Does the FDA approve the use of CBD products? Is CBD oil legal in the United States?
- In December 2018, the Agriculture Improvement Act of 2018 (also known as the Farm Bill) allowed the use of CBD from hemp as long as it had less than 0.3% of THC content present. (1)
- The 2018 Farm Bill came with a set of rules on the cultivation of hemp, stating that cannabinoids obtained from the plant are only allowed under certain requirements. (2)
- Each state in the U.S. has policies regarding industrial hemp. Texas, for instance, allows the growing and cultivation of the plant while Idaho considers its production illegal. (3-4)
- The FDA is planning to take steps to give more clarity regarding CBD use and is also considering to regulate its products similar to dietary supplements. (5)
- Epidiolex, a CBD drug used in treating two rare forms of epilepsy, has been descheduled as a controlled substance by the DEA on April 6, 2020. It was previously classified as a Schedule V drug under the CSA. (6)
What Does the Federal Law Say About CBD?
There are two types of the Cannabis sativa plant that the federal government recognizes: marijuana and hemp.
Marijuana is the more popular of the two and is grown to contain high levels of tetrahydrocannabinol or THC, the component that gives cannabis its psychoactive effect. It also contains cannabidiol (CBD), which is reputed for its therapeutic properties, although at very low levels. (7)
Hemp, on the other hand, contains high levels of CBD and a few traces of THC.
The Agriculture Improvement Act of 2018 (Farm Bill), which was signed into law in December 2018, made CBD obtained from hemp plants legal so long as it had no more than 0.3% THC. (8)
However, CBD derived from the marijuana plant is still illegal under the Controlled Substances Act as it is a Schedule I drug by the Drug Enforcement Administration (DEA). (9) This classification means that the DEA believes it does not have an accepted medical use while having a high probability of abuse.
With the Farm Bill also came a set of regulations for hemp cultivation, which states that cannabinoids acquired from hemp are only allowed if it meets certain requirements. (10) For instance, CBD-based products that contain the approved amount of THC but had hemp that was not grown by a licensed cultivator is not legal.
What Are the State Laws On CBD?
Even though the government approves CBD derived from the hemp plant, individual states are changing their laws, which are not always the same with federal regulations.
For instance, Texas has just recently allowed the growing and cultivation of industrial hemp, while Idaho still considers its production illegal. (11-12)
Some organizations maintain online databases containing the latest state laws concerning CBD, allowing for easy access to hemp policies.
Evaluation and Rulemaking of Cannabidiol
The U.S. Food and Drug Administration (FDA) released a statement on March 5, 2020, concerning their progress on creating a regulatory approach framework on CBD products.
They also sent a consumer update report on their rulemaking progress to Congress. An exciting development mentioned in the report was that the FDA is looking into regulating the said products similar to dietary supplements. (13)
The FDA is planning to take several steps in providing more clarity to the market, while also ensuring the safety of the public.
One of their primary goals is educating the public on the possible risks that are linked to CBD use. The FDA believes that there are risks involved when using these products outside of a prescription. (14)
The administration is also aiming to clarify questions regarding the safety and potential benefits of cannabidiol, urging CBD industry stakeholders to provide them with quality data. Among their areas of interest are the impacts of long-term use, sedative effects, delivery mechanisms, and pharmacokinetics. (15)
Concerning enforcement policy, the FDA sees a risk-based approach to be the most viable moving forward.
Although marketing CBD products as dietary supplements is not allowed, the FDA states that they have the authority to change this ruling at any time.
Another topic that the FDA discussed was on CBD vaping products, wherein the agency mentions that there is a high risk of toxicity problems that could arise with their use. It also emphasized that CBD for vaping cannot be sold as a drug without getting FDA approval.
The report does not provide a lot of changes in terms of policy updates as it focuses on the ongoing efforts they have in developing CBD rules. However, the FDA appears to be heeding the public, which has repeatedly entreated them to legalize the CBD market further.
Are There Any FDA Approved CBD Products?
In 2018, the FDA approved the use of Epidiolex, a drug containing CBD, to treat two rare forms of epilepsy: Dravet syndrome (D.S.) and Lennox-Gastaut syndrome (LGS). (16) It is sold as a liquid solution that is taken orally and allowed for use in patients two years of age and above.
