Wednesday, September 28, 2016

AZ at it again

AUTH/2793/9/15 - Clinical pharmacist v AstraZeneca

Case number:AUTH/2793/9/15
Case ref:Clinical pharmacist v AstraZeneca
Identifying patients suitable for Forxiga treatment and failing to provide an accurate response to the Panel
No breach:No breaches Clauses 2 and 7.2
Breach:Breaches Clauses 3.2, 7.2 and 9.1. Corrective statement and public reprimand.
Appeal:No appeal
Review:Published in the May 2016 Review

Case Summary:
​​​​A clinical pharmacist complained about an AstraZeneca leavepiece about how to create a clinical system search to identify patients suitable for treatment with Forxiga (dapagliflozin). 

Forxiga was indicated in adults with type 2 diabetes to improve glycaemic control as monotherapy when diet and exercise alone did not provide adequate glycaemic control in patients for whom use of metformin was considered inappropriate due to intolerance. It was also indicated in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, did not provide adequate glycaemic control.

The leavepiece was entitled ‘9 step guide to identify your uncontrolled and overweight patients with type 2 diabetes (T2D) who may be suitable for treatment with dapagliflozin EMIS Web Instructions’. The front page included ‘FORXIGA is not indicated for weight loss and is not recommended for use in patients with an [eGFR] < 60 mL/min/1.73m2. FORXIGA is not licensed for use with thiazolidinedione or GLP-1 agonists’. 

The complainant alleged that the search instructions were potentially misleading and could easily identify patients who would not be suitable for treatment. The instructions showed how to add criteria for body mass index (BMI), glomerular filtration rate (GFR) and glycosylated haemoglobin (HbA1c). In all cases a clinical code was added with a qualifying value. However, no time restriction was added to qualify these values. The complainant explained the flaw. Patients were supposed to have an uncontrolled HbA1c to be suitable for treatment so those with an HbA1c above 58 should be identified. However, the value should also be the most recently recorded. A patient with an HbA1c of 48 now who had previously had an HbA1c of 63 should not be included in the final search. However, by applying the instruction as specified they would be included for consideration. 

The complainant alleged that whilst he/she hoped that a clinical review would subsequently deem the patient as inappropriate for treatment, the search instructions could be construed as misleading by including such patients. By creating a sub-optimal search the usual high standards demonstrated by the pharmaceutical industry had not been maintained. 

The detailed response from AstraZeneca is given below. 

The Panel noted that the search was described in 9 steps: Setup initial search; Add Age Range to Search; Add Read Code to Search; Add Medication to Search; Add BMI to Search; Add HbA1c to search; Add GFR to search; Save and Run Report; and Build Report Output. Each step included detailed instructions and some included screenshot examples. 

The Panel noted the order of the search criteria, age, read code, and medication were followed by BMI before selecting HbA1c and GFR. The report was then run (Step 8). Step 9, Build Report Output, instructed users to add BMI (22K) and value ≥ 25 before adding columns for HbA1c and GFR but unlike BMI no values were listed for these two criteria at this step in the description in the leavepiece. In the example screenshot of the completed report which appeared below step 9, the column of BMI values was fully populated for each identified patient and appeared before the HbA1c column. Neither the HbA1c nor GFR columns were fully populated. The Panel noted AstraZeneca’s submission that the example report was generated using dummy patients in a test system and a report generated using real-life data in a live system would only include patient records that met all the search criteria and would have all the data values populated. The Panel considered that this was not clear from the leavepiece and was compounded by the screenshot heading ‘The completed report should resemble this screenshot’. The Panel accepted AstraZeneca’s submission regarding the responsibility of prescribers to make clinically reasoned prescribing decisions but considered that it was important that both the instructions and information on the nature and interpretation of the data retrieved was abundantly clear and otherwise complied with the Code. In this regard the Panel was concerned that nowhere in the leavepiece was there any mention of carrying out a clinical review nor was it referred to in the verbal briefing to the diabetes sales leadership team. In the Panel’s view, the leavepiece implied that following the 9 step guide would generate a list of uncontrolled patients with a BMI≥ 25 who were suitable for Forxiga. This would include patients who currently had an HbA1c value of less than 58 but who previously had a value of more than 58 being identified as ‘uncontrolled’. This impression was compounded by the title ‘9 step guide to identify your uncontrolled and overweight patients with type 2 diabetes (T2D) who may be suitable for treatment with dapagliflozin EMIS Web Instructions’. In the Panel’s view it might lead to controlled patients (based on HbA1c) being identified as uncontrolled and being prescribed Forxiga. The Panel considered that the leavepiece was misleading and a breach was ruled.

Whilst the Panel noted that BMI was relevant to this therapeutic area, the emphasis on BMI in the title, search criteria and the example completed report screenshot which omitted HbA1c values and the failure to refer to the need to carry out a clinical review meant that Forxiga had been promoted for some patients based solely on their weight. Forxiga was not indicated for weight loss. A breach was ruled. 

