Primer Suspect
PCR testing data , Issue 1565 BIOTECH company Primerdesign, which pocketed millions of pounds from taxpayers with its early development of Covid-19 PCR laboratory kits (Eye 1556), is now at the centre of claims that it faked validation results for one of its more recent products.

Owned by French group Novacyt, Primerdesign is said to have falsified data for a three-gene kit in order to cash in on last summer's travel demand for 'test to release' PCR tests. It is also accused of persuading the head of an NHS laboratory to provide the 'independent' validation report required before it could market its 'genesig Covid-19 3G assay', which falsely claimed the test was more than 99 percent accurate. As a result, the kit has sold in the UK and abroad mainly into the lucrative private PCR-testing market for international travellers, essential workers and those in the film, media and corporate world.

Novacyt is already at the centre of a multimillion-pound legal dispute with the Department of Health and Social Care (DHSC) over a September 2020 deal to supply PCR machines and tests to hospitals. The DHSC cancelled the contract amid claims the 'rapid' multi-testing process was not as straightforward or accurate as the company had claimed.

The Eye has now learnt that a whistleblower complained last summer to the Medicines and Healthcare products Regulatory Authority (MHRA) about the validation of the three-gene kit. This apparently followed senior project staff brushing aside widely expressed concerns over potential implications for scientific integrity and public health.

False positives
TO MEET government requirements for Day 2 testing for those entering the UK, the tests were meant to achieve 99 percent specificity and sensitivity (ie accuracy in detecting true positive and negative results) matched to at least two specific targeted Covid-19 virus genes. It is claimed the test was ultimately validated by recording a 'positive' finding if only one of the three targeted virus genes was a match, but even then it never hit the 99 percent target. It did render it, however, more liable to throw up false positives.

Although not as instantly hazardous as false negative results in spreading disease, false positives risk having a financial impact on business and individuals, distorting Covid-19 incidence and prevalence data, and putting unwarranted demands on NHS Track and Trace.

The MHRA was told that:

• Validation was rushed through without quality control or proper oversight because a £10m contract with a large testing company was at stake;

• Sample processing and data analysis, though supposedly carried out by six named staff at Gateshead's Queen Elizabeth Hospital, was in fact performed by two Novacyt/Primerdesign staff who are not identified in the validation report, thereby hiding company involvement;

• 'Unfavourable' results were wrongly discarded and test protocols were watered down and rewritten with the aim of obtaining more accurate results;

• The validation report was signed off by Natasha Walker, pathology lab manager at the hospital, on 28 May, while analysis by Primerdesign staff was still underway in early June.

Sales staff, meanwhile, were already out successfully selling the kit.

Whistleblowers have also told the Eye that last summer, after customers reported low-level positive findings in one-gene kits, Novacyt found contamination in its Southampton laboratory where it makes the kits. Instead of recalling the batches, however, it conducted tests to show the levels of background positivity and told clients to apply a cut-off point below which they should not record a positive result.

The MHRA told the Eye that for reasons of confidentiality it could not discuss Novacyt/ Primerdesign or say whether it was investigating a complaint. But one Novacyt name that might raise a red-flag with the regulator is that of Ajan Reginald, its chief technical officer until he left the company on new year's eve.

Reginald, a former dentist who was struck off for harming patients and defrauding the NHS, is also CEO of stem cell company Celixir. The MHRA is already investigating Celixir following complaints of serious research misconduct and concerns over patient safety involving trials of its 'heartcel' therapy in both Greece and more recently at London's Brompton Hospital (see Eye 1526). The Brompton trial was halted by the regulator after one of a proposed 50 heart patients had been injected with the stem-cell product.

Reginald, who had made Celixir's Stratford-upon-Avon lab available to Primerdesign, is said to have had oversight of the three-gene product and his name also appears on the contested contract with the DHSC.

