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Exa-cel on review at the FDA

Just last week, on 31 October, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee met to discuss Vertex Pharma’s Biologics License Application for Exagamglogene autotemcel (or exa-cel, and formerly known as CTX-001) — a cell-based gene therapy designed to treat sickle-cell diseases.

I have written about exa-cel many times before, both on this blog (here) and in published academic writing too. I have also spoken about it in this podcast. Exa-cel is a therapeutic product that is composed of the patient’s own (autologous) hematopoietic stem cells; however, those cells — specifically differentiation 34+ (CD34+) cells, have been edited using CRISPR/Cas 9 editing machinery (CRISPR).

In short, a CRISPR-Cas endonuclease system (CRISPRs) is a naturally occurring adaptive immune system that exists in most bacteria. These systems prevent bacteria from being infected by foreign genetic elements, such as viruses and phages. Where an infection exists, the Cas9 protein in the CRISPR will cleave or cut one strand each of double-stranded DNA to cause a double-strand break and thus decrease production of progeny viruses. Following that DSB, the genome will be repaired naturally, usually through a naturally occurring process called non-homologous end joining or NHEJ.

But this CRISPR/Cas 9 system can be ‘hijacked’ by science for therapeutic purposes. Using a guided template, the DSBs made by the Cas9 protein can be repaired in a precise and controllable manner, allowing the editing machinery of cell repair to be redirected toward doing repairs or edits that it would otherwise not do unguided.

This is how exa-cel works (in a nutshell). After the patient’s cells have been extracted, they are subject to guided disruption and repair by CRISPR. The CRISPR system make precise DSBs at the erythroid lineage specific enhancer region of B-cell lymphoma/leukemia 11A (BCL11A) gene on chromosome 2. In turn, this process disrupts GATA1 binding and abrogates BCL11A expression. Having turned off the expression of BCL11A, another gene, γ-globin (HBG1/HGB2) is expressed, creating fetal hemoglobin (HbF) production. It is quite complicated; but, in essence, the production of fetal hemoglobin allows people with sickle-cell diseases (red blood cells shaped like sickles because the cells are starved of oxygen) to be restored to health.

There are many issues and risks with this therapy, including the fact that sickle-cell disorder could be a protective disorder against malaria. But one especially concerning prospect, which is really at the core of the BLA on review currently, is the chance that the CRISPR may create cuts or DSBs at a site on the genome locus that is not in the right place. These misplaced or unforeseen cuts are known as ‘off-target effects’ or, alternatively, as indels — which means (usually unintended) insertions or deletions. The BLA puts the risks well:

One of the main concerns related to genome editing technology is risk of cleavage of genomic DNA at unintended sites due to imperfect pairing between the gRNA and the target DNA sequence. A subset of these imperfectly paired sites can be cleaved by the Cas9 endonuclease resulting in unintended edits across the genome. These sites can tolerate up to 6-mismatches between the gRNA and the genomic DNA. Since unintended edits can disrupt gene expression if present in the coding or regulatory DNA sequences, it is critical that the specificity of the gRNA be thoroughly screened to ensure off-target genome editing is minimized.

https://www.fda.gov/media/173414/download

I am still trying to get my head around the recent report of the results of the off-target analysis present in the BLA. The FDA’s BLA report states as follows:

For the cellular off-target analysis, the Applicant used three samples from healthy donors and three samples from subjects with SCD of African American ethnicity. Given the impact of the SCD on [hematopoietic stem cell] function, which can potentially change the chromatin landscape and can impact off-target editing, the merits of using healthy donor samples for such analysis is not clear.

