Table 3.

Independent investigations regarding regulatory activity in gadolinium-based contrast agents (GBCAs) and nephrogenic systemic fibrosis (NSF) in Denmark²⁵

Events	Date	Safety measures	Independent investigation
Approval of gadodiamide	18 January 1994	Contraindications: “Hypersensitivity for OmniScan®. Diminished kidney function. Must not be given to patients under 18 years old.” Pre-clinical study identifying greater liver (11%) and kidney (14%) content after OmniScan than after Magnevist® (0.03%, 0.06%) MRI in Mosby Year Book 1992; 14 days after GBCA administration, there are 10-fold greater concentrations of OmniScan than ProHance®, DOTAREM® or Magnevist	There is no cause to express critique of the National Health Board medicines department in connection with the approval of OmniScan in 1994
Change of indication	22 July 1994	Nycomed imaging AS requested amongst others to change the contraindication from “kidney reduction” to “severe kidney insufficiency (eGFR <30 ml min−1)” together with particular warnings: “hypersensitivity reactions can occur in rare instances” Additionally, contraindications with regard to persons under 18 years were added “as experience with OmniScan does not exist amongst this patient group”
Dosage change from 0.1 to 0.3 mmol per kilogram of body weight	9 August 1995	Nycomed imaging AS applied on 6 December 1994 to expand the dosage recommendation for OmniScan of 0.1 mmol per kilogram of body weight to include 0.3 mmol per kilogram of body weight for imaging of brain metastasis The Health Committee approved the dosage change, as well as an expansion of the indication for children over 6 months of age
Change of indication to general MRI	31 July 1996	Nycomed imaging AS applied for the expansion of the previously approved indication for OmniScan to include “general MRI”.
Change of contraindication	30 March 1998	Nycomed imaging AS applied for approval of changes in the product summary of OmniScan. “It is documented that gadodiamide injection at a dosage of 0.1 mmol per kilogram of body weight is safe and well tolerated in patients with severely reduced renal function (eGFR <30 ml min−1) or with end-stage renal failure treated with dialysis” Nycomed imaging AS requested to add new warnings about anaphylactic shock and problems with the use of OmniScan in patients with severely decreased kidney function Contraindications: hypersensitivity to OmniScan. Severe kidney insufficiency (eGFR <30 ml min−1) was crossed out. In the medical voting minutes, it is noted that the text was accepted The contraindication for kidney patients was not only removed in Denmark, but also in Belgium, Finland, France, Israel, Iceland, Netherlands, Norway, UK, Switzerland, Sweden, Germany and Austria	The Medicines Agency accepted all the changes The case has not been handled in a professionally correct manner. There was no professional review: the change was not submitted to the Registration Committee the officer in charge prepares a very brief presentation of the case
Expansion of use side effects	17 August 1999	Nycomed imaging AS applied for the use of OmniScan to cover central nervous system examinations in children under 6 months of age In the product summary dated 17 August 1999, the age restriction for use of OmniScan in children was partially removed
Expansion of indication	1 August 2005	Amersham Health AS applied for an indication for myocardial perfusion MRI (stress/rest and late examinations), detection and localization of coronary arterial disease
Reintroduction of contraindication	5 February 2007	Changes occurred in the product summary for OmniScan based on events surrounding reports of NSF. Urgent Safety Restriction procedure was finalized on 2 February 2007: product summary for OmniScan was edited and a contraindication for kidney patients was inserted “Gadodiamide™ is contraindicated in patients with severe renal failure (eGFR <30 ml min−1 per 1.73 m²), and in patients who have received or will receive liver transplantation” The PhVWP concluded that there was a strong indication for a causal association between gadodiamide and NSF in patients with severe renal failure. The PhVWP noted that there were relatively few spontaneous reports on NSF associated with other GBCAs. There were differences in stability of the gadolinium complex of the different substances that might impact the propensity to trigger NSF	The PhVWP was concerned about the delays in competent authorities having access to case reports that were being discussed within the professional community
PSURs		21 PSURs concerning OmniScan administration prior to the presentation of NSF were submitted
