In March 2020, FDA released a new guidance regarding the enforcement of adverse event reporting requirements for medical products and dietary supplements during a pandemic. Recognizing that the COVID-19 pandemic is likely to reduce a firm’s capacity to comply with adverse event reporting requirements, this guidance was provided to help firms strategize the use of their resources and the FDA prioritize their focus to reports related to medical products indicated for the treatment or prevention of the pathogen causing COVID-19.

Please note that although this guidance may relax some of the timeframes for adverse event reporting required by statute and regulation, the FDA still encourages all firms to plan to maintain the highest possible level of adverse event monitoring and reporting throughout the pandemic period. All adverse event data should be handled using the usual standard operating procedures, and regulatory and statutory requirements for adverse event reporting should be met to the maximum extent possible.

We’re here to help

Let Supplement Safety Solutions be your regulatory partner during these uncertain times. We can help you maintain the highest level of adverse event monitoring and reporting while you navigate the impact of the COVID-19 pandemic on your business operations. We’ll review all Adverse Events associated with the use of your supplement.  review all follow up on selected cases — including interaction with the consumer when necessary — maintain source documentation, and assess and document every Adverse Event report. When the pandemic is resolved, we’ll serve as your Responsible Person to the FDA, reporting all Serious Adverse Events on MedWatch Form 3500A or the Safety Reporting Portal (SRP) and interacting with the FDA on your behalf. Contact us today for a free consultation.

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The role of the regulator cannot be overstated. Regulation has been a fundamental aspect of the medico-industrial complex since the Pure Food and Drugs Act was passed in 1906 and the Food and Drug Administration (FDA) was established in the 1930s. Recently, the United States Dietary Supplement Health and Education Act (DSHEA) propelled the regulatory framework surrounding supplements as foods through the FDA [1]. This marks an important landmark in the FDA’s role as the regulatory watchdog for drugs and medical devices. Previously, the thinking put forth by FDA regulators, was that drugs were considered to be unsafe until proven otherwise, whereas dietary supplements were considered safe until proven unsafe. Fundamentally, this line of thought is fraught with limitations and loopholes—some of which can be dangerous and cost lives. Although the vast majority of dietary and nutritional supplements can be ingested safely and without ill effects, the lack of prior regulation led to some companies being less-than-honest in their manufacturing practices.

Introducing GMP and FSP

Published in 2007, Good Manufacturing Practices (GMP) ensured that each manufacturer was responsible for establishing the supplement’s ingredients and final specifications. In 2011, this was expanded to mandate that manufacturers had to conduct a hazard analysis and implement risk-based preventive controls for all dietary supplements through a Food Safety Plan (FSP) [2]. Although this clause was mandated by GMP, a study conducted in 2013 found that out of 44 North American herbal products which claimed to contain single herbs, only 48% of them contained any of that purported herb to begin with [3].

The Complexity of Adhering to GMP and FSP

Supplement companies today are required to not only adhere to GMP, but also perform routine hazard analysis and implement risk-based controls (including supply chain control). Hazard analysis is defined as the “steps in the process of creating that ingredient, consider what might happen at each step that could create a health hazard, determine what preventive controls are required for controlling that hazard and document the verification and validation of those controls.” If that wasn’t a mouthful, this hazard analysis can only be performed by a “preventive controls qualified individual” as well. Furthermore, this FSP must be repeated every 3 years in the life-cycle of a supplement, even after it is in the post-market stage.

Adapting to New Climates

Clearly, the FDA has tightened its vice-grip on the dietary and nutritional supplement market, and for good reason too. There should be no reason why dietary supplements should be subject to any less scrutiny than off-the-shelf drugs. However, companies that struggle to adapt to this new climate or learn the ropes fast enough to adhere to this new regulatory framework may find that their trajectories to market are stymied. Supplement Safety Solutions is an industry-leader in the supplement regulatory space. Our experts have decades of experience and are well-versed with the new and developing regulatory framework. 

We Are Entrepreneurs, Just Like You!

We fully understand budget restraints and the reality that you want to focus your time and money on areas that will help you effectively market your brand and ultimately make sales.

The fact of the matter is that we help supplement brands navigate their way, so that you don’t run into problems that could very well make things worse than you can even fathom—problems that would either cost your company exponentially more and/or risk losing your brand all together.