Additionally, it is not clear if the small number of samples used in the cellular GUIDE-seq offtarget analysis is sufficient to adequately assess off-target editing in exa-cel.

https://www.fda.gov/media/173414/download

The report then continues:

4.1.1.1 In Silico Analysis Off-Target Analysis Data for Exa-cel

The Applicant used three publicly available in silico algorithms to nominate potential off-target sites for the sgRNA SPY101 (Figure 6) based on its homology to the reference sequence.

https://www.fda.gov/media/173414/download

Notably, however, when you get to the next page on the analysis of these risks, there are a number of redactions, no doubt because these are commercially protected contents that the regulator must not disclose. On first view, it appears that these ‘in silico algorithms’ to nominate potential off-target sites is, as is said below, a ‘part of the tool.’ I am not quite sure whether that means that the tool — the CRISPR system used be Vertex — is also the same system that conducts the off-target search, or something else. Have a read:

In any case, it looks like the so-called ‘indel frequency’ is very low. As the report noted later, “In this analysis, there were no statistically significant off-target editing events observed at any of the off-targets nominated using in silico analysis.” Although it remains unclear to me precisely how the indel assessment takes place, it is worth noting that the report’s view of the findings of the sponsor are very ambiguous, and tend towards a finding that the results of the study are inadequate. As the report notes in its conclusion of the safety summary section (4.1.2):

These changes have the potential to impact the chromatin landscape of SCD donor derived CD34+ HSPCs. Since chromatin accessibility can influence off-target activity, it is not clear if GUIDE-seq analysis of healthy donor derived CD34+ HSPCs can adequately capture potential off-target editing occurring in patient cells. However, availability of SCD donor cells can be limited and should also be considered. The Applicant used a total of four samples that were from donors of African American ethnicity. Three of these samples were from SCD donors that were used in the GUIDE-seq experiment and hybrid capture sequencing experiment, and one sample was from healthy donor that was used in the hybrid capture sequencing experiment. Given the limited number of SCD samples that were used in the cellular off-target analysis, it is not clear if the GUIDE-seq analysis adequately assessed the potential off-target editing by exa-cel.

Given the ambiguity of the FDA’s assessment, which states that Vertex’s pharmacovigilance plan is still under review, it remains to be seen whether more studies will need to be provided before the FDA consider exa-cel ready for the clinic.

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The Therapeutic Goods Administration has the power to stop misleading advertising. So why can’t it stop Craig Kelly’s texts?

This article was first published in The Conversation. Read the original article.

Earlier this month, many Australians received a text message prompting them to visit the “Australian Government’s COVID-19 Vaccines Adverse Events Report.”

It encouraged recipients to “click link uaptga.info” and informed them the message was “Authorised by Craig Kelly”, a former Liberal MP who has recently joined Clive Palmer’s United Australia Party as its leader.

Was it legal? Probably, yes. But there’s still a problem.

The tricky text

The text was strange and tricky. It presented a link that formed an unlikely portmanteau of acronyms. The letters “uap” (the United Australia Party) were oddly conjoined with the acronym “tga”, which usually stands for the Therapeutic Goods Administration — the Commonwealth government’s regulator of medicines and other health treatments.

What’s more, the domain extension – “.info” – suggested the link might provide an information source.

Though unsolicited, the sending of the text was probably lawful. “Electronic messages” authorised by political parties are usually exempt from the Spam Act or may otherwise be protected as political communication.

By tapping the link, users were redirected to the United Australia Party’s media website. There, visitors encountered several image files. These were screen grabs of five pages extracted from a 73-page document generated using the TGA’s Database of Adverse Event Notifications, or DAEN.

To be clear, this “report” had not been authored by any scientist or staff member at the TGA. It was a user-generated “dump” of notification data. Not unlike a printout of the first few pages of a Google search result, the images provided some of the search results of the regulator’s adverse event notifications database.

‘Report’ or ‘data’?

The problem is these screen grabs captured some (but not all) of the TGA’s data relating to certain adverse events. The data recorded what had been notified to the TGA – as opposed to what had been reviewed or confirmed by the regulator – about patients who had received a COVID-19 vaccine.

These notifications may have come from health practitioners, members of the public, GPs, nurses, and others. It also included unreviewed notification data about Australians’ deaths.

