So just what do you get for four bucks these days? Seems like just yesterday we were demanding the right to purchase cheaper prescription meds from Canada and were told 'nadda' since there was no way to ensure their safety. Well, no sooner had the Bush Admin passed Medicare Part B than US Pharmaceuticals began to really run amuk. And the stench is simply nauseating: the mega outsourcing of drug manufacturing to developing countries to cut production costs; gobbling up generic manufacturers around the globe; and, with the complacency of the FDA, rush to market copycat drugs, which under federal law are not subject to adequate clinical trials or guidelines to ensure their efficacy or safety.
Follow me after the fold for some background and the latest developments in the rotting field of Pharmacology ..
THURSDAY NIGHT IS HEALTH CARE CHANGE NIGHT, a weekly Health Care Series (cross-posted at ePluribus Media)
Are Generic Drugs Safe: (yes, it's Fox ... but believe it or not, it's a great report!)
In a March 2008 People's Pharmacy editorial Questions About Quality Of Foreign-Made Drugs, published soon after the heparin recall, the editor says that like tvs and cellphones, about 40% of medications have been outsourced to China and India. And while the FDA is required every two years to inspect American drug manufacturers, no specific regulations exist regarding plants in foreign countries. In 2007, the FDA inspected 13 of 700 known Chinese factories manufacturing and exploring medications for export to the United States.
Investigations reveal that some plants processing heparin do so as a sideline to their sausage-casing business. As a result, these firms are not registered as pharmaceutical companies and are exempt from regulation by the Chinese equivalent of the FDA.
Pig intestines are purchased from slaughterhouses, often with no paperwork to enable anyone to track the source. If the animals were sick, there is no way to detect the disease.
Some factories are literally cottage industries with low standards of sanitation and quality control. Raw heparin may be spread out on a table in a courtyard to dry. This crude ingredient is sold to middlemen who then sell it to manufacturers around the world. Their records may also be deficient.
The problems with heparin may be especially dramatic but could represent the tip of the iceberg. Many firms in China making drug ingredients are registered as chemical companies rather than pharmaceutical manufacturers. As a result, they may escape scrutiny by the Chinese drug regulatory authorities and the U.S. FDA.
Raw ingredients for many medicines are traded around the globe and the original source may be obscured in the process.
US regulators make no bones about the fact that they have no idea how many unlicensed chemical companies are currently selling pharmaceutical ingredients. In a NYT article, Agreement with China on generics, investigators "found 82 such companies at a trade show in Milan in October and more than 1,300 chemical companies selling drug ingredients over major business-to-business Internet trading sites."
The FDA acknowledges it is it impossible to determine if contaminated drugs from inadequately regulated Asian plants results in patients becoming sicker or remaining ill, primarily since both doctors and patients rarely suspect poorly manufactured drugs as the culprit.
WalMarts $4 Prescriptions: Where are these meds coming from?
The list of eligible drugs in the $4 Prescriptions Program — available at Walmart, Neighborhood Market and Sam's Club pharmacies nationwide — represents up to 95 percent of the prescriptions written in the majority of therapeutic categories. The affordable prices for these prescriptions are available for commonly prescribed dosages for up to 30-day or 90-day supplies. Ask your pharmacist or physician about switching to 90-day prescriptions for appropriate medications. link
According to a June,2008 article India: Wal-Mart's Drug Connection, soon after the implementation of Medicare Part D, all discussion about the import of medicines from Canada ceased and within 9 months Walmart announced its plans to initiate its program to sell 150 generic drugs for $4 each. An industry analyst appearing on NewsHour said that WalMart's drugs were being imported from all over the world. Because they were allowed to choose where to buy these drugs, WalMart began purchasing generic drugs directly from manufacturers in India, Israel, China, etc. with offered significantly lower price points.
By the end of April of 2007, Planet Retail was reporting that Wal-Mart was "in advanced talks" with the largest Indian pharmaceutical exporting companies -- unknown to most Americans -- like Ranbaxy, Dr. Reddy's Labs, Cipla, Lupin and Sun Pharma. In March of 2003, the Los Angeles Business Journal reported that Cipla and Ranbaxy had 81 applications before the FDA to sell generic drugs in the United States." Under FDA law, the first company to file a challenge on a patent has six-month exclusivity rights, during which time the generic price can be as high as 80% of the original drug. This position could be worth billions to Ranbaxy.
In the same year, the FDA introduced the Para 4 filing law which incentivized US and international generic companies to initiate court cases against branded drug makers. Touted as a bid to generate competition, Para 4 rewarded generic companies if they challenged existing patents rather than waiting for their expiration. Enter Ranbaxy, India's largest drug manufacturer.
