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TO:        Mr. Gregory Anthony Howard

FROM:   The United States Food and Drug Administration

RE:        Causing the Introduction of Unapproved and Misbranded Drugs into Interstate

               Commerce

DATE:   February 26, 2019

 

WARNING LETTER

The United States (U.S.) Food and Drug Administration (FDA) recently reviewed your websites listed at the bottom of this letter and determined that you and your affiliates cause the introduction of unapproved new drugs and misbranded drugs into interstate commerce in violation of sections 301(a), 301(d), and 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. §§ 331(a), 331(d), and 355(a)]. While this letter refers to CanaRx Services Inc/CRX Intl (hereinafter CanaRx), the violations discussed apply to all entities conducting business by or on behalf of CanaRx. FDA requests that you immediately cease causing the distribution of violative drugs to U.S. consumers.

UNAPPROVED NEW DRUGS

CanaRx operates as a prescription drug provider that engages in activities to cause the introduction of unapproved new drugs from foreign sources into the United States in violation of the FD&C Act. Because these products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and/or affect the structure or function of the body, these products are drugs within the meaning of section 201(g)(1) of the FD&C Act [21 U.S.C. § 321(g)(1)]. These products are also new drugs as defined by section 201(p) of the FD&C Act [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses. New drugs may not be introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. No FDA-approved applications pursuant to section 505 of the FD&C Act [21 U.S.C. § 355] are in effect for these products. Accordingly, their introduction or delivery for introduction into interstate commerce violates sections 301(d) and 505(a) of the FD&C Act [21 U.S.C. §§ 331(d) and 355(a)]. 

Specifically, CanaRx contracts with public and private sector employers throughout the U.S. to provide select prescription drugs to employees. CanaRx acts as a broker between foreign pharmacies and the employer-sponsored health insurance plan to provide enrolled employees with prescription drugs. CanaRx accepts the employee’s U.S. prescription and facilitates its reissue under the direction of a foreign physician. The reissued prescription is subsequently filled by a pharmacy contracted by CanaRx in that foreign physician’s jurisdiction. The foreign pharmacy then ships the drug directly to the employee in the U.S. For each shipment, CanaRx uses the same templated invoice, which contains the standard disclaimer, “[d]epending on your country, our medications may appear to be different in size, shape or color.” Having this disclaimer in each invoice demonstrates that CanaRx has designed its business to operate in a manner that substitutes the FDA-approved drugs prescribed by the U.S. healthcare provider with unapproved drugs. This distribution scheme is particularly concerning, as employees are likely inclined to trust that they will receive safe and effective drugs through their employer’s “insurance” plan and may not question their legitimacy. 

The substitution of FDA-approved prescription drugs with unapproved drugs poses significant health risks to U.S. consumers. For example, CanaRx offers certain drugs on its medication lists for which the FDA-approved version is subject to a Risk Evaluation and Mitigation Strategy (REMS) program, has a narrow therapeutic index, and/or is indicated to treat serious conditions such as HIV, cancer, or hepatitis. CanaRx also offers numerous maintenance medications that are indicated for conditions such as high blood pressure, high cholesterol, and acid reflux. Furthermore, the FDA-approved versions of several drugs listed on CanaRx’s medication lists have been subject to one or more recalls in the U.S. FDA has established processes to recall unsafe, substandard, and poor quality drugs within the legitimate U.S. drug supply chain. No such safeguards exist for unapproved drugs illegally distributed in the U.S. from foreign sources such as those provided through CanaRx. Therefore, many of the foreign versions of FDA-approved drugs substituted by CanaRx may also have been subject to recalls that were not carried out in the U.S. CanaRx’s operation does not appear to provide U.S. consumers with any protection or recourse should they receive or be harmed by drugs that may have been recalled in a foreign country.

In addition, several of the unapproved versions of FDA-approved drugs offered by CanaRx have different trade names and/or dosage amounts in their labeling than their FDA-approved counterparts. Such differences can cause patient confusion and lead to medication errors. Moreover, the substitution of FDA-approved prescription drugs with unapproved versions that may have substantially different risk profiles can pose serious health risks to consumers, especially in vulnerable patient populations that suffer from serious conditions such as HIV, cancer, or hepatitis. Unapproved drugs do not have the same assurance of safety and efficacy as drugs subject to FDA oversight and may be subpotent, superpotent, or adulterated with unknown active ingredients. Treatment with drugs that may be subpotent, superpotent, or adulterated in such vulnerable patient populations can lead to drug resistance and/or therapeutic failures, and jeopardize the effectiveness of alternative drug therapies on patient outcomes.

Examples of drugs offered on CanaRx’s medication lists and a general description of their respective indications are depicted in the table below. These include drugs that are for vulnerable patient populations with serious medical conditions. Such vulnerable patient populations may have received drugs subject to a recall or may have experienced medication errors due to receiving drugs with different dosages or risk profiles, which can lead to side effects that are life-threatening.