Call on us, so that never becomes your reality. We are here to help you and your brand survive and thrive!

References

1. Bailey, R.L., Current regulatory guidelines and resources to support research of dietary supplements in the United States. Crit Rev Food Sci Nutr, 2018: p. 1-12.

2. Levin, M.D., The New Food Current Good Manufacturing Practices and Their Effect on Dietary Supplement Quality: What You Need to Know. Integrative medicine (Encinitas, Calif.), 2016. 15(5): p. 22-24.

3. Newmaster, S.G., et al., DNA barcoding detects contamination and substitution in North American herbal products. BMC medicine, 2013. 11: p. 222-222.

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Being the “Responsible Person” (RP) is a big responsibility ( no pun intended). Whomever takes on that position needs to take it very seriously, because that person is responsible for interacting with and reporting to FDA adverse events (AE) and serious adverse events (SAE). This is not a “check box” type position, to be performed by anyone at the company with some free time.

Although FDA is not explicit about the professional qualifications of the RP, manufacturers are encouraged to “use trained health care professional to elicit information from reporters.” The RP may also use computer-assisted interview technology, targeting questionnaires and other methods. At the very minimum, the RP should document efforts to obtain the minimal elements, and seek the injured person’s permission to contact their health care practitioner (HCP).

The RP is a kind of medical detective, seeking to gain a clear understanding of what happened with the AE or SAE. This will involve asking questions of the person reporting the AE, and going beyond merely regurgitating what this person presented. The benefit of having a medical background is that there are many things that can cause an AE, such as medical conditions, medications or other supplements. In addition, in my opinion, people reporting an AE are more likely to give additional information if they are speaking with a qualified health care professional .

Aside from creating a high-quality narrative and mailing the MedWatch 3500 or 3500A form to FDA, realize that the RP may be required to talk or communicate in writing with FDA about a particular case or supplement. All correspondence for a particular case should be saved electronically or in hard-copy, and be accessible should the FDA auditor request it (they can and will!). Such a request to communicate with FDA may come completely out of the blue, so you need to be prepared.

As the RP, your first duty is to gather as much information as you can about the case and then write the narrative. At the core of your work is the safety of a supplement in a typical user. You need to communicate to the company that employs you that this is your primary responsibility. While you don’t want to communicate the AE in the worst possible light for a company, you must be factual and provide clear, concise information about the case, and not sugarcoat an AE. You will also communicate to your employer (the Supplement Company) that FDA expects to see AE, and if you consistently write high-quality narratives, FDA will have more confidence in the company. Over time, that will pay dividends.

So take your job as RP seriously – it’s an important one.

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The narrative section of the MedWatch 3500A form is the heart of the SAE report, and should contain all important information about the case, presented in a reader-friendly fashion. The narrative is likely the first part of the MedWatch read by the medical reviewer (and possibly the only part!), and should be concise, well-written, and provide all important details about the case.

Remember that the minimal elements that FDA requires are:

1. An identified injured person
2. An identifiable initial reporter
3. Identity and contact information of responsible person
4. A suspect dietary supplement
5. A serious adverse event or fatal outcome

However, in order to best promote safety and demonstrate to FDA that your company is serious about safety, you need to do more than the minimal. You must demonstrate that you’re serious about safety by investigating all reports, and documenting those reports well. Let’s look at an example.

Adverse Event: irregular heart beat and passing out

Minimal Elements Approach

A nurse from a biotech company (initial reporter) called customer service at The Greatest Supplement Company, Inc., to report that a male employee (injured person) experienced an irregular heart beat and passed out (adverse event) during work hours and was transported to a nearby emergency room. The employee said that he had just started taking supplement MBC, a.k.a., Mass Building Compound (suspect dietary supplement) within the past week.

If following the minimal elements approach, the Responsible Person would simply report the text as above to FDA in the Form 3500 or 3500A [Note: it is not necessary to write out the words “initial reporter” or “adverse event” in parentheses. This was done here for illustrative purposes].

