FWD 2 FDA Delays Decision on Crofelemer for Second Time

HerbalEGram: Volume 9, Number 11, November 2012

FDA Delays Decision on Crofelemer for Second Time

Drug derived from South American Croton tree latex still being reviewed for treatment of chronic diarrhea

The US Food and Drug Administration (FDA) again has delayed its final action decision on the market approval of crofelemer, a drug derived from the latex of the South American sangre de drago tree (
Croton lechleri).1 All parties had been expecting a decision from FDA on September 5, 2012 — a date which had been extended from the initial estimated decision date of June 5, 2012 — and now they will not know if FDA approves or rejects crofelemer until the first quarter of 2013. 

The delay was announced in a press release from Raleigh, North Carolina-based Salix Pharmaceuticals,
2 which obtained a license for crofelemer’s development from Napo Pharmaceuticals, the company that owns the intellectual property rights of the drug.3 The sangre de drago (translated to English as dragon’s blood) grows in the Amazonian regions of Bolivia, Brazil, Colombia, Ecuador, and Peru.3,4 A red, blood-resembling latex leaks from the tree when its bark is cut, and it is this substance that contains the novel molecular structure crofelemer, first standardized by Shaman Pharmaceuticals. (When Shaman filed for bankruptcy in 2001, the rights to crofelemer were purchased later that year by the San Francisco-based Napo, created by Shaman’s founder and former CEO Lisa Conte.) 

While crofelemer has been studied for several indications — such as diarrhea-predominant irritable bowel syndrome, acute/infectious watery diarrhea (including cholera), and pediatric diarrhea — the crofelemer New Drug Application (NDA) currently under FDA review is for the treatment of chronic diarrhea in people living with HIV/AIDS who are on antiretroviral therapy, totaling approximately 350,000 patients in the United States.

Every drug candidate in the United States must have its NDA approved by FDA before it can be marketed to the public. Crofelemer’s NDA was submitted to FDA in December 2011, and the Administration announced in February 2012 that it would give the drug priority review status,
6 which is assigned to “drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists,” and entails a prioritization of FDA’s regulatory resources and a shortened review timeline of six months.7 Accordingly, FDA estimated that a final action decision on crofelemer would be reached in June 2012.1 In late April 2012, however, the Administration said it needed until September 5, 2012 to review the NDA, and then, in September, Salix publicized that FDA again would delay its final action decision, to be announced “by the end of the first quarter of 2013."2

In reviewing an NDA, FDA considers whether the drug — as used for its intended purposes — is safe and effective, if its benefits outweigh any known adverse side effects, if its proposed labeling is appropriate, and if it can be manufactured in a way that preserves its identity, strength, quality, and purity.8 According to Title 21 of the Code of Federal Regulations on food and drugs, the initial NDA review cycle “may be adjusted by mutual agreement between FDA and an applicant” or in the case that a major amendment to the original NDA has been submitted, either because FDA has requested additional information or because the company submitted unsolicited information, such as new study results.9,10 
As FDA cannot speak about NDAs currently under consideration, it is unclear what exactly led to the deadline adjustment, although Salix’s press release stated the current primary topic of discussion between the company and FDA is “the production and control of the crofelemer active pharmaceutical ingredient.”2

If the most recently estimated date is met, crofelemer’s NDA will have been under FDA review for at least 11 months. According to the 2011 FDA document,
Performance Report To The President And Congress For The Prescription Drug User Fee Act — legislation passed in 2002 that allows FDA to collect fees from pharmaceutical companies in return for meeting certain review timeline goals — 100 percent of priority NDAs in 2010 and 92 percent in 2011 were decided in 6 months or less.11 Thus, while FDA can and does extend review timelines, it is not common.  

When contacted for comment, a Salix spokesperson said the company’s response was limited to its press release (M. Freeman, email, October 18, 2012). In this, Salix seems to welcome the delay:
 “By taking no action at this time, the FDA has allowed for the currently ongoing dialogue between Salix and the FDA to continue,” said Salix Executive Vice-President Bill Forbes.2

Napo, however, expressed dissatisfaction with the time it is taking Salix and FDA to make a decision on the drug. According to a Napo press release, “…Today’s news means that the wait will continue until at least the end of the first quarter of 2013 — over 2 years after the successful trials were completed.”5 The AIDS Community Research Initiative of America is also disappointed with the delay, as noted in a recent letter from the organization to FDA.12

This second delay further strains the already tense relationship between Napo and Salix. In November 2010, both Napo and Salix announced positive results of a randomized, controlled, fast-tracked Phase 3 clinical trial showing that crofelemer was both safe and effective in treating HIV-associated diarrhea when compared to placebo.5 Napo representatives have said Salix should have worked efficiently to file the NDA with FDA in early 2011 after these trial results were announced, but Salix did not submit the NDA until December 2011 — 13 months later.13

When Salix did not prepare for commercial supply of crofelemer and did not file the NDA for crofelemer as quickly as Napo thought it should have, Napo filed a legal complaint for breach of contract against Salix before the New York State Supreme Court, claiming that Salix was “unnecessarily stalling the advancement of this compound.”5 According to a Napo press release: “Contrary to the promises made in the December 2008 Collaboration Agreement, Salix has failed to communicate with Napo about regulatory correspondence and failed to collaborate on regulatory strategy and product development.” Salix, however, maintains that it did nothing wrong and should continue to have rights to crofelemer.14 The case currently is in the discovery phase and expected to go before a jury sometime in 2013 (S. King, email, October 19, 2012).