Because the web page was composed of images grabbed from the TGA’s database, it also featured the TGA logo at the top. But incongruously, at the bottom of the page, there was a campaign video featuring Kelly and the UAP.

The TGA’s legislative powers may need to be expanded to cover communications that are not strictly advertisements. AAP/Dave Hunt

The text’s potential effects

Out of context, unexplained, and incomplete, the screen grabs are apt to mislead even a diligent reader of the material. But with millions receiving the text completely unprepared, it’s fair to assume that some, through no fault of their own, would draw false conclusions about it.

After all, there’s little to frame these data. Almost nothing indicates they are the unreviewed tally of notifications. And no disclaimer clarifies that the materials are silent on the all-important medical concept of causality.

Otherwise known as aetiology, this is the scientific study of how these events were caused. Such disclaimers, which actually do appear on the DAEN portal, had been mostly left off the screen grabs.

Even the footnotes that would usually help explain the meaning of each column’s contents had been excised from the screen grabs.

The regulator’s response

The TGA responded to this appropriation of its database materials in two ways.

It first made a statement confirming its lawyers had written to Kelly and his party. But that statement confirmed that only copyright infringement allegations had been raised by the regulator, together with a demand Kelly stop sharing “incomplete extracts of DAEN reports” that “could be seriously misleading”.

Less significantly, the regulator temporarily pulled the DAEN’s PDF-generation capability.

Why can’t the TGA do more?

So why doesn’t the TGA have a clear legal pathway, other than perhaps under copyright law, to stop misinformation being communicated?

In short, it’s because the texts probably do not constitute advertising.

In 2018, the TGA’s powers to control communications about medicines were increased considerably. Several reforms clarified and expanded the regulator’s authority to take civil and criminal action against individuals unlawfully advertising therapeutic goods.

The powerful new laws were quickly used to stop unlawful advertising, with one case resulting in a $10 million fine.

In 2020, a review of the reforms found them to be largely effective and fit for purpose, with some tweaks. Some COVID-related recommendations were made, including that the TGA should consider “responding to non-compliant advertising with sanctions and penalties in a timely manner”. However, the review, perhaps unsurprisingly, did not indicate that the scope or meaning of “advertising” should be widened.

The problem is that none of these reforms has equipped the TGA with powers to deal with communications that are not advertisements.

While the statutory definition of advertisements is capacious, the critical requirement is that the material is “intended, whether directly or indirectly, to promote the use or supply of the [therapeutic] goods”.

And despite a comprehensive regime of legislation for any such promotional advertisement, complete with a separate advertising code, the regime is really set up to control commercial activity that could threaten health consumers’ safety.

It’s arguable the law has not contemplated a situation in which political materials might indirectly deprecate or “demote” a therapeutic good in a way that may threaten health consumers’ safety.

Restricted and prohibited representations

Then again, the TGA has some other powers. It may take civil or criminal action against any person who publishes what the legislation calls a “restricted” or “prohibited” representation.

A restricted representation involves a promotion that refers to a disease, condition, ailment or defect that is classified as serious, such as COVID-19.

The use of this power has seen the TGA fine Pete Evans’s company almost $80,000 to date for promoting, among other products, the so-called BioCharger device for the “Wuhan Coronavirus”.

“Prohibited representations” generally relate to specific products, and prevent manufacturers making prohibited claims about them. This would include, for example, naming something a disinfectant or antiseptic when it is not.

But, again, the problem with both restricted and prohibited representations is they are actionable only when they appear in commercial advertisements or on product labels.

Moreover, the TGA’s advertising code sets out a number of important principles relating to advertising, including that it must be

truthful, balanced and not misleading or likely to mislead, including in its claims, presentations, representations and comparisons.

Again, these requirements apply only to “approved advertisements”.

The party line

Before the TGA released its statement, Clive Palmer, now chairman of the UAP, justified the widespread publication of the TGA materials. Palmer said he welcomed the “legal threats” from the TGA and claimed the “report” showed “COVID-19 vaccine treatment has been responsible for the deaths of 483 Australians and over 46,000 adverse reactions”.

