Low-cost generic drugs play a critical role in controlling escalating healthcare costs. With the vast majority of generics made partially or wholly overseas to capitalize on lower manufacturing costs, the adequate oversight of foreign manufacturing requires regulators to overcome significant geographic and cultural barriers. This is easier said than done.

To begin with, unlike most other consumer products, drugs work through a largely hidden process. If a car is a “lemon” and not fit for use, often it is apparent. Drugs, on the other hand, are complex chemical and biological molecules. They are formulated in technically specific amounts to react to hidden physiological processes within our bodies. This makes it hard to tell if a drug is a “lemon,” or in the words of pharma, the drug is “adulterated.”

Regulators worldwide answer this challenge by standardizing the process to formulate and manufacture drugs. Carefully controlled systems provide a high degree of confidence of reproducible, high-quality drugs. These processes are called current Good Manufacturing Processes (cGMPs). They ensure that the medicine meets specific requirements for identity, strength, purity, and quality. cGMP requirements apply to every aspect of manufacturing, processing, and packaging the product.

Adherence to cGMP is maintained through regulatory inspections. In the U.S., FDA frequently uses surprise inspections to ensure compliance. These inspections typically include a review of a company’s systems, processes, and records. FDA inspectors interview employees to verify that the company’s records are factual.

Regulatory inspections outside of the U.S, present jurisdictional and temporal challenges. A manufacturer located abroad receives advance notification to access the facility and often assists in procuring Visas for international travel. In many cases, inspectors seek assistance from the manufacturer to help with foreign languages, different cultures, and transportation to remote areas. These challenges remove the element of surprise which FDA uses to its advantage within the US. As FDA warning letters document, removing the element of surprise provides opportunities that can lead to skewed inspection results, even when manufacturers fail to follow cGMP.

Establishing foreign FDA offices better detects cGMP violations through more responsive action. In this way, FDA has offices in India and China and, more importantly, it has inspectors located within its Mumbai office.

These are significant steps. What remains, however, are inherent challenges such as language/dialect barriers, local systems and cultural differences. When visiting remote facilities, inspectors often rely upon manufacturer’s assistance for basic communication and transportation needs. These are systematic challenges that need to be addressed holistically because they impact the inspection process and, ultimately, the efficacy and safety of drugs consumed in the U.S.

Generic drugs are an essential part of our healthcare system.  Approximately 80 percent of prescription medications are generic, and a large percentage are produced overseas.  Although generic drugs help control healthcare costs, they raise other complex and often overlooked issues.  These complexities, some of which are identified below, underscore the importance that consumers are informed and aware of the drugs they are prescribed.

How are generic drugs different from their branded counterparts?

• Generic drugs are not required to contain the same ingredients in the same proportions.
• The process by which generic drugs are made may be different.
• Generic drugs are not subject to the same level of testing.
• Generic drugs may have a different shelf life.
•  A generic drug may be 20% weaker or 25% stronger than its branded counterpart and still be considered bioequivalent.  This means the average patient may absorb into their blood stream as little as 80% or as much as 125% of the active ingredient compared to the branded drug.

In most cases, a generic drug is not “identical” to its branded counterpart.  Approximately 90% of generic substitution occurs at the pharmacy, according to the Department of Health and Human Services.  As such, a consumer must evaluate his or her medication independently of the branded counterpart.  Here are some ways to do this:

• Educate yourself about your medication.

o   What are its expected side effects?
o   Were there any recalls?
o   Ask your Pharmacist who made the medication, where it was made, and whether he or she is aware of any manufacturing problems.
o   Ask your Pharmacist if there are alternative manufacturers. Frequently, there are multiple generic manufacturers for each drug.

• Visit FDA’s website.  FDA compiles safety and other useful information about drugs, such as potential side effects, past recalls, and known quality problems.
• Report quality issues, side effects and adverse events to FDA, the manufacturer, and your physician.   This allows FDA to detect quality issues.

An informed patient is an empowered consumer. The more you know about your medications, the better choices you will make about your health.

US journalist Katherine Eban posted on May 15 a detailed account of practices at Ranbaxy. Although I cannot comment on everything in her story, it is encouraging to see the US media take an active interest in public health and the extraordinary circumstances at Ranbaxy. With so much of this conduct tracing to India, certainly it is a matter of time before India follows suit.

My concerns for the well-being of people taking Ranbaxy drugs motivated me to act. Now that these practices have come to light, I hope that others understand why this was the right thing to do.

There have been many ups and downs since I first contacted FDA in 2005 about Ranbaxy’s widespread problems. After eight years, Ranbaxy has been held accountable for falsifying drug data, dangerous manufacturing practices, and compromised drug safety. I am proud of my work on this case and excited to see so many positive actions resulting from this effort.

Up until now, I have worked behind the scenes, helping regulators understand a complicated web of wrongdoing by a major generic manufacturer. I am grateful that I now can become a more visible advocate for improving the quality of generic drugs.