Ranbaxy, recently purchased by Japan's mega-pharmaco Daiichi Sankyo, last year was banned from importing pharmaceutical ingredients into the US:
The largest maker of generic drugs in India - Ranbaxy Laboratories Ltd - has been issued a warning letter and an import alert by the FDA in lieu of 30 generic drugs made in its two plants in India.
The Warning Lettersidentify the agency's concerns about deviations from U.S. current Good Manufacturing Practice (cGMP) requirements at Ranbaxy's manufacturing facilities in Dewas and Paonta Sahib (including the Batamandi unit), in India. Because of the extent and nature of the violations, FDA today issued an Import Alert, under which U.S. officials may detain at the U.S. border, any active pharmaceutical ingredients (API) (the primary therapeutic component of a finished drug product) and both sterile and non-sterile finished drug products manufactured at these Ranbaxy facilities and offered for import into the United States. A link to the banned generic drugs.
Make no mistake that problems with safety of generics is limited to imported medicines from developing countries... Just today, SunPharma (currently the 5th largest pharmaceutical company in India) through its partnership with Caraco Pharmaceutical Laboratories, Ltd., received FDA approval for a generic version of oxycodone.
Last year Caraco Pharmaceuticals received a an FDA warning letter because of conditions at its Detroit, Michigan plant. The FDA is withholding all future marketing approvals for medicines manufactured at the plant until the problems cited in the letter are corrected.
The letter, dated October 31, followed an inspection held at the company’s manufacturing facility in Detroit, Michigan which was initiated in May 2008. The problems cited in the warning letter included the inadequate and untimely investigation of certain incidents by the quality control unit at the facility contrary to the company’s standard operating procedures. The FDA considered some of the observations to be repeat observations.The warning comes amid mounting concern in the U.S. about the safety and effectiveness of imported drugs. Western pharmaceutical companies squeezed by dwindling drug pipelines and price pressures have outsourced a growing share of drug testing, manufacture and development to Indian companies.
Generic Substitution Facts
Shocked yet? I'm just getting started.
- Chinese drug companies exported to the US last year more than $675 million in pharmaceutical ingredients and products
- Chinese and Indian manufactures supply American consumers with nearly 350 varieties and strengths of antidepressants, heart medicines, antibiotics and other drugs
- Analysts estimate that as much as 20 percent of finished generic and over-the-counter drugs, and more than 40 percent of the active ingredients for pills made here, come from India and China. Within 15 years, they predict, as much as 80 percent of the key ingredients will come from those countries
- Difficulties with generic drugs are commonly attributable to the inactive ingredients aka excipients This can occasionally make a difference in absorption rate and processing of the active ingredient.
- Generics are not subject to clinical trials; manufacturers are only required to conduct comparative bioavailability studies, (volunteers take the original drug, followed by the generic. The rate of absorption is evaluated to ensure they are the same.)
- The WSJreported last week that pharmaceutical companies spent $47.4 million lobbying Congress in the first three quarters of 09, a 36% increase the same period a year ago.
- Pfizer, which last year announced its plan to move big time into the generics to claim its share of an estimated $520 billion by 2012, announced today plans to provide drugs free of charge to individuals who have lost their jobs and are experiencing severe financial hardship
In a call for more rigorous monitoring of both generic and brand prescriptions,Peoples Pharmacy reports that along with no requirements regarding the inactive ingredients (fillers, colors, binders) in generics, another problem is that generics can alter the formulation they utilize for release of the active ingredient "Many pills are designed to release the active ingredient over a sustained period of time. Generic products may use a different formulation. This could alter the way in which the medicine gets into the blood stream."
Case in point the generic version of Wellbutrin XL 300: Budeprion XL 30, manufactured by Israel's Teva, America's largest drug supplier, which produces "one in every 15 prescriptions in the United States. It and other manufacturers of generics make knockoff versions of pharmaceuticals produced by Roche, Pfizer, Eli Lilly, Merck and other makers of name-brand drugs after their patents expire."
From the September 23 WSJ article by Andy Georgiades:
Five months after declaring a generic version of antidepressant Wellbutrin XL safe, the U.S. Food and Drug Administration says it is prepared to conduct a human trial to get to the bottom of consumer complaints about the drug....
More than 100 complaints about the drug were filed with the FDA between December 2006 and the end of this January. Among the most common complaints were that the drug was ineffective or aggravated the condition, or caused nausea, anxiety or headache.
This past summer, [Joe Graedon, a pharmacologist and co-founder of the People's Pharmacy] and others were granted a meeting with senior officials from the FDA's Center for Drug Evaluation and Research.