Baraclude (hepatitis)	Norvir (HIV)
CellCept (organ rejection)	Reyataz (HIV)
Foradil (asthma, COPD)	Stivarga (cancer)
Gilotrif (cancer)	Tegretol (epilepsy, nerve pain)
Gleevec (cancer)	Tracleer (pulmonary arterial hypertension)
Inlyta (cancer)	Truvada (HIV)
Invirase (HIV)	Zortress (organ rejection)

MISBRANDED DRUGS

Prescription drugs, as defined in section 503(b)(1)(A) of the FD&C Act [21 U.S.C. § 353(b)(1)(A)], can only be used safely at the direction, and under the supervision, of a practitioner licensed by law to administer such drugs. Because CanaRx advises consumers that their U.S. prescriptions are being filled with less expensive, foreign approved drugs, CanaRx intends for these drugs to be used as prescription drugs. This is especially concerning considering that CanaRx offers drugs that have a narrow therapeutic index (NTI) on its medication lists. One such drug currently offered by CanaRx is Tegretol. Substituting an NTI drug without the U.S. prescriber’s direction poses significant health risks to patients. In particular, small differences in dose or blood concentration for NTI drugs may lead to serious therapeutic failures or adverse drug reactions that are life-threatening, or result in persistent or significant disability or incapacity.

A drug is misbranded under section 502(f)(1) of the FD&C Act [21 U.S.C. § 352(f)(1)] if the drug fails to bear adequate directions for its intended use(s). “Adequate directions for use” means directions under which a layperson can use a drug safely and for the purposes for which it is intended (21 CFR 201.5). The drugs obtained through CanaRx are intended to treat conditions that are not amenable to self-diagnosis and treatment by persons who are not medical practitioners. Therefore, adequate directions for use cannot be written for these drugs, and they must qualify for one of the exemptions to section 502(f)(1) to avoid being misbranded. The exemption to section 502(f)(1) found at 21 CFR § 201.100 does not apply to unapproved new drugs because that exemption requires that such drugs bear “the labeling authorized by the approved new drug application.” Furthermore, unapproved new prescription drugs also do not qualify for the exemption set forth at 21 CFR 201.115, which also requires an approved new drug application (NDA) or active investigational new drug application (IND). Consequently, a prescription drug that is a new drug and has not been approved by FDA, or is not subject to an exemption from the premarketing approval requirements under the FD&C Act, cannot qualify for the exemptions to section 502(f)(1). Because none of the exemptions to section 502(f)(1) apply, these drugs are misbranded under section 502(f)(1).  

These drugs are also misbranded under section 502(f)(2) of the FD&C Act [21 U.S.C. § 352(f)(2)] because they fail to bear “adequate warnings against use…where [their] use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application….” This is particularly concerning because certain drugs offered by CanaRx are subject to REMS programs (e.g., Tracleer and CellCept). Specifically, the REMS program for Tracleer restricts distribution to minimize: the risk of fetal exposure and serious birth defects in female patients who are exposed to Tracleer and the risk of liver damage in patients who are exposed to Tracleer. Prescribers must order and review pregnancy tests prior to the initiation of treatment, monthly during treatment, and for one month after stopping treatment. In addition, prescribers must order and review liver function tests prior to the initiation of treatment and monthly during treatment. Furthermore, to comply with the REMS program for Tracleer, this drug must be mailed to patients from pharmacies certified in the REMS program. Pharmacies are also restricted from dispensing more than a 30-day supply and must verify the required testing prior to dispensing. The REMS for CellCept requires healthcare providers to report pregnancies to a registry and has an educational component regarding fetal toxicity. CanaRx is causing important safety measures that are put in place for the FDA-approved versions of these drugs to be bypassed.  

By causing these products to be shipped to U.S. consumers, CanaRx is causing the introduction of misbranded drugs into interstate commerce in violation of section 301(a) of the FD&C Act [21 U.S.C. § 331(a)]. 

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FDA is taking this action against CanaRx because of the risks posed by its conduct in facilitating the importation of unapproved new drugs and misbranded drugs to U.S. consumers. FDA’s regulation and oversight of the drug approval process protects consumers by requiring rigorous scientific standards for new drug approval, labeling review for accuracy and completeness, and manufacturing procedures and testing performed under closely controlled conditions at FDA-registered and inspected facilities. Unapproved new drugs and misbranded drugs do not have the same assurance of safety and effectiveness as drugs subject to FDA oversight, and may be contaminated, counterfeit, contain varying amounts of active ingredients, or contain different ingredients altogether. 

Substituting an unapproved drug for the FDA-approved drug prescribed by a patient’s healthcare practitioner can negatively affect patient outcomes because the health care practitioner may unknowingly make subsequent treatment decisions based on the patient’s response to the unapproved drug. This can also cause potentially dangerous drug interactions with the patient’s other medications. In addition, sourcing drugs from uninspected, unregulated, and/or unknown supply chains can result in serious health consequences, especially in vulnerable patient populations, which may receive medications that are adulterated and are not shipped and/or stored properly. 

This letter is not intended to identify all the ways in which your activities might be in violation of U.S. law. You should promptly cease causing the distribution of unapproved new drugs and misbranded drugs to U.S. consumers and correct all other violations of the FD&C Act. Failure to do so immediately may result in further regulatory action, including seizure or injunction without further notice.  

Please notify this office in writing within 10 working days of receipt of this letter of any steps you have taken or will take to correct the violations set forth above and to prevent their recurrence. If the corrective action(s) cannot be completed within 10 working days, state the reason for the delay and the time within which the correction(s) will be completed. Your response, and any other inquiries concerning this letter, should be sent to FDA’s Internet Pharmacy Task Force at FDAInternetPharmacyTaskForce-CDER@fda.hhs.gov.