As we dig deeper into the issue of prescription drug safety and the multitude of issues surrounding the manufacture, distribution and profit from pharmaceuticals in the United States, it is becoming increasingly evident that Congressional members are under pressure to make the approval process easier.
Part One of this series looks at the gaps in the worldwide distribution systems of pharmaceuticals. Part Two examines the breakdown in oversight of the manufacturing process by the federal government. Part Three gives a glaring example of how state governments are dropping the ball. Now, we expand the scope even further.
While Michael Moore's new movie Sicko looks at the U.S. health care industry, this series takes this issue to the next level.
Ranbaxy has a plant in Paonta Sahib, India, that produces drug components as well as finished drugs. According to documents forwarded to me by Prevent Medical Error (PME), a non-profit that seeks to promote best practices, Ranbaxy has been in the center of a few issues:
In fall 2004, the World Health Organization (WHO) cited Ranbaxy’s failure to prove bioequivalence. This apparently triggered Ranbaxy to remove their remaining AIDS drugs from the WHO approval list.
It appears to have taken the Food and Drug Administration (FDA) until February of 2006 to inspect the Ranbaxy plant, and an additional three months or more to warn the company.
Similar to the WHO, in an FDA warning letter dated June 15, 2006, the agency cited the Ranbaxy manufacturing plant at the Paonta Sahib facility for stability issues:
Those deviations observed by the investigators were presented to you on an Inspectional Observations (FDA 483) form at the close of the inspection. These CGMP (Current Good Manufacturing Practice) deviations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 351(a)(2)(B)].
It is currently unknown when and if the FDA has inspected and/or cited additional Ranbaxy plants, and at this time, there have been no reported product seizures of drug components and/or finished product associated with Ranbaxy’s Paonta Sahib plant.
Although one branch of the FDA has put Ranbaxy under both civil and criminal investigation, another department within the FDA continues to approve Ranbaxy’s Abbreviated New Drug Applications (ANDA) for new generic drugs.
The FDA also continues to allow Ranbaxy to manufacture and sell new generic drugs such as zolpidem, the generic form of Ambien.
In some cases, Ranbaxy holds the exclusive rights to a generic drug for the first six months after the brand name drug goes off patent.
Because they are often less expensive than competing generic versions, the big three drug wholesalers and many pharmacies and mail order pharmacy benefits managers (PBMs) continue to distribute, purchase, authorize, bill, and sometimes dispense Ranbaxy generic drugs.
Despite reports of generic drug discrepancies, other Indian generic drug companies such as Indian subcontractor Lupin appear to remain largely under the radar screens of state and federal entities.
In the case of Indian generic drug manufacturer Wockhardt, review of the FDA’s February 2006 warning letter to the company indicate that Wockhardt has a history of record keeping and documentation issues:
Complete, true and accurate records are the foundation for good manufacturing practices (GMP). Reliable documentation is a control which raises assurance of the quality of the product manufactured. Violations concerning inadequate documentation are serious and should be handled as such.
We are also concerned that the two previous inspections also noted failure to maintain complete and accurate records, and that your firm may not have taken this type of discrepancy seriously and thus has not corrected the documentation practices of your employees. In addition, during a regulatory meeting with your firm on May 7, 2004, management indicated to us that inappropriate documentation practices have occurred at your facility. Practices such as back dating and signing for actions not performed are serious violations.”
Traditionally, the burden of proof that a prescription drug is FDA approved and legal at time of dispense and administration has been on those who profit from the manufacture, distribution, authorization and dispense of prescription drugs. Increasingly, the burden of proof appears to be shifting from those who profit to those who pay the bills.
A 2001 Lancet article reveals that, according to the WHO, India produces as much as 35% of the counterfeit and substandard drugs in the world. In addition, a recent series of Business Week articles exposes systemic infrastructure gaps in India’s water and distribution systems that likely increase prescription drug adulteration and tampering.
The FDA has many issues concerning oversight of the manufacture of pharmaceuticals within the borders of the United States:
1. Manpower – As with many governmental agencies, there are not enough inspectors to oversee the process and identify issues.
2. The Regulatory Process – When a pharmaceutical manufacturer is warned, there is an appeals process that gives the manufacturer an opportunity to respond. A company can also file for injunctive relief. During this process, the manufacture of the compounds continues.