According to clinical studies, Epidiolex is capable of reducing the number of seizures in people that take this medication. (17)
A study in 2015 on more than 80 LGS patients shows a reduction in their seizures after being given regular doses of Epidiolex for 12 weeks. Although most of them experienced adverse effects in the form of diarrhea, decreased appetite, and fever, the research hints at the efficacy of the medication and its long-term safety profile. (18)
A follow-up study in 2017 was carried out on 61 patients employing the same approach, method and time to prove the safety and efficacy of CBD on those suffering from D.S. All of the patients reported a significant reduction in the number of seizures experienced as well as the average duration of a seizure. (19)
Although scientists do not yet know the full potential of this anti-epileptic drug, the results they have seen thus far encourage the use of CBD for epilepsy.
Epidiolex Descheduled by DEA
GW Pharmaceuticals, a biopharmaceutical company that promotes cannabinoid use, announced in their press release on April 6, 2020, that Epidiolex is no longer subject to the Controlled Substances Act (CSA). The change takes effect immediately after the United States Drug Enforcement Administration (DEA) informed them of this update. (20)
Following the approval of Epidiolex in 2018, it was first assigned as a Schedule V drug in the CSA until the recent notification from the DEA, which essentially removes this designation.
This change also means the abolishing of specific rules that restricted the use of Epidiolex in the past. G.W. Pharmaceuticals is now implementing this change beginning at the state level and via the Epidiolex network.
After the process has been completed, prescriptions of the drug, just like the other non-controlled medicines, are going to be valid for a year and can be transferred easily between pharmacies.
The descheduling of Epidiolex by the DEA also allows doctors to prescribe this medicine free of the standard requirements of state prescription drug programs.
How CBD Can Appease the FDA
Last year, the FDA sent out warning letters to several CBD manufacturers making unsubstantiated claims regarding the therapeutic uses of cannabidiol. (21) This type of practice is what the FDA remains concerned with, and they plan to take action against small businesses that continue to do so.
Avoiding the ire of the FDA is crucial for CBD companies if they wish to continue their operations. Below are some aspects that retailers should be mindful of when selling CBD-based goods.
- Any type of claim should not be present in product reviews and testimonials.
- Inserting a hashtag claim (#paintreatment, #anxiety, #CBDheals) can increase the risk of a company from being warned by the FDA as hashtags are considered as claims by the agency.
- Do not like or comment on social media posts containing claims, especially since engaging in these posts substantiates the claims for others.
- The FDA also investigates popular video channels like YouTube for any CBD claims.
- A “Made in the USA” label can result in lawsuits as this should only be applied when most of the product’s components come from the U.S., including the carrier oil and packaging used.
- The agency considers infographics as claims.
Finding CBD Products with the Lowest Legal Risk
Since the federal government is still ironing out CBD regulations (22), finding CBD-based products with the lowest possible legal risk can be difficult. Experts recommend carefully checking manufacturer websites and labels before buying.
Here are the details to look for:
- Certificate of analysis – Also called a COA, this document shows the results of independent lab testing, which analyzes details like contaminants and potency. Ensure that the COA batch number matches that of the product’s packaging or label.
- Origin of hemp – Always check if the products are made of hemp that is grown in the United States. Hemp grown outside the country is subject to the production regulations overseas.
- Testing methods – Check to see if the lab doing the tests in the COA meets the “ISO 17025” standards. The methods of testing need to be validated by either the American Herbal Pharmacopoeia, the U.S. Pharmacopeia, or the Association of Official Agricultural Chemists.
- Potency – In the COA, the amount of CBD and THC compounds should also be listed both by dose and in total.
Avoid purchasing products where the manufacturer does not have this information or is not willing to share them. There are many CBD products that are incorrectly labeled and can have more THC than what is listed. (23)
Difference Between Isolate and Full-Spectrum CBD Oil
The two primary types of CBD hemp extracts sold by vendors are the crystalline isolate, also known as “CBD isolate,” and the full-spectrum CBD. Both are capable of providing possible therapeutic benefits.
With so much misinformation, it is vital that buyers understand what these two are before they decide to make a purchase.
What is a CBD Isolate?
