FDA NEWS RELEASE
For Immediate Release: Feb. 17, 2012
Media Inquiries: Morgan Liscinsky, 301-796-0397;
morgan.liscinsky@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA approves Korlym for patients with endogenous Cushing’s syndrome
Today, Korlym (mifepristone was approved by the U.S. Food and Drug Administration to control high blood sugar levels (hyperglycemia in adults with endogenous Cushing’s syndrome. This drug was approved for use in patients with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery. Korlym should never be used (contraindicated by pregnant women.
Prior to FDA’s approval of Korlym, there were no approved medical therapies for the treatment of endogenous Cushing’s syndrome.
Endogenous Cushing’s syndrome is a serious, debilitating and rare multisystem disorder. It is caused by the overproduction of cortisol (a steroid hormone that increases blood sugar levels by the adrenal glands. This syndrome most commonly affects adults between the ages of 25 and 40. About 5,000 patients will be eligible for Korlym treatment, which received an orphan drug designation by the FDA in 2007.
Korlym blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels.
The safety and efficacy of Korlym in patients with endogenous Cushing’s syndrome was evaluated in a clinical trial with 50 patients. A separate open-label extension of this trial is ongoing. Additional evidence supporting the agency’s approval included several safety pharmacology studies, drug-drug interaction studies and published scientific literature. Patients experienced significant improvement in blood sugar control during Korlym treatment, including some patients who had marked reductions in their insulin requirements. Improvements in clinical signs and symptoms were reported by some patients.
The most common side effects experienced by endogenous Cushing’s syndrome patients treated with Korlym in clinical trials were nausea, fatigue, headache, arthralgia, vomiting, swelling of the extremities, dizziness and decreased appetite. Other side effects of Korlym include adrenal insufficiency, low potassium levels, vaginal bleeding and a potential for heart conduction abnormalities. Certain drugs used in combination with Korlym may increase its drug level. Health care professionals must be aware of the potential for drug-drug interactions and adjust dosing or avoid using certain drugs with Korlym.
Korlym should never be used by pregnant women. Although pregnancy is an extremely rare occurrence in Cushing’s syndrome patients because of the suppressive effect of excess cortisol on female reproductive function, Korlym will carry a Boxed Warning advising health care professionals and patients that the therapy will terminate a pregnancy.
The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS is not necessary for Korlym to ensure that the benefits outweigh the risks for patients with endogenous Cushing’s syndrome. Several factors were considered in this determination including the following:
- There are no other approved medical therapies for this debilitating form of Cushing’s syndrome and very sick patients would suffer if impediments to access were imposed.
- The number of Cushing’s syndrome patients who will require treatment with Korlym is small, with an estimated 5,000 patients being eligible for treatment.
- The number of health care professionals in the United States who would potentially prescribe Korlym is very small and highly specialized. They are familiar with the risks of Korlym treatment in the endogenous Cushing’s syndrome population and frequently monitor patient status.
- The risks of Korlym treatment in the intended population can be managed through physician and patient labeling. The risks associated with Korlym will be outlined in a medication guide for patients.
The company has voluntarily proposed distributing Korlym through a central pharmacy to ensure the timely, convenient and appropriate delivery of the drug to Cushing’s patients or to the health care institutions where this therapy may be initiated. Most retail pharmacies are unlikely to keep adequate supplies of the drug for this rare condition and central distribution will give patients with Cushing’s syndrome better access to Korlym.
Korlym is manufactured by Corcept Therapeutics of Menlo Park, Calif.
For more information:
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
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In 2006, 205 people in the U.S were sickened and 3 died in an E. coli O157:H7 outbreak linked to baby spinach grown in California. In the aftermath, both the Food and Drug Administration (FDA and California's Department of Health Services conducted extensive
investigations into the outbreak to determine how leafy green produce could become contaminated with a microorganism normally found in the stomach of animals.
While investigators were able to successfully track the contaminated spinach to one specific field in California, and identify potential health risks such as the presence of cattle feces and wild pigs, the investigators had less success identifying the exact method by which E. coli contamination had occurred.
In response, California, the largest producer of leafy green vegetables in the nation with roughly a 75 percent market share, created its own statewide
Leafy Green Marketing Agreement. Arizona, the second largest producer of leafy green vegetables with roughly a 15 percent market share, followed suite creating its own
statewide program in September of 2007.
Unfortunately, despite the widespread adoption of these voluntary programs at the state level, foodborne illnesses linked to leafy green vegetables continue to be a problem across the country. In 2010,
E. coli-tainted romaine lettuce was recalled in 23 states after 19 people became seriously ill in Ohio, New York and Michigan.
Just this last October, the U.S. Food and Drug Administration (FDA discovered
Listeria bacteria during a random sample of romaine lettuce grown in California. And as recently at this past New Year's Eve, "a
Texas company recalled 228,360 lbs. -- 114 tons -- of spinach because it tested positive for E. coli O157:H7."
In response to industry interest, the U.S. Department of Agriculture's Agriculture Marketing Service (AMS
published an Advance Notice of Proposed Rulemaking (ANPR on Oct. 4, 2007 to explore the idea of implementing a national marketing agreement focused on reducing microbial contamination in leafy green vegetables.