PSURs	After February 2006	26 NFD/NSF cases in Denmark, Austria and the USA. Two NFD/NSF cases in Germany and Denmark with some consistent symptoms, but the diagnosis of NFD/NSF was not established. The FDA, DMA and GE Healthcare decided to inform radiologists, nephrologists and dermatologists, directly through their professional societies, by a Dear Healthcare Professional letter. Patient Insurance Association, 1 September 2006; all specialists who handle OmniScan should be aware that OmniScan should not be used in patients with kidney disease. Therefore, any use of OmniScan in patients with kidney disease after this date will, as a rule, in the eyes of the patient Insurance Association constitute a breach of the best specialist standard Contrasting the fact that the DMA at the same time in September, 2006, in the Council of Side Effects, comments that it is a problem that doctors are ceasing to use OmniScan in patients with kidney disease
Contacting the MAH	7 April 2006	The DMA forwarded the reports of side effects that they received from the Herlev Hospital. MAH sent a warning to the DMA and similar agencies worldwide about a possible side effect of OmniScan in the form of NSF Physician letter: we think that there is a possible causal relationship between gadolinium-containing contrast agents and the development of NSF/NFD, a potentially life threatening condition due to following factors: we have only seen NSF/NFD to date when we have two coincident conditions: (i) renal failure (ii) gadolinium-containing contrast administration	The DMA upon receipt of the many adverse reaction reports should at once review the entire agency's action regarding the approval of subsequent changes to OmniScan. Since adverse reaction reports referred to patients with kidney disease, there was particular interest in why the contraindication for patients with kidney disease was revoked in 1998 If the DMA in March 2006 had undertaken a thorough review of the files concerning OmniScan, an independent investigator suggested that the DMA would have found that revoking the contraindication in 1998 was based on a mistake and could have taken the appropriate precautions The DMA does not mention that the warning in May 2006 was largely influenced by the FDA publication of a warning about the use of OmniScan for patients with kidney disease
EU Side Effects Committee	29 June 2006	There was skepticism on one side regarding a correlation between gadolinium chelate use and NSF, and a push on the other side for a closer study In June 2006, at the EU level, there was a consensus that there was no basis for a regulatory measure	Mention of OmniScan was not documented at other Side Effects Council meetings, only at the meeting in September 2006 At this meeting, the DMA stated that it would be problematic to advise against the use of OmniScan based upon the available evidence
EU Side Effects Committee	January 2007	Dissuade use of OmniScan in persons with reduced kidney function. After that the SPC for these medicines were changed and adapted to the new knowledge. In the SPC, under special warnings and precautions regarding use, it is, among other things, noted that OmniScan is not for use in patients with significant kidney failure or patients with liver transplant
Parliament question	27 February 2008	What comments does the minister have with regard to the article in Dagens Medicin, entitled “At least 60 Danes have become invalids or have died after contrast agent”, and does the minister think that the DMA acted swiftly enough when suspicions arose regarding the contrast agent? The minister is asked to explain if he finds it satisfactory that the DMA in 1997 and 1998 did not make a specific assessment of the manufacturer's desire to have the contraindication regarding patients with kidney disease removed, despite earlier studies from 1992 clearly showing that patients with kidney disease were far more often exposed than healthy patients. Independent investigation is commissioned	The DMA did not mention in their statement regarding question S 1188 on February 16. 2009 that the agency had already, on 12 February 2009, discovered that there was no professional evaluation of the application to revoke the contraindication in 1997. At the same time, the DMA refers to the expert report that was attached to the application in 1997, despite that there was no professional evaluation of the said report during the processing of the application The Minister did not know the truth about the proceedings of the removal of the contraindication in 1998

DMA, Danish Medicine Agency; EU, European Union; eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; GE, General Electric; MAH, marketing authorization holder; NFD, nephrogenic fibrosing dermopathy; PhVWP, Pharmacovigilance Working Party; PSUR, periodical safety update report; SPC, summary of product characteristic.

DOTAREM®, gadoteric acid; GADOVIST®, gadobutrol; Magnevist®, gadopentetate dimeglumine; Omniscan™, gadodiamide; ProHance®, gadoteridol.

DOTAREM, Guerbet, Bloomington, IN; GADOVIST, Bayer, Whippany, NJ; Magnevist, Bayer; OmniScan, GE Healthcare; Wauwatosa, WA; ProHance, Bracco, Singen, Germany.