A CBD isolate is made from agricultural hemp and is usually extracted via the supercritical CO2 extraction method. Isolates are pure cannabidiol and do not come with the other compounds found in the cannabis plant.
When buying a CBD isolate product, one crucial aspect to consider is its brand transparency. Look for the Certificate of Analysis before purchase as this can help determine the purity and potency of the isolate.
Advantages of CBD Isolate
- CBD isolate can be versatile as it is often bought as stand-alone consumer products and is found in powdered form. This formulation means that the isolate is easy to ingest with water, mix in homemade edibles, or consume directly.
- Buyers know what they are purchasing with CBD isolate as the product only contains CBD and nothing else. CBD isolates make it convenient and easy for users to obtain the exact dosage they need.
- CBD isolates do not contain THC, which makes them especially ideal for buyers that are highly sensitive to this chemical compound.
What is Full-Spectrum CBD?
Full-spectrum CBD, on the other hand, refers to a product containing a diverse range of cannabinoids, such as having CBD, CBG, THC, terpenes, and others found in hemp. Extracting this type of CBD can be done in various ways, including the use of ethanol, supercritical CO2, and oils such as hemp oil.
Generally, CBD oil that is considered as full-spectrum possesses a cannabinoid profile very similar to that in the hemp plant.
Advantages of Full-Spectrum CBD
- The entourage effect is when all of the compounds in full-spectrum CBD oil synergize and work together to give the user various, potential health benefits.
- Full-spectrum CBD products have terpenes present, which can provide a pleasant taste and aroma to the product. CBD, considered as full-spectrum, often possess the tasty and earthy flavors of natural hemp plants.
- Compared to CBD isolates, CBD products considered as full-spectrum are often speculated to provide more health benefits due to the combination of compounds present in them.
Full-Spectrum CBD or CBD Isolate?
Choosing either a full-spectrum CBD oil or a CBD isolate depends on the needs of a person. A full-spectrum can have more possible benefits to public health, while others may prefer the precise dosage and versatility only found in isolates.
Users that would like to avoid THC content but would like to obtain the benefits of the hemp plant can look for broad-spectrum CBD. This type of product has everything (fatty acids, terpenes, and cannabinoids) like that of a full-spectrum product without the THC.
It is important for people to talk to their physician first about whether or not CBD would be suitable for them. Doing so can help them better understand any symptoms they are experiencing while also helping select the right CBD product for their needs.
Knowing that it is possible to use CBD without any concerns about health can let users test which type works best. Experiment with both CBD isolates and full-spectrum products to see the difference.
CBD and the Endocannabinoid System
After many years of research and studies, scientists learned a lot with regard to the effects of cannabis, including several crucial discoveries. Not only have they identified the active ingredient in marijuana, but they also learned of a part in the body called the endocannabinoid system (ECS).
The ECS is a unique communications system that connects both the brain and body and affects many essential functions, such as how a person moves, reacts, and feels. The human body produces natural chemicals called “cannabinoids,” which interact with the ECS to regulate crucial functions.
Scientists further discovered that this system also recognizes and responds to cannabinoids coming from external sources, especially that from the phytocannabinoid known as CBD. (24) A study in 2010 looks into the idea of manipulating the ECS by introducing cannabinoids externally. (25)
Using CBD, for instance, ailments such as the following may be helped:
- Heart Disease
- Irritable Bowel Syndrome (IBS)
CBD and the Cannabinoid Receptors in the Body
Research experts agree on two types of cannabinoid receptors in the body known as CB1 and CB2. Although their naming sounds similar, the two work differently in the human body.
Cannabinoid Receptor Type 1 (CB1)
The CB1 receptor was first discovered in 1990 and is found in the brain, the central nervous system (CNS), gonads, intestines, connective tissues, and other glands. Activating this receptor can help in relieving depression (26), lowering blood pressure (27), and improving myelin formation (28).
Cannabinoid Receptor Type 2 (CB2)
On the other hand, the CB2 receptors were discovered in 1993 and are available mostly in the tonsils, immune cells, thymus, and spleen.
The changes that occur in the function of the CB2 receptor are synonyms with almost every human disease, whether it is gastrointestinal, cardiovascular, psychiatric, autoimmune, and neurodegenerative. This receptor even has a role in kidney and liver function, the health of the skin and bone, and cancer. (29)
Can CBD Help with Addiction?
