Cardiorentis AG v IQVIA Ltd
| Jurisdiction | England & Wales |
| Judge | Mr Justice Butcher |
| Judgment Date | 10 February 2022 |
| Neutral Citation | [2022] EWHC 250 (Comm) |
| Docket Number | Case Nos: CL-2019-000064 and CL-2018-000841 |
| Year | 2022 |
| Court | Queen's Bench Division (Commercial Court) |
[2022] EWHC 250 (Comm)
IN THE HIGH COURT OF JUSTICE
BUSINESS AND PROPERTY COURTS OF ENGLAND AND WALES
COMMERCIAL COURT (QBD)
Royal Courts of Justice
Strand, London, WC2A 2LL
THE HONOURABLE Mr Justice Butcher
Case Nos: CL-2019-000064 and CL-2018-000841
Paul Stanley QC and Noel Dilworth (instructed by Hogan Lovells International LLP) for the Claimant
Neil Kitchener QC, Laurence EmmettQC andPatricia Burns (instructed by Cooley (UK) LLP) for the Defendants
Hearing dates: 18–21, 25–28 October, 1–4, 8–11, 15–18, 22 November, 1–2 December 2021
Further written submissions: 3, 6 December 2021
Approved Judgment
THE HONOURABLE Mr Justice Butcher
Table of Contents:
| Introduction | 4 |
| The Factual Framework of the Case | 5 |
| Heart Failure | 5 |
| Ularitide | 6 |
| Cardiorentis | 7 |
| The involvement of IQVIA | 7 |
| ICH-GCP | 7 |
| The General Services Agreement | 8 |
| Change Orders | 12 |
| The Protocol | 12 |
| Communications with the FDA in 2012 | 18 |
| The Addition of the Co-Primary Efficacy Endpoint | 18 |
| The amendment to the Protocol | 19 |
| Quality Assurance and the Clinical Quality Agreement (CQA) | 21 |
| Other persons and entities involved in the TRUE-AHF trial | 23 |
| Investigators | 23 |
| The Executive Committee | 24 |
| The Steering Committee | 24 |
| Documents detailing practices and procedures for the TRUE-AHF trial | 24 |
| Monitoring Guideline | 24 |
| The Quality Management Plan | 26 |
| The Protocol Deviation Management Plan | 27 |
| The Medical Monitoring Plan | 30 |
| The Statistical Analysis Plan | 30 |
| The Progress of the Trial and the sites involved | 31 |
| Key Persons involved | 32 |
| Databases and reports | 34 |
| Co-Monitoring visits, audits and inspections | 38 |
| Cardiorentis Remote Monitoring | 42 |
| DSMB Recommendations | 42 |
| The Blind Data Review | 42 |
| ICH-GCP provisions relevant to Blind Data Review | 42 |
| The Protocol and SAP as to the Blind Data Review | 46 |
| The conduct of the Blind Data Review | 46 |
| The finalised Blind Data Review Plan | 50 |
| The Results revealed | 53 |
| The Response of Cardiorentis and the involvement of SCI | 54 |
| The SCI Report | 55 |
| The NEJM Article | 58 |
| The NEJM Editorial | 65 |
| Other Studies | 66 |
| Nesiritide / ASCEND | 66 |
| Serelaxin / RELAX | 67 |
| GALACTIC | 68 |
| The Proceedings Brought | 69 |
| North Carolina | 69 |
| IQVIA's English proceedings | 69 |
| Cardiorentis's English proceedings | 69 |
| The Issues on the pleadings | 70 |
| Limitation and clarification of Cardiorentis's case at outset of trial | 74 |
| The Factual Witnesses called | 75 |
| The Expert evidence | 76 |
| Agreed facts | 76 |
| The Issues to be decided | 76 |
| The Obligations owed by IQVIA | 77 |
| General aspects | 77 |
| Medical Monitoring | 78 |
| SDV | 79 |
| CQA | 80 |
| Were there breaches of contract by IQVIA which caused there to be eligibility deviations? | 80 |
| Is the number of eligibility deviations itself indicative of breach? | 81 |
| Alleged deficiencies in training | 83 |
| Alleged deficiencies in monitoring | 85 |
| EC3 | 87 |
| The nature of the criterion | 87 |
| The facts relevant to EC3 deviations | 87 |
| Cardiorentis's case | 92 |
| IC6 | 95 |
| The facts relevant to IC6 deviations | 96 |
| Cardiorentis's case | 97 |
| Non-EC3 or IC6 eligibility deviations | 100 |
| SDV | 102 |
| Alleged breach of CQA | 103 |
| Other allegations of defective performance | 103 |
| Conclusion as to Breach | 104 |
| The BDR Process | 104 |
| Was the study unreliable or of little use by reason of inclusion of patients with eligibility or other protocol deviations? | 107 |
| Legal principles applicable to claims for wasted costs as damages | 113 |
| The assessment of waste and the relevance of benefits received | 115 |
| Application of legal principles to the facts | 116 |
| The Claim for an Injunction | 117 |
| The Counterclaim | 118 |
| Overall Conclusion | 121 |
The Hon.