AMS received more than 3,500 public comments on the ANPR. On June 10, 2009, the agency received a petition for rulemaking and a request for a public hearing on a proposed National Leafy Green Marketing Agreement (NLGMA . The
proposed marketing agreement was submitted to AMS "by a group of producers, handlers, and interested persons representing a cross-section of the national fresh and fresh-cut produce industry."
This initial proposal was designed to operate in a similar manner to voluntary marketing agreements previously implemented in California and Arizona following the 2006 outbreak.
While many in the leafy green industry praised the proposal as a huge leap forward for product safety, the proposal was also met with stiff resistance from many farmers,
especially small-scale producers. The new rules also came under attack by
consumer food safety advocates who were upset that the proposed rules would essentially allow the industry to police itself.
After taking comments and holding public hearings on the issue, the AMS proposed a revised NLGMA in the spring of 2011. This report provides an overview of how marketing agreements function in general, provides a detailed examination of the latest proposed NLGMA rules, and examines whether criticism for the latest proposed rule is legally and/or factually justified. Marketing Orders and Agreements
The Agricultural Marketing Agreement Act of 1937 (codified at 7 U.S.C. Chapter 26A provides authority for federal marketing orders administered by the USDA. Under the supervision of the AMS, marketing orders have currently been established for milk as well as numerous fruits, vegetables, and other specialty crops. Not counting milk and the latest NLGMA proposal, there are
currently 32 active marketing orders and agreements.
Marketing orders and agreements provide legal tools for agricultural producers, aggregators, processors, manufacturers, and retailers to work together to mitigate financial turmoil in the supply chain. A new marketing order or agreement must be developed by industry representatives, and then proposed to the AMS. The agency will then hold a public hearing and take public comments prior to making a final decision on whether to proceed with a rulemaking.
Prior to a proposed program being implemented, the regulation must be approved in a referendum by a two-thirds or larger majority of producers. Once a marketing order or agreement is approved, local committees appointed by the Secretary of Agriculture provide administration of the program. Marketing orders and agreements are binding on all "handlers" in the geographic area covered by the order. In general, a handler is anyone who receives the commodity from producers, and is responsible for grading, packing, transporting, or placing the farm products into commercial channels.
Marketing orders are distinguished from marketing agreements, in that marketing agreements are binding only on handlers who are signatories of the agreement. Handlers must comply with the grade, size, quality, volume, and other requirements established under the specific program.
Proposed National Leafy Greens Marketing Agreement (NLGMA
Like all marketing agreements, the proposed NLGMA is intended to be a voluntary program so handlers can choose whether or not they wish to participate in it. Unlike other marketing agreements, the NLGMA has little to do with balancing financial interests in the supply chain, but is focused entirely on providing a legal structure for farmers and handlers to efficiently comply with a new system of national food safety requirements impacting all leafy green vegetables.
While no specifics are given in the proposal, such food safety requirements would be based on the FDA's
Good Agricultural Practices (GAPs ,
Good Manufacturing Practices (GMPs , and the USDA's
Good Handling Practices (GHPs .
Under the current proposal, the marketing agreement would be governed by a 26-member Board of Directors appointed by the Secretary of Agriculture. The Board would be responsible for making policy recommendations to the Secretary for final review and approval. Any major changes to the agreement, including the Board's recommended food safety requirements and exemptions, would be sent out for public comment prior to its adoption.
Board members would be apportioned from eight administrative zones, with state's divided into groups based on geographic and climate differences. Each administrative zone would be assigned representation on the Board relative to the amount of leafy green vegetables produced within that zone. For example, administrative zone 1 -- which includes Hawaii and California -- would receive 4 representatives as California produces roughly 75 percent of all leafy green vegetables grown in the country.
In addition, the Board would include 10 designated grower representatives, with two of the 10 grower positions designated for small farmers. No company would be allowed to have more than one representative on the board, even if its operations included multiple farms in different administrative zones.
A Technical Review Committee (TRC would assist the Board in developing guidelines and procedures. The TRC would consist of members who represent production, handling and food safety experts from each zone (including organic and small business interests , experts from the USDA's agencies, and other federal agencies such as the FDA and EPA. The TRC also would have the authority to work collaboratively with industry stakeholder groups, local and state authorities, and others interested parties whose expertise the TRC might require.
The
proposed NLGMA would cover a wide range of fresh leafy green vegetables and their varieties, including: arugula, cabbage, chard, cilantro, endive, escarole, kale, lettuce, parsley, radicchio, spinach, and "spring mix" -- an industry term that describes mixtures of baby lettuces, mustards, chards, spinach, and chicories that vary based on availabilities. These vegetables could be whole or fresh-cut, or in bulk or packaged form. Under the proposed NLGMA, the Board could recommend, subject to USDA approval, the addition or removal of any leafy green vegetable from this definition. Handlers of fresh leafy green vegetables in the 50 states and the District of Columbia, also known as the production area, would be eligible to become signatories. Once becoming a signatory, participants would only handle leafy green vegetables from producers or other handlers that are also in compliance with the NLGMA.
Signatories who handle product imported from outside the United States would be required to demonstrate that those products also meet the requirements of the NLGMA. Compliance by signatories with the terms of the agreement would be mandatory. A signatory would be obligated to participate for no less than one crop year in the program. After the initial year, participants would have the opportunity to withdraw or opt out of the program.