CBD-based products can help people recover from addiction because of their ability to engage with the endocannabinoid system. Consumption of CBD can give an extra boost of cannabinoids that could help this system do a better job of regulating bodily functions.
At the time of writing, studies have shown that CBD seems to be beneficial in helping individuals recover from drug addiction. (30)
CBD for Cocaine Addiction
Cocaine is a highly addictive drug and affects the “reward” center (pleasure center) in the human brain.
A study was conducted on a group of rats that had histories of cocaine administration as they were provided a daily dose of CBD for a period of seven days. It was found that the CBD lowered the drug-seeking behavior in the rats both under stressful circumstances and when provided with cues.
The research also revealed that CBD reduced their impulsiveness and anxiety, two traits of addiction withdrawal. (31)
CBD for Nicotine Addiction
A study on a group of smokers experimented with CBD inhalers to try and suppress their cravings for nicotine, while another group was given inhalers with a placebo. The research shows the participants that used CBD inhalers smoked fewer cigarettes compared to the other group. (32)
Another study was also conducted on participants who were requested to abstain from smoking the night before. They were given an oral dose of 800mg CBD or a placebo on the following day and were shown images of cigarettes and smoking.
Although the CBD did not affect their cravings, the study showed that it reduced the pleasantness that they felt when presented with cigarette-related stimuli and cues. The findings suggest that there may be potential applications in hampering cue-induced cravings for nicotine. (33)
CBD for Opioid Addiction
Managing severe pain in the body often means prescribing opioids to help deal with this condition. However, the body can become too dependent on opioids to get relief, making it hard for certain people to stop their use.
Even worse is that the longer opioids are used, the higher an individual’s tolerance becomes. This predicament often leads to higher or even more frequent doses to achieve the same effects of the drug.
CBD binds to 5-HT1A receptors in the brain, which are the receptors that are involved in the production of serotonin. This action lowers the “reward” response of a person and, by doing so, can inhibit their dependence on opioids eventually. (34)
Studies have also revealed that CBD can reduce certain drug-seeking behavior (35) in people addicted to heroin while also lowering their cravings for the drug. (36)
Many individuals are initially offered to use opioids in managing chronic pain, but some of them end up abusing them.
CBD has been proven to offer similar pain-relieving effects, if not even better. A study also shows CBD to be more effective compared to opioids in treating pain in cancer patients. (37)
CBD for Marijuana Addiction
CBD has also been proven to reduce the withdrawal symptoms experienced with marijuana addiction. (38)
Although they are both derived from the hemp plant, the unique structure of CBD and THC allows them to have different effects on the body, and on one another. CBD is believed to counteract the effects of THC, lowering both the “high” and the anxiety that comes with it. (39)
THC can increase the sensitivity to other drugs while CBD inhibits and also lowers the reward response.
By looking at the studies above, consuming products that contain CBD may help in reducing cravings for individuals that wish to recover from addiction.
Can People Get Addicted to CBD?
CBD is well tolerated in human beings and does not cause addictiveness in both humans and animals. (40) A report from the World Health Organization (WHO) also proves that CBD use does not lead to tolerance or dependence. (41)
Although side effects can still happen, CBD, in general, is safe to use. Adverse reactions often occur when people take other medications alongside CBD since cannabidiol can change the metabolism of the liver on certain drugs.
The FDA advises against the use of CBD on pregnant and breastfeeding women, including children, since research on the CBD’s safety among these populations is insufficient.
A person that experiences the following side effects should stop taking CBD and consult with a physician:
- Dry mouth
- Low blood pressure
- Change in appetite or bodyweight
How to Take CBD
There are different types of products available for CBD, allowing users to select a suitable method of ingestion for them.
- Inhalation – Oral inhalation of CBD oil allows the compound to enter the bloodstream and take effect immediately. There are various CBD vape oils to choose from, and they come in a variety of flavors.
- Topical application – Various topical products that contain CBD oil are available, including balms, creams, salves, and lotions. A person can rub the topical directly on their skin, letting the CBD interact with the cannabinoid receptors found under the epidermis.