Why This Case Matters

Throughout these last eight years, I have learned a lot about how the US drug supply works. Estimates vary, but conservatively, approximately 80% of the generic drugs sold in the US have ingredients that come from overseas. As much as 40% of generic drugs dispensed in the US are fully manufactured in facilities that are outside the continental United States.

This leads to a very important question: How do we ensure that when you go to your neighborhood pharmacy to get your prescription filled, the generic substitution made by your pharmacist is as effective and safe as the branded drug prescribed by your physician? This is a question that merits careful consideration given the widespread use of generic medicines in our healthcare system. After all, HHS data establishes approximately a 90% substitution rate where a generic equivalent is available at the pharmacy.

Thankfully, a lot has changed in the eight years since I became aware of this issue. FDA now has offices in China and India, the two countries that account for a majority of the manufacturing facilities that make generic drugs for the US market. There are inspectors stationed in the Mumbai office who conduct inspections of the manufacturing facilities in India without planning for an international trip, applying for visas, and informing the manufacturer weeks in advance to expect them on a certain date.

However, these actions are just the beginning.

Because the global supply chain is so complex, there are opportunities for contamination of our drug supply along the way. Regulations are evolving, but their implementation in countries and cultures that are different than the US pose significant challenges to our healthcare system. Hopefully, this case offers an opportunity for a public dialogue on this topic and will drive diverse perspectives and shape the right policy for us.

While those of us involved in this case have worked hard, I know our work has just begun. Through this blog, I hope to foster a conversation about how we can continue this important work and enlist others in keeping our drug supply safe in the US and other countries.

I welcome your comments and input as we discuss various facets of this issue.

As I’m sure you all can imagine, this has been a very busy week for me. However, amid all the activity, I wanted to take a moment to thank everybody for the kindness and support you have shown me. I am proud of my work to improve drug safety and excited to see such a positive response to this effort.

After eight years of hard work on the case, I am very relieved to be able to reconnect with friends and loved ones. In the coming days, I hope to begin responding to the many kind messages I have received from all over the world since news of this case broke on Monday.

Many thanks again.

FOR IMMEDIATE RELEASE – Washington, D.C. (May 13, 2013)

Today, the United States government brought to a conclusion an eight-year criminal and civil investigation of Ranbaxy Laboratories Limited, India’s largest generic drug company, and Ranbaxy, Inc., Ranbaxy Pharmaceuticals, Inc., Ranbaxy Laboratories, Inc., Ranbaxy USA, Inc., and Ohm Laboratories, Inc. (“Ranbaxy”). Ranbaxy has agreed to pay $500 million to resolve allegations of falsifying drug data and systemic manufacturing violations. Ranbaxy USA Inc. has pleaded guilty to multiple criminal violations. Dinesh Thakur served as the whistleblower in this case and is the former Ranbaxy Director and Global Head, Research Information & Portfolio Management.

Statement by Dinesh Thakur:

“I am relieved that the government’s investigation has concluded. I am thankful for the remarkable effort of United States Food and Drug Administration, Department of Justice, United States Attorney’s Office for the District of Maryland, USAID, and State Medicaid Fraud Control Units. Their work has been tireless and dedicated.

“Eight years ago, as the Director of Project & Information Management at Ranbaxy, I discovered that the company falsified drug data and systemically violated current good manufacturing practices and good laboratory practices. Ranbaxy’s management was notified of these widespread problems. When they failed to correct the problems, it left me with no choice but to alert healthcare authorities.

“I worked with U.S. regulatory authorities for two years to expose the fraud. In furtherance of this effort, I filed a lawsuit to hold Ranbaxy accountable. It took us eight years to help government authorities unravel a complicated trail of falsified records and dangerous manufacturing practices that threatened to compromise the quality and safety of Ranbaxy drugs. Along the way, the government barred the importation of Ranbaxy drugs, held the company accountable for its data fraud under FDA’s Application Integrity Policy, and required it to implement corrective measures to prevent the problems from recurring.

“As a senior pharmaceutical executive, I understand the importance of regulatory oversight in ensuring drug quality and safety. There are unique challenges in a global drug market, which is highly dependent on international manufacturing and distribution. In fact, approximately 78 percent of prescription drugs dispensed in the United States are generic, and a growing percentage of drugs – both generic and name brand – is manufactured overseas. This case highlights the need for effective regulation that applies to drugs sold in the United States, regardless where they are manufactured.
I would like to thank FDA’s Office of Criminal Investigation, United States Attorney’s Office for the District of Maryland, Department of Justice, USAID, and Andrew M. Beato, Bob Muse, and Rory Kelly of Stein Mitchell Muse & Cipollone LLP. I hope that our actions and this case have helped to improve the quality and safety of drugs in the United States and abroad.”

FOR MORE INFORMATION
Please visit www.dineshthakur.com

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