While the program is voluntary for handlers of all sizes, any producer who sells to a handler that is a signatory to the NLGMA would be required to adhere to the marketing agreement. Small farmers participating in farmers markets, CSAs, or other direct sales to consumers may choose not to participate in the marketing agreements, provided they don't sell any of their leafy green vegetables to a signatory handler. Once adopted, all signatory handlers and their growers would be subject to an audit by the AMS Inspection Service. AMS Inspection Service would have the authority to accredit other entities and license their auditors to audit on its behalf, including National Organic Program (NOP certified agents, FDA inspectors, and third-party auditing services accredited by FDA.
This presents the potential to streamline the audit process facing many producers in today's market, thus improving operations and reducing costs. For example, the proposal would permit the program to evolve whereby an organic producer could include the NLGMA food safety standards as a component of the overall organic system plan and receive a single audit. The proposed NLGMA "would provide the Board authority to establish marketing research and development projects, and or promotional activities, including paid advertising, to assist or promote the efficient adoption, implementation, and marketplace acceptance of the agreement and leafy green vegetables." A Research and Development Committee would assist the Board in carrying out these actions.
The costs of these programs and the audit verification fees would be paid for through assessments of the signatory handlers. The price of these assessments would be recommended by the Board and must be approved by the USDA. These assessments would not be allowed to exceed $0.05 per 24-pound carton equivalent of leafy green vegetables. As assessments are based on the volume of a handler's transactions, large handlers would pay more assessments than small handlers participating in the program.
The AMS believes the proposed NLGMA will have a number of important benefits for producers, handlers, and consumers. "A primary benefit of the proposed agreement is the reduced likelihood of food contamination outbreaks in leafy green vegetables... in the United States."
This would not only benefit consumer health, but also the economic viability of the industry since it is estimated "that a food contamination outbreak could lead to a 10 percent long-term reduction in demand for leafy green vegetables." The 2006 E. coli outbreak alone was estimated to have cost leafy green producers $12 million dollars, and U.S. retailers as much as $63 million in lost profits.
Criticism of the Latest NLGMA Proposal
Both proponents and opponents of the latest NLGMA agree that food safety is a priority that needs to be better addressed by regulation. There is also no question that the most recent NLGMA is a more well thought out and balanced version of the regulation that what was initially proposed in 2009.
Yet, critics of the latest proposal -- including the
National Sustainable Agriculture Coalition (NSAC and the
National Organic Coalition (NOC -- contend that the AMS failed to adequately address at least four main concerns:
- whether the AMS is the proper agency to handle food safety regulation governing leafy green vegetables
- whether a marketing agreement is the proper regulatory tool to carry out national food safety regulations
- whether Congress has already addressed this particular food safety issue with the Food Safety and Modernization Act passed in December of 2010
- whether the NLGMA still unfairly burdens small to medium sized producers who wish to participate in the program
Is AMS the Proper Agency to Oversee Leafy Greens?
Three federal agencies are traditionally involved in U.S. food regulations. In general terms, the
USDA is responsible for all issues involving meat, poultry, dairy and eggs. In contrast, the
FDA is responsible for all other food and food additives. Finally, the
Federal Trade Commission (FTC is involved in the regulation of food advertising.
The proposed NLGMA even recognizes the FDA's expertise in food safety regulations involving leafy green vegetables as the
AMS intends the Board's final food safety regulations to reflect the FDA's published GAPs and GMPs, in addition to the USDA's GHPs. It also makes clear that the AMS intends to follow any existing or new FDA regulations that would impact food safety regulation or audits carried out by the agency.
In contrast, AMS has not traditionally been involved in food safety regulations or their enforcement, even within the USDA. Instead the AMS is involved mainly in assisting producers to market their products. This includes providing standardization, grading and new services for its five commodity programs -- dairy, fruit and vegetable, livestock and seed, poultry, and cotton and tobacco. It also includes overseeing the
National Organic Program (NOP and facilitating both domestic and international marketing efforts for U.S. agriculture. Which is not to say that either USDA as a whole, or AMS in particular, lack expertise when it comes to developing or enforcing new production standards. After all, in addition to developing marketing orders and agreements, AMS is also responsible for helping to create international quality standards for agricultural products.
Its role in overseeing NOP has also provided it the opportunity to implement a farm-based audit program designed to facilitate the needs of both small and large producers. In addition, the USDA as a whole has been heavily involved in the implementation of the
Hazard Analysis Critical Control Point system (HACCP currently utilized in meat, seafood, dairy, and juice production. This flexible system of scientifically based production standards -- designed to reduce microbial contamination during processing -- has been widely adopted by the food industry in
Europe and much of the United States.
Thus, while AMS may not be the foremost expert in food safety regulation involving leafy green vegetables, the agency certainly has both the scientific expertise and experienced personnel to carry forth all the provisions proposed under the NLGMA.
Are Marketing Agreements the Proper Regulatory Tool for Food Safety Regulations?