- Sublingual application – People can apply CBD oil directly under their tongue by using a small dropper. This allows for precise dosing, and the effects can be felt in as little as twenty minutes while lasting five times longer.
- Oral ingestion – CBD products such as chocolates, gummies, and baked goods are also sold for a more appealing flavor.
CBD Dosing Guide
At the time of writing, no official guidelines on CBD dosing have been released yet. That is why most of the available dosing advice tends to be anecdotal in nature.
Most people generally find it useful to follow a dose of 1 to 6 mg of CBD for every 10 pounds of body weight. However, past studies show that the participants in the research took higher CBD doses, even reaching as much as 800 mg.
With the lack of an official dosing guide, it is always best to consult a doctor first before deciding to take any CBD product. These medical professionals can provide an appropriate CBD dosage that complements a person’s body weight, the severity of a symptom, any addiction history, and more.
CBD that is obtained from the hemp plant is now starting to see more legality changes in favor of its use in modern medicine and for its reported therapeutic properties.
Events like the signing of the Farm Bill in 2018 and the descheduling of Epidiolex as a controlled substance help push CBD and its health benefits into the limelight.
However, the topic of CBD legality is continuously in flux, and there are strict requirements that need to be followed in the use of its products today. Those who are interested must continue to stay updated on the latest news concerning CBD to avoid legal repercussions.
It is always best to first consult a physician before deciding to include any form of CBD in a regimen.
- Hudak, J. (2018, December 14). The Farm Bill, hemp legalization and the status of CBD: An explainer. Retrieved from: https://www.brookings.edu/blog/fixgov/2018/12/14/the-farm-bill-hemp-and-cbd-explainer/.
- Hudak, J. op. cit.
- Texas Department of Agriculture. Retrieved from: https://www.texasagriculture.gov/RegulatoryPrograms/Hemp.aspx.
- Idaho Office of Drug Policy. Cannabidiol (CBD). Retrieved from: https://odp.idaho.gov/cannibidiol/.
- U.S. Food and Drug Administration (2019, December 31). Report in Response to Further Consolidated Appropriations Act, 2020. Retrieved from: https://hempsupporter.com/assets/uploads/FDA-CBD-Report.pdf.
- GW Pharmaceuticals (2020, April 6). GW Pharmaceuticals plc and Its U.S. Subsidiary Greenwich Biosciences, Inc. Announce That EPIDIOLEX® (cannabidiol) Oral Solution Has Been Descheduled And Is No Longer A Controlled Substance. Retrieved from: http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-1.
- Stuyt E. The Problem with the Current High Potency THC Marijuana from the Perspective of an Addiction Psychiatrist. Mo Med. 2018;115(6):482‐486.
- Hudak, J. op. cit.
- U.S. Drug Enforcement Administration (2020, May 5). Retrieved from: https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf.
- Hudak, J. op. cit.
- Texas Department of Agriculture. op.cit
- Idaho Office of Drug Policy. op.cit
- U.S. Food and Drug Administration. op. cit.
- Abu-Sawwa R, Stehling C. Epidiolex (Cannabidiol) Primer: Frequently Asked Questions for Patients and Caregivers. J Pediatr Pharmacol Ther. 2020;25(1):75‐77. doi:10.5863/1551-6776-25.1.75
- Silvestro S, Mammana S, Cavalli E, Bramanti P, Mazzon E. Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials. Molecules. 2019;24(8):1459. Published 2019 Apr 12. doi:10.3390/molecules24081459
- Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Mar 17;391(10125):1085-1096. doi: 10.1016/S0140-6736(18)30136-3. Epub 2018 Jan 26.
- Pauli CS, Conroy M, Vanden Heuvel BD, Park SH. Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects. Front Pharmacol. 2020;11:63. Published 2020 Feb 25. doi:10.3389/fphar.2020.00063
- GW Pharmaceuticals. op. cit.
- U.S. Food and Drug Administration (2019, November 25). FDA warns 15 companies for illegally selling various products containing cannabidiol as agency details safety concerns. Retrieved from: https://www.fda.gov/news-events/press-announcements/fda-warns-15-companies-illegally-selling-various-products-containing-cannabidiol-agency-details.