Introduction
1. This case involves a claim by the Claimant (‘Cardiorentis’), a company interested in developing pharmaceutical and biotechnology products, against the Defendants in respect of the conduct of a Clinical Trial, and a counterclaim in respect of unpaid fees relating to that Clinical Trial. The Clinical Trial in question has been given the name TRUE-AHF, standing for Trial to Evaluate the Efficacy and Safety of Ularitide Intravenous Infusion in Patients Suffering from Acute Decompensated Heart Failure.
2. The First Defendant is a major contract research organisation (or ‘CRO’), whose business includes providing clinical trial services, research and other services for the pharmaceutical, medical device and biotechnology industries. It was formerly known as Quintiles Ltd. The Second Defendant is a company incorporated under the laws of North Carolina. It is an indirect parent company of the First Defendant. It was formerly known as Quintiles Inc. In this judgment, save where it is necessary to distinguish them, I will refer to the Defendants as ‘IQVIA’. In many of the documents to which reference is made, the name used is ‘Quintiles’, and I have not sought to change these.
3. This case involved looking in detail at the contractual arrangements for, and the conduct and results of, the TRUE-AHF study. A great deal of the factual material relating to the origin, background to, course of and results of the Trial were not in issue or not significantly in issue. To understand the issues in the case it is necessary to understand many of these matters. Accordingly, the next section of this judgment contains a summary of them. Its contents were largely common ground. To the extent it was not, it represents my findings based on the documentary evidence.
The Factual Framework of the Case
Heart Failure
4. Heart failure (‘HF’) is a syndrome encompassing a variety of cardiac diseases which progress to imposing on the heart injury, cellular loss, overload and change in dimensions making the heart less efficient in supporting blood supply to other organs and thereby making them dysfunctional. The disease usually progresses chronically, with some relatively, and seemingly stable, ‘compensated’ periods, albeit with a continuous slow decline of health and with a permanent risk of sudden death. Occasionally the disease enters ‘decompensated’ episodes of rapid worsening, called ‘Acute Decompensated Heart Failure’ (‘ADHF’), which is a life-threatening condition, occasionally complicated by death, and usually requiring hospital admission for appropriate care.
5. There are multiple causes of decompensation. Some relate to aggravation of the underlying cardiac disease, such as myocardial infarction, angina and hypertension; others to drug interactions. Non-compliance with a patient's drug therapy or dietary restrictions are also frequent causes. Excessive fatigue related to intense exercise, the advent of cardiac arrhythmia or of pulmonary infection can be causes of excessive work being imposed on the heart and can precipitate decompensated HF.
6. The major symptoms of HF are related to congestion: ie fluid accumulation in the body and mainly in the lungs related to poor cardiac output and reduced renal excretion of water and sodium. The cardinal symptom is shortness of breath, or dyspnoea, related to lung oedema. ADHF is characterised by dyspnoea at rest. Dyspnoea which is aggravated when the patient is in the recumbent position is an indication that the patient is severely affected. ADHF may also be diagnosed by radiological evidence. In cases of ADHF chest X-rays will typically show bilateral fluid accumulation.
7. Brain natriuretic peptide (‘BNP’) and N-terminal pro BNP (‘NT-pro BNP’) are molecules from the same natriuretic peptide family, which are produced in the heart. The production of these hormones is stimulated when stress is imposed on the heart. In normal conditions, such production helps the heart cope with excessive exercise, helping blood vessels to dilate (vasodilation), unloading the heart and enabling sodium and water to be more readily excreted from the kidneys, thus preventing congestion. In HF, permanent excessive stress on the cardiovascular system produces an excessive chronic increase of these hormones, and this is further amplified during acute episodes such as ADHF. There is a direct relationship between blood levels of the natriuretic peptides, BNP and NT-pro BNP, and the severity of heart failure. They are accordingly referred to as ‘biomarkers’. The presence of BNP and NT-pro BNP in the blood above a certain level is an indicator of the degree of HF; a drop in the level of BNP / NT-pro BNP indicates that the heart is under less stress and there is less congestion.
8. Cardiac troponins are a group of proteins which help regulate the contraction of the cardiac muscle. Where myocardial cells are injured troponin is released into the blood. This makes troponin a useful biomarker of heart injury.
9. The demographic distribution of patients with acute HF follows that of chronic HF. It mostly affects the elderly. Women and men are equally affected. More men than women are, however, affected by reduced ejection HF (ie where the heart has difficulty pumping rather than filling) because the dominant cause of this is coronary artery disease which affects men more than women.
10. Acute HF is a global public health problem and is one of the leading causes of hospitalisation (and mortality) worldwide, especially in the USA.
Ularitide
11. The drug which was the subject of the TRUE-AHF trial at the centre of these proceedings is ularitide. Ularitide is a chemically synthesized analogue of urodilatin, a human endogenous natriuretic peptide that is expressed in the kidney and regulates renal sodium and water...
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