When considering whether it is appropriate to use a marketing agreement to address food safety, it is important to examine how Congress has historically created food safety legislation. Over the past hundred years,
Congress has passed many acts to improve food safety in this country, including the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, the Egg Products Inspection Act, the Federal Meat Inspection Act of 1906, the Poultry Products Inspection Act of 1957, and most recently, the Food Safety Modernization Act of 2010.
In almost all cases, these acts did not set forth specific food safety laws, but delegated the responsibility to the FDA or the USDA. This was not an ethical consideration, but a practical consideration as Congress has generally relied on agency expertise to formulate science based standards for the safety of the public. Proponents of using a marketing agreement to enact food safety regulation thus contend that it is simply another example of how an agency can use its scientific expertise to carry out the intent of Congress under the Agricultural Marketing Agreements Act of 1937.
Critics of the recently proposed NLGMA provide two separate reasons why a marketing agreement is the wrong regulatory tool for food safety: (1 it is unethical to make food safety a marketing issue, and (2 Congress never intended marketing agreements to address food safety issues as just another quality issue.
The first question is challenging, as there is neither one set of ethical standards that society adheres to under all circumstances, nor one type of regulatory tool that Congress always uses to address food safety issues. However, in its
public comment to proposed NLGMA, NSAC stated the problem as thus: "The members of the National Sustainable Agriculture Coalition have issued a statement containing 16 core principles about food safety. The very first of those principles states: Food safety is noncompetitive and transparent. Everyone who lifts a fork has a right to safe and healthy food, just as they have a right to choose foods based on the qualities most important to them. "Food safety" should not be a competitive marketing food-trait, lest the most vulnerable people end up with access to only the least safe food, or simply fewer choices. Every person has a right to expect the safest possible food, and a right to absolute transparency about its production processes, no matter what they can afford to pay for it. Completely open, public information about what makes a food 'safe' is not negotiable."
While this argument is compelling, it does seem to suggest that the secret goal of the NLGMA is to create a more expensive, less microbial contaminated food, which will then be marketed to consumers as a superior product compared with those leafy green vegetables not produced under the program.
Given that marketing agreements are generally only targeted toward producers and handlers, not consumers, this is more than a little incongruous. The proponents of the NLGMA stated at the public hearing that the promotion and advertising to be conducted under the program would be targeted at those within the leafy green vegetable industry, and not consumers.
There is also nothing in the record that would suggest that the general public would be any more aware of the NLGMA than they are aware of other marketing orders and agreements regulating the sale of milk and other agricultural products. Moreover, even if consumers did believe there were tangible health benefits to eating NLGMA-certified leafy green produce, it would certainly not be any more of a competitive advantage than what is already enjoyed by organic and local food producers who often advertise that their product is healthier and safer than conventionally produced foods. Yet even if it is not unethical, there is still the question of whether Congress ever intended AMS to utilize marketing agreements to address food safety as just another quality issue.
In its public comment to the proposed NLGMA, NSAC stated the problem as thus:
"The House version of what became the 2008 Farm Bill (Food, Conservation, and Energy Act of 2008 authorized the implementation of specialty crop marketing agreements for food safety. Industry sought this amendment precisely because they believed, correctly, that current law did not provide for comprehensive food safety controls via marketing agreements.
After heated debate, the Conference Committee rejected the House provision, precisely based on the argument that marketing agreements are not the right instrument to address food safety concerns and that the Agricultural Marketing Service is not a food safety agency.
Put simply, the leafy green and other specialty crop industry associations lost in their legislative campaign to change the law to provide authority for food safety marketing agreements such as the pending NLGMA. In order to save face, the industry scrambled to get language added to the Conference Report indicating that some marketing orders already issued by USDA have included "quality related provisions intended to enhance the safety of commodities" and that therefore the proposed statutory change was unnecessary.
This "cover your losses" report language flies in the face of the industry's arguments in pursuing the amendment to begin with, and is at any rate irrelevant to the current consideration of the NLGMA. The NLGMA is not a broad marketing agreement that happens to touch on a few quality-related provisions that have some effect on food safety. It is through and through a food safety agreement, period."
While this legislative history may be 100 percent accurate, it does not change the wording of the Act, or the broad delegation Congress originally gave to USDA and AMS to create marketing agreements. In 1937,
Congress created the Act to protect farmers from price fluctuations created by market disruptions that impacted interstate commerce.
To accomplish this goal, Congress delegated to the Secretary of Agriculture several important duties, including the powers to: (1 "establish and maintain such orderly marketing conditions for agricultural commodities in interstate commerce as will establish, as the price to farmers, parity prices", and (2 protect producers and consumers from "unreasonable fluctuations in supplies and prices."
Given the detrimental impact of food safety outbreaks on agricultural markets, it is a problem that clearly falls within scope of the Act, regardless of later Congressional hearings and discussions. There is also no language in the Act that would exempt food safety issues from the wide range of other qualities issues covered under the Act. Therefore, the AMS is well within its delegated duties to utilize marketing agreements to address purely food safety related issues. Not because they are a quality issue, but because they directly impact the price of leafy green vegetables in interstate commerce.
Did Congress Already Address This Issue in the FSMA?
There is no question that the Food Safety Modernization Act of 2010 (FSMA was the most important food safety legislation passed by Congress in decades. The real question is whether Congress fully addressed the food safety issue the NLGMA intended to regulate, thus making the proposed NLGMA conflict with the governing law.