- U.S. Food and Drug Administration. What You Need to Know (And What We’re Working to Find Out) About Products Containing Cannabis or Cannabis-derived Compounds, Including CBD. Retrieved from: https://www.fda.gov/consumers/consumer-updates/what-you-need-know-and-what-were-working-find-out-about-products-containing-cannabis-or-cannabis.
- Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;318(17):1708–1709. doi:10.1001/jama.2017.11909
- Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3):833. Published 2018 Mar 13. doi:10.3390/ijms19030833
- Scotter EL, Abood ME, Glass M. The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol. 2010;160(3):480‐498. doi:10.1111/j.1476-5381.2010.00735.x
- Valverde O, Torrens M. CB1 receptor-deficient mice as a model for depression. Neuroscience. 2012 Mar 1;204:193-206. doi: 10.1016/j.neuroscience.2011.09.031. Epub 2011 Sep 19.
- Godlewski G, Malinowska B, Schlicker E. Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats. Br J Pharmacol. 2004;142(4):701‐708. doi:10.1038/sj.bjp.0705839
- Gomez O, Sanchez-Rodriguez A, Le M, Sanchez-Caro C, Molina-Holgado F, Molina-Holgado E. Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. Br J Pharmacol. 2011 Aug;163(7):1520-32. doi: 10.1111/j.1476-5381.2011.01414.x.
- Basu S, Dittel BN. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol Res. 2011;51(1):26‐38. doi:10.1007/s12026-011-8210-5
- Gonzalez-Cuevas G, Martin-Fardon R, Kerr TM, et al. Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle. Neuropsychopharmacology. 2018;43(10):2036‐2045. doi:10.1038/s41386-018-0050-8
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Rare and Orphan Diseases Challenges: Clinical Development and Clinical Practice
Cara Cassino, MD1; May Orfali, MD2; and Robert J. Charnigo3; Deborah L. Marsden, MD4
1Worldwide Research and Development, Pfizer Inc, New York, New York; 2Specialty Care Business Unit, Pfizer Inc, Cambridge, Massachusetts; 3Specialty Care Business Unit, Pfizer Inc, Collegeville, Pennsylvania and 4formerly of Rare Disease Research Unit, Pfizer Inc, Cambridge, MA.
Although rare diseases individually aﬀect small populations, the 7000 identified rare diseases collectively aﬀect more than 50 million people in the United States and Europe combined.1 Most rare diseases have a genetic basis, 85% are serious or life threatening, and >50% aﬀect children. Approved treatments are available for <5% of rare diseases, and for many, the outcome is fatal.2 Drug developers and practitioners share challenges in delivering eﬀective treatments to patients
with rare diseases.
CHALLENGES IN CLINICAL DEVELOPMENT
Rare diseases may aﬀect only a few thousand or even fewer patients worldwide; hence, trials enrolling hundreds of patients may not be practical or even possible. Despite this, rare disease medications are held to similar standards of evidence for marketing authorization as are medications for common diseases.3 For common diseases, these standards generally require conduct of a Phase 3 clinical program consisting of 2 well‐ controlled trials or 1 large robust trial held to stringent statistical criteria.4 However, in the rare disease arena, less‐conventional methodologic approaches may be employed to demonstrate clinical benefit with smaller study populations.5 In 2011, of 28 new molecular entities approved for orphan indications by the US Food and Drug Administration, 54% were based on phase 3 data, 29% were based on phase 2 data alone, and 7% were based on case reports only.2 Thus, a range of data sources not traditionally considered “pivotal” are important in drug
development for rare diseases. These may include combined evaluation of single case studies, systematic reviews, and observational studies.3 For enzyme deficiency diseases, well‐characterized short‐ and long‐ term consequences of the deficiency, and a clear understanding of the pharmacokinetics and pharmacodynamics of the compound, can guide studies of small numbers of patients.1 The sample size of hemophilia trials (which range from 50 patients/trial for hemophilia A to 20 patients/trial for hemophilia B) is based on regulatory guidance and not on statistical power calculations, owing to the rarity of the disease. Within‐patient comparisons in a predictably progressive disorder can provide data to support a benefit–risk assessment. Targeted therapies for well‐characterized genetic defects may demonstrate clinically relevant benefit even in very small sample sizes because of the uniformity of the study population and the ability of the drug to address the defect. Variability—whether in terms of disease phenotype, underlying pathophysiology, pharmaco‐ dynamics, or pharmacokinetics—is a threat to successful drug development for rare diseases, as it will increase the number of participants required. Eﬃcient study design and analysis require a clear understanding and limitation of potential sources of variability.3 The choice of the primary end point also can pose a considerable challenge. Because of sparse clinical data, the “most appropriate” clinical end point may not be known or validated. Natural history data, if collected systematically, can support the selection of the primary end point and provide historical controls as a valid basis for comparison for novel therapies. Validated biomarkers may be considered when recruitment of a suﬃcient number of patients to study a given clinical end point may be exceedingly diﬃcult or take an unreasonable length of time. However, selection of a surrogate marker
requires a reasonable likelihood, based on epidemiologic, pathophysiologic, or other evidence – to predict benefit. Establishing the safety profile of a novel rare disease drug may be even more challenging. Small study populations and limited exposure restrict understanding of potential risks at the time of approval . Fulfillment of postapproval safety surveillance commitments is generally required to ensure that long‐term safety data are systematically collected and assessed. These studies bring with them complexities, particularly given the challenges of extended duration in the setting of an evolving therapeutic landscape.