In a later press conference, Palmer rationalised the distribution of this incomplete data as “nothing more than circulating a government report”. He also expressed an intention to subpoena and examine TGA and Health Department officials in any future litigation.

The regulator’s explanation

Before these statements, TGA head John Skeritt had already made clear in a radio interview that these data were to be regarded with great caution. As he noted, the regulator had only found that nine Australians had died in circumstances where there was an aetiological (or cause-and-effect) association with a vaccine.

Given this clarification, the United Australia Party’s stated wish to investigate the health department and the TGA rings strange. But it follows other actions taken by Clive Palmer though his foundation in 2020 relating to therapeutic goods.

In April and May 2020, the Palmer Foundation imported some 32.9 million “doses” of hydroxychloroquine — some time before vaccines had been designed — as a gift to the Australian government’s National Medical Stockpile. The donation was announced in newspaper advertisements across the country.

By May 2020, some 7 million tablets had been tested and analysed in a TGA-certified facility and entered into the government’s strategic reserve.

But hydroxychloroquine had never been approved for the treatment of COVID-19 in Australia. And by the time the donated shipment reached the health department, hydroxychloroquine had already been restricted to five specialties of medical practitioner.

Therapeutic goods and modern politics

COVID-19 has thrown up new challenges for therapeutic goods regulation. And it would seem that when dubious claims about medicine are made by politicians in the political – as opposed to the commercial – context, neither the therapeutic goods law nor the Australian consumer law is likely to provide a clear way of stopping them.

Of course, the implied freedom of political communication, first recognised by the High Court of Australia in 1992, will usually be expected to give a strong protection to politicians who share relevant information with their would-be electors or (re-electors).

Still, in recent years, the intensifying state of unchecked political speech has led to a push from politicians and legal experts alike for federal truth in political advertising laws.

Although some will express doubt about the practicability of these proposed reforms, it may be that, until some such reform is realised, we must take our scientific data from politicians with a healthy pinch of salt.

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A Remedy for False Cures?

Australia’s Therapeutic Goods Administration has been more vigilant in policing advertisements for unproven COVID-19 ‘treatments’. But have some slipped through the cracks?

This article was first published on Pursuit. Read the original article. It is co-authored with Professor Megan Munsie.

Beware false COVID-19 cures.

The COVID-19 pandemic has seen the emergence of multiple dangers. The obvious public health danger is the novel coronavirus strain and the disease itself.

But a secondary threat has emerged for health consumers.

Since March, several unregistered ‘treatments’ for COVID-19 have been advertised to the public. Most are untested and unproven.

A controversial example was the Biocharger NG, a “hybrid subtle energy revitalization platform”. That product was unlawfully promoted as a COVID-19 remedy by former celebrity chef Pete Evans. Evans’ company was issued infringement notices totalling $A25,200.

Although no clear cases of liability have arisen in Australia, it’s not difficult to imagine these advertisements causing harm. In a period already witness to anxious consumer behaviour, a spell of pharmaceutical panic-buying might just be too predictable.

The administrative body responsible for controlling drug advertising in Australia is the Therapeutic Goods Administration (TGA). The TGA wields considerable regulatory power to ensure no individual or company promotes unproven therapeutic goods to the public.

In recent months, the TGA has used its powers rather vigilantly. But unlike the newly-crafted emergency orders declared in our states and territories, the TGA’s swift and strict response comes from pre-existing levers.

The TGA’s Regulatory Clout

The TGA’s ability to act against “restricted” and “prohibited” advertisements emanates from legal amendments made as long ago as 2003.

But more recent changes have enhanced the TGA’s powers.

Following a major review, the TGA became the sole complaints handling body for drug advertising nationally in 2018. Further amendments that year gave the TGA a more punitive offence regime.

In many ways, COVID-19 has been the first real test of this greater regulatory clout.

Communication over Complication

But the TGA is a complicated organisation with complicated rules.

