Call for More Transparency in Gray Area of Post-Approval Drug Studies

Marlene Busko

May 06, 2020

Sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes "have received several serious safety warnings since approval, but the number, timeliness, and strength of these safety communications have differed between American, Australian, Canadian, and European regulators," a new report reveals.

The investigators used the example of this drug class to examine how the four regulatory bodies subsequently communicated the risks identified in post-marketing studies.

For SGLT2 inhibitors, there were reports of diabetic ketoacidosis (DKA), lower limb amputation, severe genitourinary infections, fracture, and acute kidney injury (AKI) with canagliflozin, dapagliflozin, and empagliflozin — from the time when these first members of this new class of oral diabetic drugs were approved until 2018.

"Greater transparency in decision-making would increase the accountability of both regulators and industry and allow more informed treatment choices to be made," say PhD candidate Alice Bhasale from the University of Sydney, Australia, and colleagues in their analysis published online April 30 in BMJ.

Her coauthors are Barbara Mintzes, PhD, an associate professor of pharmacy, also at the University of Sydney, and Ameet Sarpatwari, JD, PhD, an epidemiologist and lawyer from Harvard Medical School, Boston, Massachusetts.  

"We think that regulators should provide public access to post-market safety reports submitted by industry to regulators," which are currently not available or heavily redacted, they told Medscape Medical News in a joint email.

"In an ideal world, collection and reporting of post-market safety data would not rely on industry," they added.

But in the meantime, "public access to post-market safety data, including the safety reports provided to regulators would enable independent assessment of these reports."

However, "our focus was more on the warnings and differences in regulatory decision-making than in an assessment of the overall research evidence," they continue, and not, for example, to interpret the risks of AKI versus renoprotective benefits of SGLT2 inhibitors, or to evaluate amputation risk.

Several clinicians invited to comment on the analysis noted how "issues for regulators are not as black and white as they may seem" and "post-marketing assessment of adverse events is fraught with difficulties in interpretation."

Differences in Timing, Clarity, and Strength of Warnings

"Medicines regulators have an important role in ensuring that newly uncovered risks of approved drugs ['post-market' adverse effects] reach prescribers and patients," Bhasale and colleagues write.

They examined how five safety issues of SGLT2 inhibitors were communicated to prescribers by the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), Health Canada, and the Australian Government Therapeutic Goods Administration.   

They found differences in the number of agencies that issued advisories about DKA and lower limb amputation (all four agencies); AKI and fracture (only Health Canada and the FDA); and severe genitourinary infections (only the FDA).

The timing of the advisories differed by 19 days to 13 months.

"The FDA issued more safety advisories but was not always the first to act," the authors note.

There was an overall lag in transmitting information about the amputation risk with canagliflozin in the CANVAS trial.

Health Canada cited this risk in 2013, when it did not initially approve this drug, but none of the four regulatory agencies issued warnings about the risk until the EMA did so in 2016.

The researchers also found that after extensive negotiations between the FDA and Janssen about the risk of amputation, the FDA agreed to delete "numbers needed to harm" from the prescribing information.

"Regulators have the authority to unilaterally compel industry to make safety-related changes to prescribing information," they write, "but surrounding negotiations can weaken safety messages — as seen with lower limb amputation — and delay risk communication."

On the issue of fracture risk, the EMA was more reticent than the FDA to attribute this to canagliflozin and to communicate the risk to prescribers.

The authors speculate that "fewer safety advisories could arise from regulators' uncertainty about the strength of post-market findings or from perceived drawbacks of frequent notification, such as alert fatigue or excessive alarm."

"And regulators must balance the resources they assign to post-market safety with the attention they give to new drug approvals."

The FDA, they note, currently publishes extensive data about new drug approval and decisions and is one of the only regulators to publish verbatim meeting transcripts, but it is less transparent about post-market safety information.

The EMA has legislation that supports greater transparency, including after drug authorization, than that of other regulators.

FDA Balancing Act, Patients' Misplaced Fears

Invited to comment, Anne L. Peters, MD, said that the more harmonized the warnings and advisories from various regulators are, the easier it is to understand the real risks.

"However, I doubt we will ever see all regulatory agencies working together," said Peters, who is director, Clinical Diabetes Program, University of Southern California (USC), Los Angeles, and professor of clinical medicine, Keck School of Medicine of USC.

Importantly, "post-marketing assessment of adverse events is fraught with difficulties in interpretation," she told Medscape Medical News in an email.

"When I helped identify some of the first SGLT2 inhibitor-induced cases of DKA," Peters continued, "I saw how carefully the FDA had to balance harm and benefit from making a new statement about the risks of the drug class."

"Too often people stop taking a medication they need out of misplaced fear from something they hear on the news," she noted, "which is clearly not what is intended."

Clinicians "want people to continue taking effective drugs, with more awareness of risks and how to minimize them."  

"Personally I wish we had better systems for post-marketing surveillance, but short of that, I think we need to be working with patients to minimize side effects that we do know of, as well as be aware that there are those that may yet be identified," Peters said.

SGLT2 Inhibitors Underutilized, Safety Data Are Nuanced

Meanwhile Deepak L. Bhatt, MD, MPH, of Brigham and Women's Hospital Heart & Vascular Center, Boston, Massachusetts, said: “The biggest problem with SGLT2 inhibitors is that they are underutilized."