A Botanical Drug Designation for Crofelemer?

The language used in Salix’s press release announcing the second delay indicates that crofelemer is being reviewed as a “botanical” drug. According to Napo, crofelemer previously had been considered a new chemical entity (NCE) due to its highly purified nature and characterization as such for at least 20 years.5 But Salix is now referring to crofelemer as “a complex mixture that is the first botanical product to be reviewed by the [FDA] for oral use.”2

Napo is unhappy with this apparent change. While hundreds of new drugs approved by FDA have been natural products or naturally derived products filed as NCEs, FDA has never approved a botanical drug for oral use.5 (In 2006 FDA approved a topical botanical drug, Veregen® Ointment [Medigene AG; Martinsried, Germany] — the only botanical drug approved thus far —  which contains a proprietary blend of phytochemicals produced from a partially purified water extract of green tea leaves [Camellia sinensis].15)

Napo has indicated that a botanical designation throws uncertainty into the chances of crofelemer becoming approved, and that it is an inappropriate classification because crofelemer is an isolated, purified, chemical entity that is safer and more effective than raw dragon’s blood latex.5 A 2011 HerbalGram Herb Profile noted that crofelemer is one purified proanthocyanidin oligomer out of the sap’s “abundance of chemical constituents… including alkaloids, diterpenes, lignans, phenols, phytosterols, proanthocyanidins, steroids, and tannis.”3 Although a botanical drug also can be an NCE in some instances, according to the FDA’s Guidance for Industry for Botanicals, any substance that is a “highly purified or chemically modified substance derived from natural sources” cannot be considered a botanical drug.16

“In substantial and documented communication with the FDA from 1991 through 2011,” wrote Napo in its press release, “crofelemer was described and referred to by all parties — including Salix — as a NCE drug, not a botanical drug.”5

Although Napo considers crofelemer to be an NCE, it is FDA that determines which classification correctly applies to a drug. A peer reviewer of this article noted that there are some advantages to having a drug reviewed as a botanical drug, including that a chemically complex botanical
drug may not be easily replicated and, therefore, it is usually not be possible to produce a generic formulation, whereas NCE patents expire after about 20 years.

Napo, meanwhile, is seeking to have purified crofelemer approved by FDA as a veterinary drug for companion animals that are on chemotherapy and experiencing severe diarrhea.

—Lindsay Stafford Mader


  1. de Bruyn J. FDA again delays ruling on Salix drug. Triangle Business Journal. September 5, 2012. Available here. Accessed October 11, 2012.

  2. FDA continues review of crofelemer new drug application beyond PDUFA goal date of September 5, 2012 [press release]. Raleigh, NC: Salix Pharmaceuticals; September 5, 2012. Available here. Accessed October 18, 2012.

  3. Engels G, Brinckmann J. Dragon’s blood. HerbalGram. 2012;92:1-4. Available here. Accessed October 11, 2012.

  4. Lindner KS. Blood of the dragon: the sustainable harvest and replanting of the Croton lechleri tree. HerbalGram. 2009;84:56-65. Available here.

  5. Napo learns FDA to continue review of crofelemer NDA [press release]. San Francisco, CA: Napo Pharmaceuticals; September 5, 2012. Available here. Accessed October 24, 2012.

  6. Salix Pharmaceuticals announces FDA granting of priority review designation for the crofelemer NDA for treatment of diarrhea in patients with HIV/AIDS on anti-retroviral therapy [press release]. Raleigh, NC: Salix Pharmaceuticals; February 7, 2012. Available here. Accessed October 24, 2012.

  7. Fast track, accelerated approval and priority review. US Food and Drug Administration website. Available here. Accessed October 24, 2012.

  8. New drug application (NDA). US Food and Drug Administration website. Available here. Accessed October 24, 2012.

  9. 21 CFR § 314.60, § 314.96, and § 314.100. Title 21 Code of Federal Regulations: Food and Drugs. US Food and Drug Administration. Available here. Accessed October 24, 2012.

  10. Senak M. When does FDA extend a PDUFA date? Eye on FDA. August 30, 2010. Available here. Accessed October 25, 2012.

  11. FY 2011 Performance Report To The President And Congress for the Prescription Drug User Fee Act. US Food and Drug Administration. Available here. Accessed November 1, 2012.

  12. Letter from D. Tietz to D. Griebel re: crofelemer, NDA number 202292 (IND 51818). AIDS Community Research Initiative of America. October 17, 2012.

  13. Salix Pharmaceuticals announces NDA submission for crofelemer for the treatment of HIV-associated diarrhea [press release]. Raleigh, NC: Salix Pharmaceuticals; December 14, 2011. Available here. Accessed October 24, 2012.

  14. de Bruyn J. Salix partner cries foul, wants drug back. Triangle Business Journal. February 17, 2012. Available here. Accessed October 11, 2012.

  15. Stafford L. Chinese herbal medicine clears US FDA Phase II trials. HerbalGram. 2010;88:58-59. Available here.

  16. Guidance for Industry on Botanical Drugs Products. US Department of Health and Human Services. US Food and Drug Administration, Center for Drug Evaluation and Research. June 2004. Available here. Accessed October 25, 2012.