The Panel however did not consider that the instructions were misleading on the narrow point that no time restrictions were included in the search criteria for BMI, GFR and HbA1c as alleged. No breach was ruled. The Panel considered that high standards had not been maintained and a breach was ruled. On balance the Panel did not consider that the circumstances warranted a ruling of a breach of Clause 2 which was used as a sign of particular censure. 

Following notification of the outcome of the case, the complainant noted that, in its response, AstraZeneca had provided inaccurate information about how EMIS could be searched. AstraZeneca initially responded that the information, which it could not validate, was provided by an agency; the agency had confirmed its understanding of the search capabilities of the EMIS system. The complainant was informed and subsequently provided further and better particulars which were provided to AstraZeneca. The company subsequently accepted that the information it had provided was incorrect. 

Detailed comments from the complainant and AstraZeneca are given below.

Following receipt of the additional information from both parties the Authority asked AstraZeneca to respond including in relation to a possible report under Paragraph 8.2 of the Constitution and Procedure. 

The original Panel reconvened and considered the matter in relation to Paragraph 8.2 of the Constitution and Procedure. The Panel noted that AstraZeneca had provided the requisite undertaking. 

The Panel considered that AstraZeneca had not paid sufficient attention to a number of aspects of the production, certification and use of the leavepiece in question. Although the company had been let down by its agency, which had knowingly provided it with an inaccurate response on one point, its governance of the agency had been extremely poor and AstraZeneca had not undertaken sufficient checks when certifying the material and responding to the complaint. The Panel noted that even a brief perusal of the EMIS website, which it had undertaken on conclusion of this case, revealed the comment that ‘Emis web allows you to extract and report on their latest blood pressure reading’. Further, the recent material provided by the complainant indicated, contrary to AstraZeneca’s earlier response, that the latest readings could be extracted. This was now not disputed by AstraZeneca. 

The Panel noted that AstraZeneca had initially submitted that at the WebEx and teleconference on 20 and 26 May a copy of the leavepiece was shown and certain points were explained verbally. The Panel had raised concerns regarding the lack of any written briefing. However, it subsequently transpired that slides had indeed been shown and then distributed to at least one sales manager. The Panel was concerned that one slide described Forxiga as ‘The metformin …’ and that it was ‘to be habitually prescribed as the first choice add-in across the pathway for T2D patients who would benefit from HbA1c control and Weight Loss’. Forxiga was not so licensed. The Panel noted that these claims had not been the subject of complaint. The Panel was also concerned that the final slide stated that each team was to agree how it should be used locally. In the Panel’s view this should have come to light in AstraZeneca’s enquiries before it responded to a question from the Panel regarding representatives’ briefing material. The Panel was concerned that this material had not been before it when it considered the complaint and it was extremely concerned that the material was not certified. 

The Panel was also concerned about the certification process in relation to the leavepiece. It was difficult to see how the leavepiece could have been certified unless the signatories had been able to satisfy themselves that when used on the EMIS web system the instructions and output complied with the Code. This had not been done. 

The Panel was extremely disappointed by the conduct of AstraZeneca as outlined above. Self-regulation relied, inter alia, upon the provision of complete and accurate information to the Panel. It noted the steps undertaken by AstraZeneca to address the issues raised but, nonetheless, considered that the circumstances warranted reporting the company to the Appeal Board under Paragraph 8.2 for it to consider in relation to Paragraphs 11.3 and 11.4 of the Constitution and Procedure. 

The Appeal Board noted the Panel’s comments above about AstraZeneca’s failings with regard to the production, certification and use of the leavepiece in question. 

The Appeal Board noted AstraZeneca had limited expertise with regard to the EMIS Web clinical system and in that regard had relied upon its agency which had let it down. Nonetheless the company’s failings went way beyond merely relying on the agency’s expertise. The company had demonstrated extremely poor governance in this matter. This was not acceptable. The Appeal Board did not understand why representatives had not received a detailed briefing given the complexity of the EMIS system. AstraZeneca had taken full responsibility for its failings and had acted to ensure that such failings did not reoccur. Nonetheless, the Appeal Board considered that it was fundamental for effective self-regulation for companies to provide accurate information to the Panel and for failing to do so and for exercising poor governance it publicly reprimanded AstraZeneca in accordance with Paragraph 11.3 of the Constitution and Procedure. 

The Appeal Board noted the Panel’s rulings and in particular its view that instructions given in the leavepiece might lead to controlled patients (based on HbA1c) being identified as uncontrolled and being prescribed Forxiga. This raised issues of patient safety. This was unacceptable. Consequently the Appeal Board decided, in accordance with Paragraph 11.3 of the Constitution and Procedure, to require AstraZeneca to issue a corrective statement to all recipients of the leavepiece to clarify the position. [The corrective statement appears at the end of the report].​​​

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