Special edition: Regulatory Focus

Sharfstein floats new regulatory framework dialing in on safety and backing off on claims

By Hank Schultz contact

- Last updated on GMT

Sharfstein floats new regulatory framework dialing in on safety and backing off on claims

Related tags: Dietary supplements, Dietary supplement, Fda

Former FDA official Dr Joshua Sharfstein, MD, has proposed a new paradigm for the regulation of dietary supplements. The underlying shift would be a move from an attitude of “benefit versus risk” to one of “access with safety.”

"The key equation in drug regulation is benefit versus risk," ​said Sharfstein. "That is, do the potential benefits from using the drug outweigh the potential risks?"

"This framework, however, has led to gridlock for dietary supplements. An alternative framework is access with safety. That is, can we find a way ensure that dietary supplements are safe for consumers to take?”

Industry observers met the proposal with cautious enthusiasm.

“I think there is a move within the industry to accept that there may be a need for a change along these lines,”​ Marc Ullman, an attorney Of Counsel with the firm Rivkin Radler LLP, told NutraIngredients-USA.

Weaknesses of current regime

In a paper published in the Nov. 2 edition of the journal Drug Testing and Analysis​, Sharfstein, along with co-author Akshay Kapoor laid out the history of dietary supplement regulation since the advent of DSHEA and what they see as the critical failures of that regime. Sharfstein, who is associate dean for public health practice and training at the Johns Hopkins Bloomberg School of Public Health, said the key sticking point preventing meaningful progress in fixing the situation is a disagreement over whether and to what degree supplements work, and a fundamental disconnect on how best to prove those benefits, whatever they may be.

Sharfstein and Kapoor, a recent Johns Hopkins graduate, laid out some of the most glaring failures of the current regulatory regime. Large numbers of tainted products masquerading as dietary supplements can be found on the market, often tainted with APIs such as sibutramine or phenophthalein in the case of weight loss products, erectile dysfunction drugs and their analogues in sexual products and steroids and other APIs in the case of sports formulations. The paper also details the widely reported examples of adulteration, in which botanical ingredients such ginkgo or black cohosh are cut with other substances, either closely related species or wholly unrelated material that can help fool certain chemical tests.

The authors also cite the relatively poor industry record in complying with GMP regulations and the enormity of the task facing the agency:

“There is poor compliance with manufacturing standards for dietary supplements. For more than 15,000 domestic and international manufacturers of dietary supplements sold in the United States,the FDA conducts just 400 inspections. The agency finds significant deficiencies in about two-thirds of all the inspections it conducts, with most facilities cited for multiple, serious violations,”​ they wrote.

Enforcement handcuffs

The paper also takes a look at how difficult the enforcement of existing regulations has proven to be. As matters stand, it is incumbent on Federal authorities to prove that a case of adulteration or spiking exists before moving on to enforcement actions.  This allows bad players lots of room to maneuver, as they can fairly easily reformulate with a new analogue of an API before FDA has been able to adequately characterize the existing adulteration.

“Over the last 21 years, the agency has cited hundreds of products for violating the law, but has only sought injunctions or criminal prosecutions against a small subset of them. From 2002 to 2008, the FDA and the Department of Justice only successfully criminally prosecuted 14 companies,”​ the paper says.

Access over efficacy

The authors note that there is no question about supplements going away any time soon. The paper cites the statistic of more than 100 million frequent users of the products in the US market, and notes that another paper in the same journal details a long history of public pressure on legislators to allow the sale of these products, pressure that preceded DSHEA’s inception by decades. The authors went further to state that users want the freedom to take the products even if they are not completely convinced they have measurable health benefits.

“Consumers of dietary supplements have long cared far more about FDA oversight of safety than efficacy.  . . . a recent survey found that more than only 25% of supplement users ‘responded that they would cease their use of a supplement if public health authorities stated it was ineffective.’ These results were consistent with a 2001 study that found more than two-thirds of users would still take their favorite dietary supplement even if the FDA found it to be ineffective,” ​they wrote.

But the authors went on to state that consumers do seem to want assurances that the products have been proven to be safe.

“Four in five supported allowing the government to ‘remove dietary supplements from the market if FDA shows that they are unsafe,’ ” ​the paper notes.

Three phase proposal for change

Given that mindset on the part of consumers, how could the regulatory regime be revamped to best give consumers what they seem to want?  Sharfstein and Kapoor said that the agency should shift to putting more eggs into the safety basket.

“Instead of a broad review of claims by the FDA, new legislation would prioritize stronger oversight of identity of supplements and risk to consumers,” ​they wrote.