Rapid expansion
PRIMERDESIGN was a small, well-regarded molecular diagnostics company until the pandemic opened up a new world market for Covid-19 testing. As with other biotech players, developing polymerase chain reaction tests to detect Covid-19 was a relatively simple process: PCR has been used since the 1990s to identify infectious diseases and genetic changes. But Novacyt was quick off the mark, developing one of the UK's first coronavirus testing kits in January 2020, which was soon approved by the World Health Organization and won regulatory approval in the UK and US. The company rapidly expanded its manufacturing, recruited dozens of new staff and revenues soared.

The £178m profits for 2020, boosted by the pandemic, came in significant part from two UK government contracts, signed in April and September that year supplying PCR tests, instruments, related kits and support services to hospitals. But the September deal went sour amid reports that the lab testing process was not easily compatible with NHS swab tests, was too complex and time consuming – and was producing sensitivity results lower than Novacyt had indicated.

Government lawyers are now involved in a £100m-plus dispute with Novacyt. The DHSC said it could not comment on legal proceedings or contractual arrangements but told the Eye: 'We have always been clear that government contracts must demonstrate value for taxpayers and good commercial judgement.'

Big hit
NOVACYT's 2021 half-year accounts, however, show the company has taken a big hit due to the dispute. Despite maintaining that it has 'strong grounds to assert its contractual rights', the Anglo-French operation is writing off £40.8m of DHSC revenue, £6.9m in manufacturing costs and a further £28.9m to write down the value of stocks of the Covid-19 tests it had built up in expectation of further government contracts.

Another factor affecting its fortunes is the government's new Coronavirus Test Device Approval (CTDA) register, which requires suppliers of Covid-19 tests to submit the data on their products for approval by the UK Health Security Agency. The register was introduced to allay widespread concern about the reliability of both PCR and lateral flow tests. In November, Novacyt announced that its genesig Covid-19 Real-Time PCR test which targets one gene had been approved, while its Promate one-gene tests remained on a temporary list awaiting validation.

Novacyt said it was awaiting updates on another eight products it had submitted for CTDA approval but as of 1 November they cannot now be sold in the UK. That includes the three-gene kit, now at the centre of claims of scientific fraud, although it seems it can still be sold abroad.

The Eye put the whistleblower allegations and relevant questions to both Novacyt and to the Gateshead Health NHS Foundation Trust. Both chose not to answer or deal with them, instead issuing brief statements. The trust said: 'Our pathology department is a world-leading facility which processes millions of tests every year – and as such, our skilled staff follow all procedures and protocols to the highest standards.'

Novacyt said: 'The genesig COVID-19 3G product has been subjected to a comprehensive and rigorous performance evaluation. The product was deemed highly sensitive in the analytical study, producing a limit of detection (LOD) of ? 1 copy/µl of SARS-CoV-2 whole viral genome RNA. This analytical study formed the basis of its CE mark.'

The statement added that the product 'has also been the subject of multiple, successful, external independent evaluations undertaken by travel testing providers as a part of their own validation processes prior to the product being used'. It also confirmed that data, the analytical validation and the clinical performance studies for the kit had been sent for the new CTDA authorisation, but said the product, 'along with hundreds of tests from other manufacturers is still awaiting approval'.

However, a CE mark is merely a self-declared assurance that the manufacturer, ie Novacyt itself, has checked that the product meets EU safety, health or environmental requirements.

As one expert in molecular biology told the Eye: 'The analytical sensitivity of the limit of detection, cited by Novacyt, ie the ability to pick up one genome copy, is not the same thing as the clinical sensitivity in detecting the proportion of true positive results. For this validation, there needed to be 99 percent true results which were never met. If the initial validation was flawed and not performed independently, then it should not have been sold to travel testing companies or indeed anyone else until such time as a proper independent validation with the stated sensitivity of 99 percent was achieved.'

Insiders suggest a number of staff have left in recent months, concerned over scientific standards. Novacyt CEO Graham Mullis has also departed, but not until he had pocketed £8.5m from last year's bonanza. With a possible MHRA investigation looming, and increased scrutiny by the government and its auditors of the vast profits made by manufacturers and suppliers who got rich quick from the pandemic, his timing was perhaps fortuitous.