Regulating Botanics: A Bespoke Approval Model For Herbal Medicines? | PharmaBoardroom

Regulating Botanics: A Bespoke Approval Model For Herbal Medicines?

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Herbal-based medicines or botanics have attracted strong attention around the world as part of a growing consumer enthusiasm for natural products, and in the face of a ‘prescription cascade’ in which severe side effects from combinations of classic medicine are becoming a health risk in themselves. However, regulatory frameworks have, in general, struggled to keep pace in properly integrating this branch of medicine.

“The FDA estimates that adverse drug reaction has become the fourth biggest driver of mortality in the United States and a full 42 percent of American citizens over the age of 65 are taking a concoction of five drugs or more on a regular basis”

Saad Harti, Legacy Healthcare

Today, the vast majority of medicines that patients ingest in mature markets tend to be chemically synthesized, potent compounds with unique mechanisms of action, often carrying adverse side effects, untested long-term toxicities and unknown drug-drug interactions. Many believe that this conventional treatment paradigm needs substantial revision. Pointing to studies that suggest that adverse drug reaction is becoming a leading cause of death and that spending on unhelpful drug combinations is an unnecessary and counterproductive drag on health expenditure, numerous practitioners are nowadays instead advocating the widespread use of botanical therapies to manage the symptoms of chronic disease.

“The FDA estimates that adverse drug reaction has become the fourth biggest driver of mortality in the United States and a full 42 percent of American citizens over the age of 65 are taking a concoction of five drugs or more on a regular basis,” notes Saad Harti, of Legacy Healthcare, who believes that such a treatment paradigm is “far from desirable in a world in which fewer people are dying from acute illnesses, but more patients find themselves needing to live with and manage pro-longed chronic disorders that are non-life threatening, I think it’s fair to say that, in numerous jurisdictions, the regulatory mechanisms for dealing with herbal therapies have been sub-optimal and that this has dissuaded many of the big pharmaceuticals players from conducting proper R&D in this domain, but still, requiring day-to-day treatment.” “Current treatment pathways, in many cases, no longer fit with what patients truly expect from a treatment for their chronic disorders: improved quality of life, without triggering other issues so we are suggesting the use of botanics as a complementary therapy to address these shortcomings,” he asserts. In response, drug developers such as Legacy Healthcare, have thus been taking botanical ingredients that people consume on a regular basis and turning them into medicines.

For botanics and phytopharmaceuticals to really go mainstream, however, regulators will need to redefine their approval and assessment frameworks to render them more in keeping with the properties of this specific branch of medicine. acknowledges Charles Wu of the FDA’s Botanical Review Team. “It is precisely because we recognize the value that some of these products can bring and the unique characteristics that botanics exhibit, that the FDA’s Center for Drug Evaluation and Research (CDER) first established a dedicated review team in 2003, then applied a tailor-made set of regulatory policies and ultimately issued updated guidance in 2016,” he says.

While cheered to see the American regulator taking something of a lead on this issue, many would-be botanical drug developers highlight that the path to securing FDA approval for such products remains long, tortuous and uncertain. According to the American Botanical Council, “although more than 500 IND applications have been submitted to FDA for botanical drugs, thus far, only two botanical drug NDAs – namely Veregen®, a topical treatment for genital warts and Fulyzaq™), an oral medication for HIV-related diarrhea – have been put forward and received approval.” Thus while many sponsors have successfully accomplished the IND step over the past 15 years, a mere two have ever reached the final NDA phase.

“Although more than 500 IND applications have been submitted to FDA for botanical drugs, thus far, only two botanical drug NDAs have been put forward and received approval”

Charles Wu, FDA Botanical Review Team

What accounts for this massive discrepancy? “Failure to show clinically relevant and statistically significant efficacy is the single most common reason why most drugs — not just botanical drugs — fail to reach the NDA step,” explains Wu. “Botanical drug products differ markedly from classic synthetic chemical products often displaying unique features such as complex mixtures and lack of a distinct active ingredient which complicate the quality control process making it considerably more challenging,” he points out. Essentially, “because botanical products contain a complex mixture of components, active ingredients may not be fully identified and one may encounter considerable variations in chemical composition and bio-pharmacological activity, which means that Conventional CMC approaches used for quality control of small molecules alone sometimes are simply not sufficient,” elaborates Wu.

Therefore, although many sponsors may firmly believe that their product works, the stringent criteria in place for drug approval in many jurisdictions consisting of documented safety and efficacy from one or more multicenter adequate and well-controlled clinical studies, proves simply too high a barrier for some botanic drug developers to surmount. “Not all botanicals are safe, but by using extracts from the ones our bodies are used to ingesting, we have the chance to develop very safe drugs with few side effects and long-term toxicity,” counters Harti. “Our drugs inherently register much better tolerance profiles than synthetic drugs because rather than extracting a single molecule, we take everything so what is being consumed is as close as possible to what people would be ingesting naturally on a regular basis… Incidentally this also means that we can collect data from the public domain, which you obviously cannot do with a brand new, untested chemical entity, so there is even an acknowledgement of a priori safety,” he argues.

Despite the harsh reality on the ground that, between themselves the FDA and EMA have, so far, only approved three innovative botanical drugs, Harti remains steadfastly optimistic. “We’re still in the early days of this niche and it is normal for regulators to be cautious and hesitant in embracing this sort of disruption, but the direction in which treatment pathways are shifting dictate that it is only a matter of time before a tipping point in reached,” he confidently predicts.

Writer: Louis Haynes

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