CHALLENGES IN CLINICAL PRACTICE
Even aGer drugs are approved for rare diseases, practitioners are faced with substantial challenges. Weighing the potential benefits versus risks of new treatments in the face of limited safety data at the time of approval has implications for initiation of therapy. Diagnosis may be delayed, owing to lack of awareness and diagnostic test limitations.6 Recombinant enzyme replacement therapy (ERT) for several of the lysosomal storage diseases (LSDs) has been at the forefront of rare disease therapeutics and can serve as an example of the successes and the ongoing challenges. Most LSDs are diagnosed in specialty clinics, and it may take many years for patients to finally be referred, especially those with later‐onset, less‐ severe phenotypes. In Gaucher disease, a defect of the
lysosomal enzyme glucosylceramimde synthetase results in a broad phenotypic spectrum. Patients with the most severe LSD have both central nervous system (CNS) and systemic disease, due to severe mutations that result in little to no residual enzyme activity. The less severe, most common phenotype (Gaucher disease type I) has no CNS involvement but does have a broad spectrum of systemic involvement.7 While ERT has been very successful for treating many of the systemic features of Gaucher’s, it has been less successful in the treatment of debilitating bone disease resulting from ineﬃcient uptake of the recombinant enzyme into the long bones. The recombinant enzyme does not cross the blood–brain barrier, so it does not treat the CNS disease. Similar ERTs have been developed for the mucopolysaccharidoses, types I (Hurler, Hurler‐Scheie, and Scheie syndromes), II (Hunter syndrome), and VI (Maroteaux‐Lamy syndrome). Again, ERT may successfully treat the systemic symptoms, but the enzyme does not cross the blood–brain barrier and therefore does not treat the CNS disease. Treatment is also available for Pompe disease, a defect of lysosmal acid α‐glucosidase, resulting in accumulation of glycogen primarily in muscle. The clinical phenotype ranges from severe muscle weakness with cardiorespiratory insuﬃciency in infancy to slowly progressive proximal limb‐girdle muscular dystrophy in adults. Although ERT successfully treats the cardiomyopathy in infants and slows the progression of muscle disease in both infants and older patients, it cannot reverse the damage already done to skeletal muscle. Therefore, even if therapies for rare diseases exist, the unmet medical need remains, and development of alternative therapies that address these persistent disease manifestations remains important. For some conditions, clinical trials may oﬀer the only access to potential therapy, so patients and caretakers are eager to participate. The decision about when to initiate treatment represents another challenge to the management of rare diseases. Because there is a wide spectrum of disease, decisions as to which patients to treat may be influenced by the cost of treatment (which can be upwards of $200‐ 300,000/year in adults) and the impact on a patient’s quality of life (eg, biweekly intravenous infusions). For example, Fabry disease, an X‐linked dominant disorder due to a defect in α‐galactosidase A, causes the ubiquitous accumulation of globotriaosylceramide in the vascular wall of capillaries, primarily in the kidneys, gut, skin, and brain. The typical presentation in males is heat intolerance, acroparesthesia, and gastrointestinal dysfunction in childhood and adolescence, progressing to renal disease in early adulthood, then end‐stage renal failure and death, usually by middle age. Other complications can occur, such as cryptogenic stroke, cardiomyopathy, and arrhythmia. Female carriers are also aﬀected, but with a variable phenotype and a less predictable disease course. Cardiac disease or stroke may be presenting features. Treatment may halt progression, but usually will not reverse disease. Symptomatic males are generally treated upon diagnosis, oGen aGer