In brief, the
FSMA directs the FDA to: (1 develop preventative science based food safety standards for covered facilities, (2 conduct regular inspections of covered facilities to hold them accountable, and (3 require importers to perform supplier verification activities. It also provides FDA with mandatory recall authority and requires enhanced collaboration activities with other state and federal agencies involved in food safety.
Looking at the plain language of both the NLGMA and FSMA, there is some clear overlap when it comes to regulating leafy green vegetable producers and handlers. Under the FSMA, FDA is directed to develop preventative science based food safety standards for these groups and conduct regular inspections. Under the NLGMA, the AMS will be developing preventative science based food safety standards and conducting annual audits. In a best-case scenario, the two sets of rules would be identical and no conflict of law would be created.
Moreover, if the rules drafted under the NLGMA are more stringent than those drafted by FDA, then both systems could mutually exist and complement each other. After all, the NLGMA is a voluntary system so if its handlers and growers want to hold themselves to higher standards than the FDA then who is to complain.
On the other hand, if any of the food safety standards promulgated under the NLGMA are lower than those produced by FDA, than the rules promulgated by FDA would clearly take precedence. This is for two reasons: (1 the FSMA was passed by Congress more than 70 years after the Agricultural Marketing Adjustment Act of 1937, and (2 FSMA is a more clear delegation of Congressional power when it comes to developing science based food safety standards.
FDA also has mandatory recall authority if food produced under the NLGMA is not sufficient to meet FDA standards. Yet, such an outcome will only occur if the two agencies completely ignore each other's rule making processes, and this seems unlikely since the FSMA clearly directs agencies to work more closely on issues regarding food safety. In response, critics of the NLGMA point out that the FSMA also included the Tester Amendment which exempted qualified facilities--either a very small businesses or those making less than $500,000/yr.--from much of the new regulation. In its public comments, NSAC framed the issue as thus:
"We have sought repeated unqualified assurances from USDA that all of the protections carefully built into the FSMA by Congress to protect the interests of small and mid-sized farms, diversified farming operations, direct market operations, and local food producers would be fully recognized and scrupulously respected under the NLGMA. No such unqualified assurances were forthcoming. In fact, to the contrary, we were told by the Administrator that the ultimate decisions on issues like this would rest with the Review Committee and that while it is assumed that FDA regulations and implementation process will be adopted by the NLGMA, there is a chance these particular issues would be among those that the NLGMA might amend through the process established in the proposed Agreement."
The problem with this line of argument is that the NLGMA is a voluntary system, whereas the FSMA is a mandatory system. As such, the two systems of regulation are not really in conflict as no qualified facilities exempted under the FSMA have to participate in the NLGMA, and those facilities who choose to participate under the NLGMA essentially consent to be bound to USDA-AMS rulemaking.
This will be an important consideration to many small to medium sized operations who will need to balance the economic benefits of participating in the NLGMA, with the increased financial costs associated with annual audits and bringing their operations into compliance.
An Unfair Burden to Small- and Medium-Sized Operations?
As the NLGMA does not contain any specific production standards to date, it is difficult to know with any certainty what its financial costs will be for producers and handlers involved in the program.
In general terms, three financial costs are anticipated for those who wish to participate: (1 the initial costs of bringing one's operation into compliance with the program, (2 the cost of annual audits, and (3 the annual costs of maintaining compliance as the program evolves and changes. These additional costs could potentially be balanced out by increased market stability, and a greater ability for participants to sell product into both domestic and international markets.
Based on cost estimates from a University of California report, AMS estimates "the total one-time modification costs at the farm level" to be "between $1.2- and $3.0 million, and an estimated average range of $14-$34 per acre for modification costs." On top of this initial cost would be annual compliance costs estimated at $2.7- to $4.4 million, or $30-50 per acre.
Of course, these estimates do not include the costs for California and Arizona producers currently involved in state marketing agreements. The producers from these two states are estimated to have spent $6.1- $14.7 million to bring their operations into compliance with their current rules, and spend between $13- to $21.7 million in annual compliance costs.
Annual handler assessments for the program would range between $5.7- to $28.6 million depending upon the whether the assessment was the program minimum of $0.01 per carton, or the program maximum of $0.05 per carton.
Based on these estimates, a hundred acre leafy green vegetable operation in Arkansas would spend between $1,400 to $3,400 in one-time compliance costs and between $3-5000 annually to maintain compliance. Such costs are hardly insignificant for small to medium sized operations, especially for those who might otherwise be exempt from similar regulations under the Tester Amendment of the FSMA.
The only silver lining is that the proposed NLGMA is a voluntary program for handlers to participate in. As such, producers should definitely discuss their financial operations with their handlers to determine whether the economic benefits of participating in the NLGMA would offset their estimated costs.
Will Leafy Greens Producers Support the Agreement?
In drafting its proposed marketing agreement, the NLGMA has provided producers and handlers with one potential tool to help reduce foodborne contamination in their production systems.
Whether it becomes law will ultimately depend upon what changes the agency makes after the latest round of public comments, and whether the proposed marketing agreement will be supported by a 2/3 majority of all leafy green vegetable producers in the nation. The effectiveness of such an agreement is also difficult to estimate, as the Board will need to be appointed and make its recommendation to the Secretary of Agriculture.
