-registration changes. A change of the substance provider was recommended due to the fact that the products made by the manufacturer may be hazardous for patients. URPL failed to verify if the responsible entity discharged the post-registration obligations, although the entity was informed in June 2020 that in case the obligation to change the active ingredient provider “immediately after receiving the licence” was not met, the decision to admit IZAS-05 to the market could be suspended or withdrawn. IZAS-05 was admitted to the market in November 2020 although the responsible entity did not meet the post-registration obligations. In December 2020, the entity informed URPL that it was in the process of complying with the obligations and that the GMP certificate was not reinstated to the active ingredient producer. Nevertheless, URPL did not take any measures to suspend or withdraw the licence to market autosyringes. Only after 1.5 years from granting the licence, URPL informed NIK that the licence suspension procedure would be started because the responsible entity did not meet the post-registration obligations made in the course of the registration procedure. The product is still listed in the Register of Medicinal Products admitted to the market.
Conditional marketing authorisations granted – what next?
In the audited period, 140 conditional marketing authorisations were granted under the national procedure. The President of URPL did not ensure proper supervision over compliance with additional conditions set out in those decisions. They did not provide specific dates to meet the conditions, and the following clause was mostly used: before or after bringing the product to the market, respectively. It turned out, though, that URPL could not establish the date on its own of bringing the product to the market and should rely on information from responsible entities in that respect. The entities, however, not always informed the Office about bringing a product to the market for the first time (which they were obliged to do). In case the responsible entity fails to meet the conditions laid out in the said decisions, in line with the Pharmaceutical Law Act, the President of URPL withdraws the authorisation.
Delays in processing post-registration changes
Post-registration changes in this case were the so-called significant changes which consisted in adding a new therapeutic indication. Out of 33 positive decisions on post-registration changes under the national procedure, as many as 15 of them were reviewed with delay of three to 289 days. In case of Arechin, only within one day based of the decision of URPL President of 13 March 2020, a new indication was added for that medicine: supportive therapy in betacoronavirus infections. According to NIK the documentation submitted by the responsible entity did not provide sufficient grounds for adding that indication. There were no results of clinical trials confirming the medicine was effective in treating patients with COVID-19. The change acceptance was also not justified by an external expert’s opinion made at URPL’s request or explanations given by that expert. It needs to be stressed that the first COVID-19 patient was diagnosed in Poland on 4 March 2020 and already on 13 March 2020 the therapeutic indication for Arechin was extended.
During the audit, NIK requested the 21 dedicated COVID-19 hospitals to provide information about using Arechin to treat COVID-19 patients. Information was provided by 13 hospitals. In April 2020, nearly half of patients from those hospitals were treated with Arechin, whereas in March 2020 it was less than ⅓. In subsequent months, that number was going down and in September it was less than ⅒ of patients. In the audited period, 276 deaths of COVID-19 patients treated with Arechin were reported in those hospitals. In the opinion of the hospitals’ management, in case of two patients the deaths could have been caused by the administration of Arechin.
In October 2020, seven months after the decision was issued to add the said therapeutic indication, the responsible entity filed a request in URPL to delete the indication requested in March 2020. The reason was that results of international clinical trials SOLIDARITY and RECOVERY were published which proved that using chloroquine in COVID-19 patients fails to reduce mortality, shorten the hospitalisation period or prevent the necessity to introduce mechanical ventilation in patients, as compared with standard treatment.
The President of URPL did not take any actions ex officio to change the Summary of Product Characteristics of Arechin, despite the fact that initial results of the RECOVERY trial were published in June 2020 and in October 2020 final results of both RECOVERY and SOLIDARITY trials. The new therapeutic indication added in March 2020 was deleted on 23 October 2020, upon request of the responsible entity.
Headcount issues of URPL
The headcount problems of URPL were some of main reasons why the processing of requests for registration and post-registration changes of medicinal products was delayed.
In the audited period, 53 employees quit the job in URPL and ⅓ of 11 recruitment processes did not end in hiring new employees. The main reason was low salaries. According to NIK, the lack of employment stability caused by high staff turnover and low efficiency of recruitment, poses a threat to the execution of statutory tasks of the Office responsible for citizens’ safety related to medicines.
Chief Pharmaceutical Inspector
The Chief Pharmaceutical Inspector failed to monitor the timeliness of communicating the fact of bringing medicinal products to the market for the first time by responsible entities. Also, the Inspector did not issue decisions about withdrawing a medicinal product from the market in case of no notice about bringing the medicine to the market within the statutory period, although part of responsible entities did not meet the deadline. Besides, the Inspector not always discharged the legal obligation to immediately send the registered product for qualitative research. No procedure was introduced to monitor the implementation of GIF’s decision to send the medicinal products for qualitative research. According to NIK, this may pose a threat to patients. In the case qualitative research of a medicine admitted to the market for the first time in Poland takes several months or even years from bringing the product to the market, a lot of patients will use the product before it is tested by an independent laboratory. Moreover, there is a risk that there are medicinal products in the market which never underwent qualitative research.
Key recommendations
To the President of URPL:
- to streamline the process of registering medicinal products and processing post-registration changes;
- to stop accepting post-registration obligations in the form of information;
- to ensure effective supervision over the way responsible entities fulfil the conditions specified in marketing authorisations.
To the Chief Pharmaceutical Inspector:
- to take immediate efforts , in cooperation with URPL and the National Medicines Institute, to:
- identify medicinal products which – although brought to the market – did not undergo qualitative research,
- issue decision to withdraw such products from the market or make sure the research is done without delay.
To the Minister of Health:
- to facilitate solving headcount problems of URPL.
De lege ferenda proposal to amend the Pharmaceutical Law:
According to NIK the notification about the date of bringing a medicinal product to the market should be obligatory. At the same time, the statutorily defined sanctions imposed for the failure to notify GIF about bringing a medicinal product to the market within the statutory period should be diversified, depending on the scale of breaching information duties.
It is essential to specify a date of sending a sample of the medicinal product for qualitative research and set a deadline for the research.
NIK has filed two reports of possible criminal activity allegedly committed by the President of the Office for Registration of Medicinal Products to the prosecutor’s office.