After years of incremental tinkering, the therapeutic goods legislation is diffuse and intricate. If this legal complexity alienates consumers at the best of times, it must bewilder during a global pandemic.

The administration’s principal regulatory powers come from the Therapeutic Goods Act 1989 (Cth). But several subordinate materials, including the Therapeutic Goods Regulations 1990 (Cth), the Therapeutic Goods Advertising Code (no 2) 2018 (Cth) (or, ‘the Code’ for short) and dozens of guidance documents, supplement this primary law.

The pandemic has required the TGA to improve its communications to cut through this complexity. Now more than ever, up-to-date guidance has been crucial to reach stakeholders and consumers.

To that end, the regulator has issued several important warnings on its main website and in its specialised ‘advertising hub’.

As COVID-19 was just emerging, the TGA announced that any therapeutic goods advertisement referring to the ‘novel coronavirus’, whether explicit or implied, would be a “restricted representation”.

Although the warning did not explain the mechanics of the legislation, identifying and controlling “restricted representations” is central to the TGA’s advertising controls.

So, What Exactly is a ‘Restricted Represntation’?

The primary law defines a “restricted representation” as a representation about therapeutic goods referring to a disease, condition, ailment or defect that the Code classifies as “serious”.

Back in 2005, the Code listed a range of “serious” diseases, stopping advertisers from promoting related treatments without permission. But today, the Code provides more flexible criteria.

A ‘serious’ disease may be one that, for instance, requires practitioner-led diagnosis, testing or screening.

COVID-19 was quickly identified as a serious disease, and advertising referring to it was said to be a restricted representation. But what kinds of penalties can be imposed?

Enforcing restricted Representations

In 2018, the TGA introduced a new offence regime for unlawful advertising.

Publishing an advertisement likely to result in harm was now an aggravated criminal offence, punishable by a jail term of up to five years and a fine of up to $A888,000 (or both). Civil penalties for non-compliant advertising could incur fines of more than $A1.1 million for individuals or $A11.1 million for body corporates.

Given the quantum of these maximum penalties, it’s arguable that the actually-issued infringements have been minor.

In June, a Sydney-based chemical company was fined $A63,000 for unlawfully advertising a medicine known as RibaMin. On its website, the ingestible tablet was described as a “low-cost effective treatment for the devastating COVID-19 virus (and possibly other related viruses or mutations)“.

It was the lone ‘pharmaceutical’ amid a host of maintenance chemicals, including concrete polishing and graffiti control products.

Earlier in June, a Cairns-based technology company was fined $A50,4000 for advertising a large tank said to produce a purified form of molecular hydrogen as a treatment for COVID-19.

In addition to these novel products, a Melbourne-based company was fined $A12,600 for unlawfully advertising a seemingly more conventional product – a COVID-19 test kit. But as the advertisement referred to COVID-19 without TGA permission, it was a restricted representation.

Evaluating the TGA’s Response

Though the pandemic has tested all levels of Australia’s healthcare system, it has been a special test for the TGA.

From all appearances, the TGA has been more vigilant than ever in policing non-compliant advertising during the COVID-19 pandemic. However, it’s possible some non-compliant advertising has slipped through the cracks.

In early April, the US Federal Drugs Administration (FDA) wrote to a Perth-based company promoting herbal remedies to animals, including COVID-19 treatments.

The FDA warned the company that it had violated US law by making its products available for purchase by US citizens.

But it seems no infringements were issued to the company by the TGA, possibly due to a regulatory exception that excludes homeopathic practitioners from the regulatory regime, or because the goods were not advertised for human use.

Moreover, the TGA has been criticised for not imposing more stringent penalties during the COVID-19 period.

As one critic noted, the fine imposed on Pete Evans’ company for advertising the “energy revitalization platform” is less than the cost of just two of those unapproved devices.

Time will inevitably reveal whether the TGA has responded adequately to the unlawful advertising of unapproved products during COVID-19. What’s clear, however, is that the TGA has never been better equipped to control false cures than now.