This will lead to yet more rulemaking, and additional opportunities for public comment. As such, proponents and opponents of the NLGMA should not expect any final food safety production standards for at least another 18 to 24 months.
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Judd Jensen is pursuing his LL.M. in Agricultural and Food Law at the University of of Arkansas. Prior to returning to law school, he worked in food safety and quality assurance for nearly a decade.
MENLO PARK, Calif. - February 17, 2012
Corcept Therapeutics (NASDAQ:CORT announced today that the U.S. Food and Drug Administration (FDA has approved Korlym™ (mifepristone 300 mg Tablets as a once-daily oral medicine to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have diabetes mellitus type 2 or glucose intolerance and have failed surgery or are not candidates for surgery.
"We appreciate the FDA's diligent attention to our NDA and its grant of approval on the PDUFA date," said Joseph K. Belanoff, M.D., the company's Chief Executive Officer. "We plan to make Korlym available to patients by May 1 through a distribution system designed to support both patients and prescribers."
Corcept will be the sole marketer of Korlym. "A relatively small number of endocrinologists regularly treat patients with Cushing's syndrome," added Dr. Belanoff. "These doctors can be reached without a large sales and marketing infrastructure." The company has begun hiring Medical Science Liaisons to inform practitioners about the drug, which will be dispensed by the leading specialty pharmacy company CuraScript SP, a subsidiary of Express Scripts.
"Korlym is a significant advance in the treatment of patients suffering from the debilitating symptoms of Cushing's syndrome," said Robert L. Roe, M.D., Corcept's President. "For the first time, these patients have access to an approved therapy when surgery has failed or is not an option."
Korlym clinical trial investigator Amir Hamrahian, M.D., Department of Endocrinology, Diabetes and Metabolism at the Cleveland Clinic said, "There are not many effective treatment options for patients with Cushing's syndrome. Although surgery is standard first line treatment for the disease, it is not always successful and not all patients are candidates. As part of the clinical trial, I have used Korlym successfully and my patients continue to do well on the medicine. I'm excited to be able to continue using Korlym in these patients and others who need it. This medicine's approval gives me a much needed tool to better treat patients."
Dr. Hamrahian's comments were seconded by Maureen V., a patient in Corcept's Phase 3 clinical trial: "I had pituitary surgery to treat my Cushing's syndrome. Unfortunately, my surgery wasn't successful. I was lucky to get into the study and get Korlym treatment. I have been taking the medicine successfully for over a year, and I am extremely happy that it was approved by the FDA. Now I know I'll be able to keep taking it. It has made a big difference in my life."
Clinical Trial Results Supporting FDA Approval
The clinical data supporting the FDA approval of Korlym resulted from an uncontrolled, open-label, multi-center, 24-week phase III study of 50 patients who had endogenous Cushing's syndrome and were either not eligible for or had relapsed from surgery and were either glucose intolerant (29 patients or had hypertension (21 patients . Within the glucose intolerant group, 60 percent of patients had a greater than 25 percent reduction from baseline in the area under the curve in the oral glucose tolerance test. In this group, mean hemoglobin A1C (HbA1C was reduced from 7.4 percent to 6.3 percent. All 14 patients with above-normal HbA1C levels at baseline experienced reductions. Eight of these 14 normalized their HbA1C. Antidiabetic medications were reduced in seven of the 15 patients with diabetes mellitus type 2 and remained constant in the others.
Patients who responded to therapy were allowed enrollment in an extension trial. Eighty-eight percent of the patients who completed the trial chose to do so.
A peer-reviewed analysis of the study results will soon be published in a leading journal.
Patients in the study started Korlym treatment on a dose of 300 mg administered once daily. Their dose was then titrated to maximum clinical effect. As indicated in the medicine's label, physicians prescribing Korlym may determine the appropriate dose for each patient by assessing tolerability and degree of improvement in Cushing's syndrome manifestations. In the first six weeks, these manifestations may include changes in glucose control, anti-diabetic medication requirements, insulin levels and psychiatric symptoms. After two months, assessment may also be based on improvements in cushingoid appearance, acne, hirsutism, striae, decreased body weight, along with further changes in glucose control.
About Korlym™ (mifepristone 300 mg Tablets
Korlym is a once-daily oral medication that blocks the glucocorticoid receptor type II (GR-II to which cortisol normally binds. By blocking this receptor, Korlym inhibits the effects of excess cortisol in Cushing's syndrome patients.
The FDA has designated Korlym as an Orphan Drug for treatment of the clinical manifestations of endogenous Cushing's syndrome. Orphan Drug designation is a special status designed to encourage the development of medicines for rare diseases and conditions. Because Korlym is an Orphan Drug, Corcept will have marketing exclusivity consistent with the FDA's designation until February 2019.
About Cushing's Syndrome
Endogenous Cushing's syndrome is a rare and life-threatening endocrine disorder that results from long-term exposure to excess levels of the hormone cortisol. This excess is caused by tumors that usually occur in the pituitary or adrenal glands that over-produce, or prompt the over-production of, cortisol.
