Drugs that are on the market but are not approved by the FDA are more common than you might think. Even some physicians might be unaware that the drug they are prescribing has not been approved, meaning it has not undergone the rigorous standards of safety and efficacy testing that the FDA requires for new drugs. This obviously poses a significant health concern and risk to patients and physicians alike. A large portion of these unapproved drugs are products known as DESI drugs. DESI drugs were introduced in a previous blog post, and recent developments have made the topic worth reviewing.

In addition to the health benefits for patients, getting NDA approval for marketed drugs, and in particular DESI drugs, can be an enticing target for pharmaceutical developers. As these products have been on the market for decades, many have a vast bank of supporting literature and clinical studies that can be relied upon in support of, or sometimes in lieu of, Sponsor run studies. This would make the product eligible for approval via the 505(b)(2) pathway, shortening the cost and required time for product development. In addition, as many of these products have never been approved in any indication or dosage form, they could qualify as new chemical entities (NCEs) and be eligible for up to 5 years of exclusivity.

History of DESI Drugs

Drug regulation has a long history of development. The Federal Food and Drugs Act of 1906 was the first legislation passed in an effort to reduce medical falsehood. There were no barriers to market for new drugs, but the Bureau of Chemistry was granted the authority to test food and drugs for “adulteration or misbranding”. In this way the federal government took the first steps to ensuring the accuracy of a product’s label.

However, these standards were still very loose, and did not take into account the potential safety of the products. In 1937 the elixir sulfanilamide was found to be responsible for at least 107 deaths, mostly children. Sulfanilamide had been used safely for years in tablet and powder forms for the treatment of streptococcal infections, and a liquid formulation followed: sulfanilamide dissolved in diethylene glycol. In the rush to meet demand, no toxicity studies were conducted; the formulation was chosen solely on the ability to dissolve sulfanilamide and the sweet taste that was expected to be popular with children. A month after the first shipments, reports began to trickle in to the American Medical Association (AMA) and FDA that the liquid sulfanilamide was resulting in deaths, and studies by the AMA confirmed that the toxic chemical in the elixir was the diethylene glycol. Due to the regulations at the time, the FDA was only able to seize the elixir under the premise that the name “elixir” implied the solution contained alcohol, and as it did not the product was considered to be misbranded. Had the product been called a “solution” as opposed to “elixir”, FDA would have had no authority to remove the drug from market.

In response, The Food, Drug, and Cosmetic (FD&C) Act was passed in 1938 and required new drugs to demonstrate that they were safe before they could be marketed. This law was designed to protect patients from the types of tragedy caused by the sulfanilamide elixir, and the thalidomide disaster in the 1960’s is evidence of the law’s success. Thalidomide was approved in several European countries and Canada for treating morning sickness in pregnant women. However, when the marketing company petitioned for US approval, the FDA demanded additional safety information.  During the resulting delay, the drug was linked to birth defects in over 10,000 children, and thalidomide was never marketed in the US. Less than 100 US children were exposed to the drug due to the FDA’s regulatory process.

As successful as the 1938 FD&C Act was, it was missing a key component: drug efficacy. In 1962 the Kefauver-Harris Amendments were made to the FD&C Act requiring that drugs be safe AND effective before they could be marketed. The FDA implemented a program called the Drug Efficacy Study Implementation (DESI) to review the safety and efficacy of drugs approved between 1938 and 1962. Therefore, these drugs approved during this time are commonly referred to as DESI drugs. DESI drugs were allowed to remain on the market until they were re-reviewed as long as they weren’t substantially changed. The DESI program removed many products that were deemed to not be effective, but there was no comprehensive list of drugs approved and marketed at the time and not all drugs were re-reviewed. As a result, many DESI products remained marketed without a formal approval.