Some of that has to do with cost, but some of it is lack of full dissemination of the data to practicing physicians across multiple specialties who care for patients with diabetes, he said.

"Especially compared with older diabetes drugs, the efficacy data supporting use of SGLT2 inhibitors are incredibly strong; their safety profile overall is very good," he told Medscape Medical News in an email.

"So, it is important to first take this 30,000-foot view, and I think that is really the bottom-line for practicing physicians," he said.

Although, he added, "Of course they should be aware of potential for side effects, including genital mycotic infections and DKA, with caution in use in patients who may be volume depleted or at risk for AKI."

Regarding the specific points raised in the article, "being a regulator is a difficult, largely thankless job," Bhatt said, "and the data are much more nuanced than it may seem."

For example, there was a significant increase in amputations in one trial of canagliflozin (CANVAS), but not another (CREDENCE), he continued.

"Does that mean it is a 'real' finding? Should any warning only apply to that drug or is it a class effect? There is always some degree of uncertainty in the clinical trial world, even with large trials, and issues for regulators are not as black and white as they may seem," he said.

Renal and CV Benefits Far Outweigh AKI Risk

Lastly there is the issue of how clinicians should interpret the risk of AKI with SGLT2 inhibitors versus renoprotection seen in the clinical outcome trials.

In CREDENCE, the first dedicated renal trial of one of these agents, patients with type 2 diabetes and chronic kidney disease had better outcomes with canagliflozin than placebo. The agent was subsequently approved by the FDA in September 2019 for additional indications of reducing the risk of end-stage kidney disease and worsening of kidney function, among others.

The other SGLT2 inhibitors are being studied in renal outcomes trials, including dapagliflozin in patients with CKD in DAPA-CKD, which was stopped early at the end of March because of overwhelming efficacy of the drug.

And as just recently reported, a new study found renoprotective benefits of SGLT2 inhibitors in a broad range of real-world patients with type 2 diabetes.

Invited to comment on the current analysis of post-marketing safety warnings, David Z.I. Cherney, MD, PhD, told Medscape Medical News that "The difficulty with having these different [safety] signals from these reporting databases versus trials is that potentially they'll scare patients or doctors from using these medications when there isn't a good reason to be concerned about it."

Cherney, a nephrologist and clinician scientist at the University Health Network, Toronto, Ontario, Canada, said: "There are now trials in more than 40,000 people looking at AKI, and clearly there is a lower incidence" than was first identified, by around 25%.

The safety signals of AKI were probably from sicker, older men taking drugs (such as certain antihypertensives) that can increase risk of kidney injury, he said.

Mikhail Kosiborod, MD, agrees. "The risk of AKI has actually been shown to be significantly lower with SGLT2 inhibitors than placebo in several large outcome trials, in addition to the observed long-term nephroprotective effects," he told Medscape Medical News in an email.

"There are a number of 'safety concerns' mentioned in the prescribing labels for these agents that have not ultimately been demonstrated to be clinically relevant issues in large outcome trials. AKI is one of them, but there are several others," said Kosiborod, of Saint Luke's Mid America Heart Institute, Kansas City, Missouri.

Bhatt added that "for many patients with diabetes, the renal (and cardiovascular) benefits of SGLT2 inhibitors far outweigh the risks of AKI."

"Again, careful physician judgment is needed — for example, in dehydrated, critically ill, hospitalized patients or in those with unstable renal function, it wouldn't be the time to initiate therapy."

Randomized Trials, A Potential Solution

Bhatt said he thinks the best solution to the important issues raised in the BMJ would be more randomized data because this is the best way that physicians (and regulators) can make informed decisions.

Observational data of how a drug (or device) is performing in real life can be useful to identify unexpected, rare safety signals, but even "big data" cannot take the place of randomized trials.

"While industry has done a very good job at funding cardiovascular outcome trials in patients with diabetes (because the FDA mandated such trials), head-to-head trials within a drug class would almost never get funded," Bhatt said.

"Large healthcare systems could easily do point-of-care randomization of one SGLT2 inhibitor versus another, and this would ultimately provide data about any differences in efficacy or safety."

The research was supported by funding from the University of Sydney and Harvard University Mobility Scheme. The authors have reported no relevant financial relationships.

Bhatt has been involved with several diabetes CV outcome trials, including ones with multiple SGLT2 inhibitors as well as other classes of diabetes drugs. He has received research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company.

Cherney has received honoraria from Boehringer Ingelheim/Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometric, Bristol Myers Squibb, and Novo Nordisk, and has received operational funding for clinical trials from Boehringer Ingelheim/Lilly, Merck, Janssen, Sanofi, AstraZeneca, and Novo Nordisk.

Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis.

Peters serves on the advisory board for Medscape Diabetes & Endocrinology and has served on advisory boards for Abbott Diabetes Care, Becton Dickinson, Boehringer Ingelheim, Eli Lilly, Lexicon, Livongo, Medscape, Merck, Novo Nordisk, Omada Health, Optum Health, Sanofi, and Zafgen; received research support from Dexcom, MannKind, and AstraZeneca; and served as a member of a speakers bureau for Novo Nordisk.

BMJ. Published online April 29, 2020. Full text

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