Although cortisol at normal levels is essential to health, in excess it causes a variety of problems, including hyperglycemia, upper body obesity, a rounded face, stretch marks on the skin, an accumulation of fat on the back, thin and easily bruised skin, muscle weakness, bone weakness, persistent infections, high blood pressure, fatigue, irritability, anxiety, psychosis and depression. Women may have menstrual irregularities and facial hair growth, while men may have decreased fertility or erectile dysfunction. More than 70 percent of Cushing's syndrome patients suffer from glucose intolerance or diabetes.
The treatment of an endogenous Cushing's syndrome patient depends on the cause. The first-line approach is surgery to remove the tumor. If surgery is not successful or is not an option, radiation may be used, but that therapy can take up to ten years to achieve full effect. Surgery and radiation are successful in only approximately one-half of all cases.
If left untreated, Cushing's syndrome has a five-year mortality rate of 50 percent.
An orphan disease, Cushing's syndrome occurs in about 20,000 people in the United States, mostly women between the ages of 20 and 50.
Conference Call Information
Corcept will hold a conference call on Tuesday, February 21, 2012 at 9:00 a.m. Eastern Time (6:00 a.m. Pacific Time to discuss this announcement. To participate in the live call please dial 1-800-264-7882 from the United States or +1-847-413-3708 internationally. The pass code is 31838602. Please dial in approximately 10 minutes before the start of the call.
A replay of the conference call will be available through March 6, 2012 at 1-888-843-7419 from the United States and +1-630-652-3042 internationally. The pass code is 31838602.
IMPORTANT SAFETY INFORMATION
WARNING: TERMINATION OF PREGNANCY
See full prescribing information for complete boxed warning.
has potent antiprogestational effects and will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with Korlym, or if treatment is interrupted for more than 14 days in females of reproductive potential.
Contraindications
- Pregnancy
- Use of simvastatin or lovastatin and CYP 3A substrates with narrow therapeutic range
- Concurrent long-term corticosteroid use
- Women with history of unexplained vaginal bleeding
- Women with endometrial hyperplasia with atypia or endometrial carcinoma
Warnings and Precautions
Adrenal insufficiency
: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.
Hypokalemia
: Hypokalemia should be corrected prior to treatment and monitored for during treatment.
Vaginal bleeding and endometrial changes
: Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy.
QT interval prolongation
: Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval.
Use of Strong CYP3A Inhibitors
: Concomitant use can increase plasma levels significantly. Use only when necessary and limit dose to 300 mg.
Adverse Reactions
Most common adverse reactions in Cushing's syndrome (≥ 20% : nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy.
To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
Drug Interactions
- Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with Korlym
- CYP3A inhibitors: Caution should be used when Korlym is used with strong CYP3A inhibitors. Limit mifepristone dose to 300 mg per day when used with strong CYP3A inhibitors.
- CYP3A inducers: Do not use Korlym with CYP3A inducers.
- Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with Korlym.
- Drugs metabolized by CYP2B6: Use of Korlym should be done with caution with bupropion and efavirenz.
- Hormonal contraceptives: Do not use with Korlym.
Use in Specific Populations
- Nursing mothers: Discontinue drug or discontinue nursing.
Please see the accompanying full Prescribing Information including boxed warning at
www.corcept.com/prescribinginfo.pdf
Please see the accompanying Medication Guide at
www.corcept.com/medicationguide.pdf
About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. Korlym, a first generation GR-II antagonist, is the company's first FDA-approved medication. The company has a portfolio of new selective GR-II antagonists that block the effects of cortisol but not progesterone. Corcept also owns an extensive intellectual property portfolio covering the use of GR-II antagonists, including mifepristone, in the treatment of a wide variety of psychiatric and metabolic disorders. The company also holds composition of matter patents for its selective GR-II antagonists.
Statements made in this news release, other than statements of historical fact, are forward-looking statements. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances that clinical results will be predictive of real-world use, or regarding the pace of Korlym's acceptance by physicians and patients, the reimbursement decisions of government or private insurance payers, the effects of rapid technological change and competition, the protections afforded by Korlym's Orphan Drug Designation or by Corcept's other intellectual property rights, and the cost, pace and success of Corcept's other product development efforts. These and other risks are set forth in the Company's SEC filings, all of which are available from our website (www.corcept.com or from the SEC's website (
www.sec.gov . We disclaim any intention or duty to update any forward-looking statement made in this news release.
CONTACTS:
Invvestor Contact
Charles Robb
Chief Financial Officer
Corcept Therapeutics
650-688-8783
Media Contact
Alissa Maupin
Communications Strategies, Inc.
973-635-6669
Devices Are the Future of DrugsBy: Norbert Sparrow 30 January, 2012
Last week, I posted an article on medtech insider that listed five reasons why medical device manufacturers should consider attending Pharmapack Europe in Paris on 15 and 16 February 2012. One of those reasons was a conference session titled, Why Medical Devices Are the Future of Drugs. The topic intrigued me and I wanted to know more, so I called up Dr. Yves Tillet, CEO of Paris-based consultancy White-Tillet, who will be addressing this subject on 16 February. Here’s a preview of the case he will make to Pharmapack Europe conference attendees.