Mr. Graedon said there was a "consensus" by the end of the meeting that the two sides could collaborate on a study that would involve patients who reported problems with the generic after taking the branded version. But he can't begin a recruitment effort until he is given the details of the study design, and he is still waiting to hear from the FDA on that. link
A 2007 Washington Post article FDA Scrutiny Scant In India, China as Drugs Pour Into U.S. notes that the pet food scandal raised the level of fear over contamination, counterfeit or ineffective or understrength imported drugs.
"As the manufacturing goes to China and India, the risk to human health is growing exponentially," said Brant Zell, past chairman of the Bulk Pharmaceuticals Task Force. The group represents American drug-ingredient makers that filed a citizen's petition with the FDA last year asking the agency to oversee foreign firms more aggressively.
Speaking before a hearing of the Senate HELP Committee on April 24, 2008, Janet Woodcock, Director of the Center for Drug Evaluation and Research at the FDA acknowledged that drug companies outsource operations because of "lower, less stringent standards in some parts of the world," in addition to lower labor costs in developing countries." Link
What you need to know
A pharmaceutical company that wishes to market their generic drug must offer proof of bioequivalency to the FDA. In order to be bioequivalent, the active ingredients in a generic drug must be absorbed at a similar rate and in a similar amount as the brand name drug. The generic does not have to act exactly the same as the brand name drug, but it does have to fall within certain guidelines set by the FDA. These guidelines may vary from drug to drug.
In a 2007 report the AMA published policies H-125.984 and Policy H-125.984, outlining policy suggestions regarding substitution of generic drugs. They suggested that FDA "B"rated generics be illegal, that the FDA, the ADA and the US Pharmacopoeia work together "to more effectively inform physicians about the bioequivalence of generic drugs", that Congress "provide adequate resources to the FDA to continue to support an effective generic drug approval process."
They additionally recommended that physicians designate their preference for a brand name drug by writing "Do Not Substitute" (or other phrases or designations as defined by state law) that a pharmacist "orally explain to the patient that the generic drug product being dispensed is from a different manufacturer or distributor and, if possible (eg, for solid oral dosage forms), visually show the product being dispensed to the patient..."
The Pharmacist's Letter provides charts detailing information on Generic Substitution for Commonly Prescribed Drugs and State Regulations on Generic Substitution, including whether their laws require they adhere to the Yellow Book.
The New Bible - The Electronic Orange Book
Hopefully, after reading this you'll be sure to consult with your pharmacist to ensure a dispensed generic is bioequivalanet to its brand counterpart. But you should also check out prescriptions you've already filled. The label MUST provide information on the drug's manufacturer. (In my case, I discovered one of my prescriptions comes from Caraco...)
Become familiar with the FDAsElectronic Orange Book which contains listings of drugs and their bioequivalency status. The online version is regularly updated as new generics are approved and is searchable by active ingredient or brand name.
Glossary
Some terms you might want to become familiar with:
- Generic prescribing: A physician uses a generic name, leaving the choice of brand to dispensing pharmacist.
- Generic substitution: The pharmacist initiates substituting a different or unbranded drug product with the same same chemical entity and dosage, instead of the brand name prescribed by physician.
- Therapeutic substitution: The pharmacist dispenses a pharmaceutical or therapeutic alternative for the physician-prescribed drug without consulting the physician. This denotes replacement of the prescribed drug with a chemically different drug within the same therapeutic category.
- Pharmaceutical Equivalents. Drug products which have the same active ingredient(s, dosage, means of administration, and identical in concentration and strength.
- Active pharmaceutical Ingredients (API): the primary therapeutic component of a finished drug product
- "A" v "B" rated Generics: The FDA considers generics therapeutically equivalent to brand name innovator products "A-rated," and those that are not therapeutically equivalent "B-rated."
- Abbreviated New Drug Application (ANDA): data on a generic drug product which is submitted to the FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, for review and approval. "Generic drug applications are called "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, a generic applicant must scientifically demonstrate that its product is bioequivalent (i.e., performs in the same manner as the innovator drug). Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public." Link
- Narrow Therapeutic Index Drugs: Since even a small changes in the dosage of an NTI drug can cause toxic results, patients require constant monitoring to ensure efficacy. Examples include minophylline, carbamazepine, lithium carbonate, phenytoin, theophylline and warfarin sodium (NTI Drugs: caution for malpractice)
References
Chinese generics
General Substituions
Chinese and Indian generic safety
Sources
Fierce Pharma
Safety Concerns Raised About Some Generic Drugs
Generics
Walmarts Generic Drug Plans