3. FDA Funding – It is estimated that 40% of the FDA’s operating budget comes from the sale and licensing of rights to pharmaceuticals, so the agency’s funding is largely dependent on the industry it is charged with regulating, leading to complex and shifting priorities within the FDA.
4. State Pharmacy Boards – Most state pharmacy boards are under-funded and lack resources and jurisdiction to adequetely oversee the three big drug wholesalers, large chain pharmacies and PBMs. Oftentimes, state pharmacy boards include representatives from these companies.
It appears that oversight is even more of a problem overseas. According to a recent Washington Post article, pharmaceuticals and pharmaceutical components manufactured in China, India, Japan and Europe are not inspected as often by the FDA. In 2006, according to FDA records, 32 inspections were conducted in India and 15 in China. Some of these inspections were done as part of the approval process and not for quality control oversight, although the FDA would not comment on the nature of these 47 inspections.
This is in contrast with the 1,222 quality control inspections conducted in the United States in 2006. It is estimated that 20% of finished pharmaceutical products and 40% of active ingredients come from China and India.
It is predicted that within 15 years, 80% of the components of pharmaceuticals will come from these two countries
Setting the Standard
With the revelations that there are glaring irregularities in the manufacture of pharmaceuticals and the oversight by US federal and state regulatory agencies, you would think that Congress would move to strengthen the rules governing all of these industries. Instead, Congress is seeking to relax the rules, ostensibly to lower cost to the consumer to justify the increased lack of oversight.
In 1984, Congress passed the Hatch-Waxman bill, expanding the distribution of generics to reduce cost to the patient. The strength of this bill was FDA enforcement. Today, with the proliferation of adulterated and fraudulent pharmaceuticals through the Internet, the FDA has proven that it can’t or worse, won’t keep up.
Powerful forces are now lobbying Congress to provide an FDA framework for the production of biogeneric drugs – generics in the area of biologics. Biotech or biologics are not chemically manufactured but produced from live cells, and are used to treat a variety of chronic and terminal patient populations, including AIDS, diabetes and cancer.
American biotech companies are increasingly outsourcing drug research and purchasing outsourced raw ingredients, creating a framework that allows for the approval and production of Indian and Croatian biogeneric drugs. This may serve as a catalyst for American biotech companies to hasten the outsourcing of biologic production, and along with it, high paying biotech jobs.
It has been evidenced that in the past, the pharmaceutical, distribution, dispense and insurance industries all appear to have allowed for the introduction of adulterated compounds into the mainstream manufacturing, distribution and dispense systems in violation of standards. The sale of adulterated pharmaceuticals to unwitting patients can be debilitating.
Biologics involves increased scrutiny. Since these are live cultures, they are often infused so they have a direct route to vital organs and the central nervous system. Given the compromised condition of the patient population, any change or alteration of the manufacturing process can render the drug toxic, and the negative effects are immediate, and in many case life-threatening or even fatal. Biologics are much more sensitive to process changes than chemically manufactured drugs, although both scenarios can be dangerous. Most also have short shelf-life and require highly specialized (and expensive) handling in order to maintain product integrity and FDA approval. Lengthening the amount of time that biologics drugs spend in Indian or Croatian distribution and shipping channels doesn’t intuitively make a whole lot of sense.
It is evident that state and federal governments have gaps in their control of the manufacture, distribution and dispense of pharmaceuticals in the United States. The FDA is failing to inspect the multitude of generic pharmaceutical manufacturing plants that are springing up throughout the world to meet the increasing demand, just as they appear to be failing to provide quality control for pharmaceuticals made in the United States.
Now, the United States wants to open the door to biogenerics. With little or no oversight of the process, the results could be disastrous for the patients who need these medicines to heal them.
But the cost savings is so significant, some will say. Who cares if it may kill you? The prescription only costs you $4!
If the label says zolpidem, the patient should be able to rest easy knowing that he or she has received zolpidem. Is that too much to ask?
Written with help from Prevent Medical Error, a nonprofit organization that seeks to promote best practices. As a nonprofit, Prevent Medical Error has accepted contributions from donor holdings in UnitedHealth Group. Bristol Myers Squibb, Pfizer, and Forest Labs.