High-Quality Approach

If the Responsible Person is doing his/her job at or for the Supplement Company, additional investigations should occur. These may include contacting the user, getting permission to talk to the treating nurse and emergency room physician, obtaining additional medical history and medical records. After having a ten-minute conversation with the injured person, a five-minute conversation with the ER physician, and reviewing the emergency room notes, the Responsible Person writes the following narrative.

A nurse from Biotech Company ABC called customer service at The Greatest Supplement Company, Inc., to report that a 25-year-old male employee experienced an irregular heart beat and passed out (adverse event) during work hours and was transported to a nearby emergency room. When seen in the emergency room, the patient’s heart rate ranged between 180-200 beats per minute (bpm), and the electrocardiogram showed supraventricular tachycardia. The patient’s blood pressure was 100/60 mm Hg, and he complained of feeling slightly lightheaded. He was given Verapamil 10 mg by intravenous push, and within 2 minutes, his rhythm reverted to normal sinus rhythm with a rate of 80 bpm, and he became symptom-free. He was observed for another hour in the ER, and told to contact his primary care physician the next day. The ER note documented a weight of 240 pounds and a height of 5’10”.

Additional history obtained from the patient revealed that he had been taking the supplement Hydroycut 2 tabs twice a day, and green tea extract product approximately four times per day. He had started taking Supplement MBC (2 scoops per day) during the past week in order to put on muscle. During the 4 days prior to the ER visit, he complained of having a head cold, and had taken an over-the-counter nasal decongestant with phenylephrine.

Company Comment (optional): in the opinion of the Responsible Person, these events are not likely related to Supplement MBC, but rather to Hydroxycut, phenylephrine or a combination of the two. Supplement MBC does not contain any cardiac stimulatory components, while Hydroxycut and phenylephrine are known to increase heart rate, and have been associated with rapid heart rate.

Which report of would you like FDA to see?

Which report provides better information on the safety of your product?[/vc_column_text][/vc_column][/vc_row]

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The assessment of causality – whether the supplement caused the adverse event (AE) – is a very important part of the safety assessment. Although the lawyers out there would argue that it’s very difficult (if not impossible) to prove that a supplement caused an event, there are some factors strongly in favor of causality. These include:

1. Did the event happen in close proximity to taking the supplement? This may be minutes or hours, but certainly within a reasonable time since taking the supplement.
2. Does the AE make sense? (a.k.a., biologic plausibility). Fat burners tend to have ingredients that stimulate the sympathetic part of our nervous system, and frequently are associated with rapid heart rate, high blood pressure, or palpitations, to name just a few. If these AE occur, this makes “sense”, given the mechanism of action of the supplement.
3. Does the same AE happen a second time? (a.k.a., positive re-challenge). This is the most powerful factors suggesting causality. If an AE happens twice in a row, especially if it is severe, it makes sense to not try it again, and, of course, to report the AE to the manufacturer.
4. Has it ever been reported in published literature or with a similar product? In my opinion, there is a reporting bias in the literature about AE associated with dietary supplements. By this I mean that if a physician has a patient who experiences an AE with a dietary supplement, then s/he is more likely to report it to the company compared with a drug (even if the AE is identical!). But if someone has taken the time to report an AE in a publication, and it makes sense, then it is more likely to be causally related to the product.

So what’s the value in carefully investigating causality? First of all, you get valuable information about your product, which is important, because you as the manufacturer are responsible for assuring the safety of your supplements. If you discover that one of your supplements consistently causes adverse events, you might either modify your label, withdraw the product, or decide to reformulate or re-engineer your supplement, in order to minimize the AE.

Secondly by noting the causality in your AE narrative, you’re writing to a standard that the FDA reviewer is accustomed; i.e., the same standard that pharmaceutical and biologics companies adhere to when they send in an AE report.

Finally, while you’re investigating potential causality for an AE in a user of one of your products, realize that you may find alternative causes for the event, which may be more likely to have caused the AE. This is important, and you would note this in the causality assessment.

Sometimes, the event is not consistent with your product’s safety profile, but the timing (i.e., occurred shortly after taking the supplement) makes it difficult to rule out a causal relationship. In that case, write, “The event is not consistent with the known AE profile of the supplement, and in the opinion of the manufacturer, this event is not related to supplement use. However, the temporal relationship makes it impossible to rule out the product as a potential contributor to the event.”

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