Most drugs are administered via a systemic route, says Tillet, and to ensure that the medication reaches the target site, it is administered in large concentrations. “If you are able to target just the tumour, for example, you can use much smaller quantities of the drug, and thus improve the risk-benefit ratio,” explains Tillet. Moreover, drugs that did not get past phase 2 of the drug development process “because of toxicity issues can be rehabilitated by being administered locally,” he adds. Introduced into the body in much smaller quantities and precisely delivered to the target site, the drug no longer poses a threat to healthy cells.
During his presentation, Tillet will describe various types of innovative drug-delivery systems that are transforming the practice of healthcare. I asked him if there were any that he finds especially promising. After some thought, he pointed to microsphere technology and phototherapy.
“For cancer treatments, the microsphere carries the drug to the target site and isolates the tumour by preventing blood from getting to it.
The cytotoxic agent acts on the tumour, which can’t spread,” says Tillet. Phototherapy is also very promising, he adds, because a laser is used to activate the drug only after it has reached the target site.
Traditionally, drugs have been formulated for delivery via a systemic route, notes Tillet, and this can cause a number of issues. At the Pharmapack Europe conference, Tillet will explain in some detail how combination products can eliminate these problems and fundamentally change the way in which serious conditions are treated.
Leerink Swann's Global Healthcare Conference 2012 featured two presentations and several more private discussions featuring Center for Drug Evaluation and Research ("CDER" Director Janet Woodcock, M.D., as well as her colleagues, Steven Kozlowski, M.D., CDER's Director of Office of Biotechnology Products, and Keith Own Webber, Ph.D., CDER's Deputy Director, Office of Pharmaceutical Science, Acting Director, Office of Generic Drugs. The trio presented a discussion "Biosimilars Take the Stage" followed by Woodcock's Keynote Address on "New Trends in Drug Regulation and Innovation", and several smaller question-and-answer-format meetings regarding these topics and more. This is part one of a two-part series and concerns the biosimilars presentations. Part two will be posted on Tuesday.
Leerink's biosimilars session was moderated by Joshua Schimmer, M.D. and Jason Gerberg, J.D./M.B.A. with co-moderators Seamus Fernandez and Joseph Schwartz. Kozlowski provided some preliminary remarks followed by a question-and-answer format by the moderators. Kozlowski explained that the purpose of FDA's first set of biosimilars guidances, which we initially reported on
here, was to set the scientific framework for approaching biosimilar product development and provide some interpretations of the new statutory terminology. Kozlowski explained that FDA decided to take a "totality of the evidence" and "stepwise approach", where the structural similarity of the biosimilar, as demonstrated by the sponsor, drives the development of the clinical program to support approval.
Woodock added that FDA has had a challenge to retrain their reviewers to think of biosimilar review as an "inverted pyramid." Typical drug review includes pre-clinical studies followed by increasingly large clinical studies, culminating in pivotal, larger-scale studies to demonstrate the safety and efficacy of the product that become the focus of the approval, i.e., the regular pyramid (pre-clinical on top, phase III clinical trials on the bottom . In contrast, biosimilar product development is envisioned to be characterized as spending a bulk of the resources up front, characterizing the innovator's product and the biosimilar (i.e., the top of the pyramid to lead to smaller clinical studies to demonstrate similarity or test for immunogenicity or other elements that require testing, not duplicating the safety and efficacy testing that was already conducted by the innovator.
www.accessdata.fda.gov/scripts/medwatch. --- Image 2: Two models of the Spinbrush are shown here. To help prevent injury, inspect the Spinbrush for damage or loose bristles before each use, and always supervise children and adults who may need assistance when using it.--- On the Net:
The Missouri Department of Health and Senior Services received the following news release regarding seven lots, approximately 574,000 bottles, of Infants' TYLENOL Oral Suspension, 1 oz. Grape. The item was distributed nationwide.
The full recall product list is:
Product Name | Lot Numbers | UPC Code |
Infants' TYLENOL Oral Suspension 1oz. Grape | BIL0U00, BIL0V00, BIL3500, BJL2D00, BJL2E00, BJL2T00, BJL2U00 | 300450122308 |
The recall was initiated after receiving a small number of complaints from consumers who reported difficulty using the Infants' TYLENOL SimpleMeasure dosing system.
No adverse events associated with this action have been reported to date and the risk of a serious adverse medical event is remote.
Consumers can continue to use Infants' TYLENOL provided the flow restrictor at the top of the bottle remains in place. If the flow restrictor is pushed into the bottle, the parent or caregiver should not use the product.
Adverse events that may be related to the use of this product may be reported to U.S. Food and Drug Administration's (FDA MedWatch Adverse Event Reporting Program either online, by regular mail or by fax:
- Online:
www.fda.gov/medwatch/report.htm5
- Regular mail: Use postage-paid, pre-addressed Form FDA 3500 available at:
www.fda.gov/MedWatch/getforms.htm6. Mail to address on the pre-addressed form.
- Fax: 1-800-FDA-0178.
The full recall can be found at
www.fda.gov/Safety/Recalls/ucm292537.htm?source=govdelivery.
The highly-anticipated weight-loss pill, Qnexa, may cause heart problems and birth defects in pregnant women, U.S. officials say, as the drug goes for FDA approval.
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