This new regulatory model proposed by Sharfstein and Kapoor would consist of three main branches instituted in phases, the first of which would be a pre-market product registration process. While the current regulatory framework does include some pre-market notification aspects, such as facility registrations, structure/function claims or for new dietary ingredients, overall the authors said that FDA is hamstrung in its enforcement efforts by not knowing what is supposed to on the market. A registration process would give FDA a way to quickly remove products that have tried to do an end run around this requirement and would give the agency a tool to exclude products marketed by repeat offenders, which has been a troubling aspect of the current regulatory climate. 

A second phase would consist of setting standard testing procedures for botanical ingredients to better ensure that what’s on the label is actually in the bottle. This second phase would also include a bolstering of the adverse event reporting process.

A third phase would bore in the safety aspect of claims to focus on those that are most likely to result in consumes deciding to forego medical treatment in favor of a supplement or claims in classes of products that pose special risk, such as tainted sexual enhancement products.

“Where all other approaches have failed, the FDA should have special authority in case that products marketed with a specific set of claims are overwhelmingly likely to pose a risk to the public,”​ the authors wrote.

Instituting new regulatory frameworks requires more manpower than the agency can currently bring to bear. In recognition of this, the authors propose a user fee framework similar to those that existing the pharmaceutical and medical device industries. 

Cautious optimism

“I think it’s interesting that it discusses registration rather than pre-market approval. In my view it as a very significant acknowledgement that pre-approval is not an appropriate model for these products,” ​Ullman said. “In the case of the call for mandating specific tests, I don’t think the proposal goes beyond the the theory or the spirit of the GMPs. I think it could be a best practices guidance type of document kind of along the lines of what we see from ABC.”

Ullman said the idea of backing off on claims regulation could be a significant step forward in streamlining the regulatory structure.

“I think we can have some recognition that to some extent that for concerns about claims the plaintiffs bar might not be an inappropriate place to look at these.  Or perhaps the state attorneys general, except in the cases of claims that might some real safety concerns such as cancer claims,”​ he said.

“As long as it doesn’t pre-market authorization I like the idea of pre-market registration,” ​said Mark LeDoux, CEO of contract manufacturer Natural Alternatives International. LeDoux has been spearheading an ad hoc industry group that has been formulating a proposal similar in some respects to that put forward by Sharfstein and Kapoor. 

“I’m interested in his second phase of recommendations that deals with product identity and validated reference materials  and standard testing techniques. That has always been an issue in this industry and if FDA could offer its expertise in a cooperative effort with industry to come up with those and publish them that would be helpful,”​ he said.

LeDoux said he also welcome any proposal that could help put more teeth into the enforcement of regulations.

“I think there needs to be a tacit recognition that we are dealing with a criminal element knowingly violating the law and hiding behind DSHEA to do it. There has to be a clear recognition that that kind of behavior will no longer be tolerated. When enough people start getting actual jail time it could have a deterrent effect,”​ LeDoux said.

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1 comment

The danger of standardized identity approaches

Posted by James Neal-Kababick,

With over two decades in the industry and extensive expertise as the pioneer of phytoforensic investigations into dietary supplements of botanical and non-botanical origin, I caution stakeholders regarding the application of unified standard testing methods/procedures for identity and authenticity of ingredients or label claim as a stand alone solution. Our laboratory has detected numerous novel and innovative schemes for adulteration that spoof existing accepted methods from phosphate detergents in chondroitin to sophora in ginkgo to x-bond analogue drugs and so many more. Until the industry embraces the orthogonal testing approach (identity by multiple approaches both targeted and non-targeted) and commitment to ongoing proactive surveillance, stakeholders will always be at risk when purchasing ingredients not produced in their own facility where they have boots on the ground continuously. That does not mean a yearly visit to an offshore facility. I have personally tested thousands of adulterated samples over the decades and experience proves that bad actors will work to spoof your testing when they know what you are doing. Therefore, approaching identity and other metrics from various angles is critical to avoiding being caught up in the latest fishing expedition. Yes, collaborative standard test methods are a vital part of a total quality program but too many companies have their identity/assay testing on a one legged stool or are using limited targeted or over-focused non-targeted methods that show only part of the picture. While you can never say 100% pure, experience shows that the more you do to examine a test sample the higher the chance of finding adulteration and fraud when it happens and it will happen. One test can often find what another will miss. Therefore, combining methods and utilizing a suite of informational and release data sets will help mitigate the risk if it is done in a strategic manner. Given the substantial challenges faced by manufacturers, nobody can take the risk of existing in a static analytical world. What is great cutting edge methodology today is often very limited tomorrow so continuous innovation and reinvestment into proactive surveillance by someone or a team of someones who know the issues, is equipped with the toolkit needed (ever changing due to rapid analytical technology advancements) and can rapidly adapt to the dynamic market (cross expertise to use real time multiple approaches on the fly) is the best means to reducing risk of novel and unknown schemes before that ingredient is in your facility and product.

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