Unapproved Drugs Initiative: Cracking down on unapproved drugs

In 2006, the FDA introduced the Unapproved Drugs Initiative with the aim of removing unapproved drugs from the market, including DESI drugs and new drugs that were marketed without FDA approval. They also released a corresponding guidance: Marketed Unapproved Drugs Compliance Policy Guide, Sec. 440.100, Marketed New Drugs Without Approved NDAs or ANDAs (Docket No. FDA-2011-D-0633). The initial program utilized risk-based enforcement in order to concentrate its resources on products that posed the highest threat to public health. This included:

• Drugs with potential safety risks
• Drugs that lack evidence of effectiveness
• Health fraud drugs
• Drugs that present direct challenges to the new drug approval and over-the-counter (OTC) drug monograph systems
• Unapproved new drugs that also violate the Act in other ways
• Drugs that are reformulated to evade an FDA enforcement action

On September 19^th 2011, the Agency updated the guidance, stating that the risk-based enforcement approach only works for unapproved drugs on the market before the September 19^th date; after that date, any unapproved drug is subject to enforcement without prior notice, with the guidance itself serving as prior notification. One recent example is that of Ascend Laboratories, who had more than $11,185,000 worth of unapproved drugs seized in 2014. DESI drugs that had been approved under the DESI process would be considered approved without an NDA/ANDA only if the drug was the same indication and dose.

There are numerous benefits to getting NDA approval for “grandfathered” drugs. NDA approval demonstrates to physicians and patients that a drug is effective and safe, making it possible for them to have the necessary information to adequately understand a drug product’s risk/benefit profile. NDAs outline what the APIs/excipients are, the importance of which is clearly demonstrated in the sulfanilamide example; the API seemed safe and effective after years of use, yet the excipients in the elixir proved to be deadly. The Sponsor of an NDA has to demonstrate how the API and excipients will be manufactured and that the manufacturing process can reliably reproduce drug products of the same identity, strength, quality, and purity. This is particularly important for the prevention of drug shortages. Finally, for pharmaceutical companies, the approval of DESI drugs can potentially come with 5 years of exclusivity. While this exclusivity can come with price increases for patients, the patients are getting a higher quality product with greater certainty of safety and efficacy.

NDAs for DESI Drugs: example cases

As previously stated, approval for DESI drugs can often come with shortened development programs via the 505(b)(2) pathway. For example, Eclat Pharmaceuticals received NDA approval for Bloxiverz (neostigmine methylsulfate) in 2013. Neostigmine methylsuflate was first introduced in the 1930’s, and therefore had been unapproved and grandfathered into market for over 70 years. Because of decades of use as an effective cholinesterase inhibitor (indicated for postoperative reversal of effects produced by nondepolarizing neuromuscular blocking agents), no clinical studies were conducted specifically for Bloxiverz, and instead published literature on existing trials were relied upon for NDA approval. Not having to conduct clinical trials for approval saves Sponsors valuable time and money in their development process.

The push to remove DESI products also benefits patients by the removal of products that are ineffective. One such example is Xenaderm (trypsin ointment) that was marketed by Healthpoint Ltd. Trypsin had been used as an ointment for skin wounds for decades, but the approval for trypsin ointment had been rescinded in the 1970’s due to a lack of proven efficacy. However, Healthpoint continued marketing Xenaderm, commonly used in nursing homes to treat bedsores, and failed to disclose to the Centers for Medicare and Medicaid Services that Xenaderm did not have FDA approval. Nursing homes do not have to pay for prescription drugs given to Medicaid beneficiaries, and instead the pharmacies suppling nursing homes bill the federal government. As a result of not having FDA approval, Xanaderm should not have been eligible for Medicaid reimbursement, and therefore Healthpoint was charged with costing Medicaid $90 million for a product deemed ineffective. This is just one such example of the huge cost to taxpayers when ineffective products are left unchallenged on the market.

Premier Consulting has vast experience in 505(b)(2) drug approvals, the common pathway for obtaining an NDA for DESI and other marketed drugs, and can assist with development and regulatory strategies. Please contact us for more information.