significant organ damage has already occurred. However, when there is a family history, aﬀected individuals may receive a diagnosis presymptomatically. There is no current consensus about when to treat these patients.8 For women, it is even more complicated. Some physicians advocate treating as soon as a diagnosis is made, even if the recognizable symptoms are relatively mild, because of the risk of stroke, while others recommend waiting until symptoms become apparent.9 The ethics of screening newborns for disorders that may not present until later in life, the possible nondetection of females with Fabry disease, and the overall risk/ benefit of newborn screening are the topics of much discussion. In the United States, the decision as to which disorders are included in the newborn screening panel lies with individual states, so the uptake will vary according to local influences, such as patient/parent advocacy and economic factors. Newborn screening initiatives for 5 of the LSDs (Gaucher, Fabry, Pompe, Krabbe, and Niemann‐Pick) are currently being piloted in several states, and legislation has been passed mandating the introduction of testing in Illinois, Missouri, and New Mexico, to begin as early as 2012.10,11 New York state has been screening for Krabbe disease since 2006. The impact of newborn screening remains to be seen, but given the experience with the rapid expansion of newborn screening for other rare inborn errors of metabolism, it is likely that this will become routine for other disorders.
Rare diseases tend to be progressive and debilitating conditions and oGen life threatening, for which there are few, if any, available treatment options. Precision medicine may open the door to more specific targets, creating the potential to demonstrate real clinical benefit with small studies. However, given the complexity of the rare disease clinical development and treatment landscapes, coordination and eﬀective partnerships between academic centers, industry sponsors, and regulators, and health care providers, caregivers, and patients themselves will be key to advancing the potential for new treatment options.
- Eurordis, “Rare disease: Understanding this Public Health Priority” Nov 2005. http://www.eurordis.org/ IMG/pdf/princeps_document‐EN.pdf. Published November 2005. Accessed March 26, 2012.
- US Food and Drug Administration. Fast track, accelerated approval and priority review. http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm. Updated August 2, 2012. Accessed March 26, 2012.
- European Medicines Agency. Guideline on Clinical Trials in Small Populations. Doc. Ref. CHMP/ EWP/83561/2005. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003615.pdf. Published July 27, 2006. Accessed March 26, 2012.
- Wellman‐Labadie O, Zhou Y. The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? Health Policy. 2010;95:216‐228.
- Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer. JAMA. 2011;305:2320‐ 2326.
- Orphanet. About rare diseases. http://www.orpha.net/consor/cgi‐bin/Education_AboutRareDiseases.php?lng=EN. Updated March 7, 2013. Accessed March 26, 2013.
- Grabowski GA, Petsko GA, Kolodny EH. Gaucher disease. Scriver’s OMMBID Web site. http://www.ommbid.com. Accessed March 26, 2012.
- ClinicalTrials.gov. A study of Fabrazyme in pediatric patients with Fabry disease (NCT00074958). http:// www.clinicaltrials.gov/ct2/results?term=fabry. Accessed March 26, 2012.
- Weidemann F, Niemann M, Sommer C, et al. Interdisciplinary approach towards female patients with Fabry disease. Eur J Clin Invest. 2012;42:455‐462.
- Marsden D, Levy H. Newborn screening for lysosomal storage diseases. Clin Chem. 2010;56:1071‐1079.
- Illinois Department of Public Health. Newborn screening disorder panel. http://www.idph.state.il.us/ HealthWellness/disorderinfo.htm. Accessed March 26, 2012. Address Correspondence To: Cara Cassino, MD Vice President WW Research and Development Pfizer Pharmaceuticals 235 East 42nd Street New York, NY 10017 Phone‐ +1‐212‐733‐0652