There have been questions raised in the last few weeks as to what it means when the U.S. FDA says a particular drug is adulterated. Although the U.S. FDA has clear criteria by which the agency determines if a particular drug is adulterated, for most patients, the key question is whether – and how – a lay person who does not work in a regulatory agency can identify an adulterated drug.  Quality-related defects are not very obvious to detect, yet they have a significant impact on overall public health.

How can we tell if a drug is adulterated?

Identifying and getting to the root cause of risks posed by poor product quality is addressed by the industry in two different ways. Product Quality Complaints are a category of “data” collected from the consumer (“the patient”) by the pharmaceutical manufacturers where the defect is obvious. For example, if the glue on a pain relief patch doesn’t stick to the skin for the prescribed period of time to allow the medicine to be topically administered, it is an obvious quality defect that a consumer can see. Consumers typically report such defects to the manufacturer, which is required to conduct an investigation into each such report and take corrective action.

More challenging are those drugs that act in a manner inconsistent with the data that was reviewed by the U.S. FDA in granting approval for market access. If the drug is metabolized faster or slower than it ought to be, thereby increasing or decreasing its concentration in the bloodstream, its affect may be much more severe. An example of such a case is Budeprion XL¹ (generic Wellburtin), which was eventually recalled from the market. Such undesirable side effects, which are called adverse events, are much harder to detect. This is the second mechanism by which the problems with the quality of a drug are identified.

Regulatory agencies like the U.S. FDA have clearly articulated guidelines for pharmaceutical manufacturers to collect and report all such reports of Adverse Events. Over a reasonable period of time, one can effectively evaluate the frequency and the trends of unlisted (those that haven’t been seen earlier) adverse events and correlate them to the quality of its manufacture.

Is there a better process for identifying adulterated drugs?

Historically, product quality complaints have been effective in identifying package deficiencies (broken tablet strips, malfunctioning injector pens, etc.) and problems with storage conditions that impact the stability of the product (discoloration of the product, degradation, “bad smells” emanating from the drug product, etc.). Most patients do not take the drug when such defects are apparent.

Adverse events, on the other hand can give us a lot more information about the way an adulterated drug behaves. If, on a consistent basis, one begins to notice these side effects that are not listed on the label of the drug, there is a reason to suspect something untoward is happening with its usage.  Let’s consider the example mentioned earlier in a little more detail.

Budeprion¹ (generic Wellbutrin) is a good example to consider. The first indication of something being wrong with this formulation came from the unexpected adverse events in patients taking this narrow therapeutic index medication. As often is the case, patients who were dispensed the generic form of this medication began to notice that the generic formulation, Budeprion XL, made them woozy, sick to their stomach or even suicidal. This is a well-documented case that was pursued by concerned citizens and helped result in U.S. FDA action. There are many anecdotal cases that haven’t yet been subjected to the same scientific rigor to link product quality to safety. One such example is generic Sumatriptan (Imitrex), a migraine drug for which there is anecdotal evidence that the generic causes “rebound headaches” that are often more prolonged than the original migraine.

It is critical for patients and providers to report if a drug does not behave as it should, as unexpected adverse events are an important red flag that can indicate safety problems. The recently released report on Countering Falsified and Substandard Drugs from the Institute of Medicine² makes this point. It says “When pharmacovigilance systems indicate lack of medicines efficacy, these signals should be followed. In-depth investigations can eventually produce data on the specific consequences of falsified and substandard medicines.”

Poor quality manifests itself as either “lack of effect” or “serious adverse events,” which are easily identifiable. In both case, regulators rely on patients and providers to raise specific concerns, which get rolled up into aggregate safety reports. This reporting apparatus is an important and effective way of ensuring drug safety. However, as with all communication technology, regulators should consistently strive to ensure that reporting is as easy and intuitive as possible for patients and providers.

Why does the U.S. FDA tell us to continue taking adulterated drugs?

A question emerges regarding what to do when the U.S. FDA tells us to continue taking drugs that are “adulterated.” We have seen this happen with Ranbaxy drugs over the last several years. The U.S. FDA is a science-based organization, and it first needs to establish a causal relationship between adverse events and the drug quality before asking us to stop taking these medications. Unfortunately, this is easier said than done. 

Reporting of adverse events for multi-sourced products (generics) needs attention. Historical data shows that adverse events are reported less frequency for generics than brand name drugs. This needs to significantly improve. Given the differences between generic formulations and their brand name counterparts (which I addressed in a previous blog post), it becomes so much more important to collect as much data on adverse events as possible for generic drugs. As consumers, we all need to be more proactive in reporting any adverse events for our medications to the U.S. FDA.

The U.S. FDA has a robust system and a process for collecting and analyzing adverse event data. A higher reporting rate of individual case reports and a deeper analysis of trends over longer periods of the aggregate case report data will allow the U.S. FDA to identify any potential safety signals that could be directly linked to product quality.

References:

¹ http://management.fortune.cnn.com/2013/01/10/generic-drugs-quality/?iid=SF_F_River#comments

²  http://www.nap.edu/catalog.php?record_id=18272

One of the key determinants of high quality, safe and effective medicines is the role of a national drug authority in holding pharmaceutical manufacturers accountable for violating cGMP standards.

The recently released report on “Countering the Problem of Falsified and Substandard Drugs”¹ from the Institute of Medicine of National Academies (IOM) is an excellent review of the current state of the manufacture of fraudulent medicines.

This report provides an excellent compilation of the drivers for adulteration and the impact of these substandard and falsified drugs on public health as well as a discussion about what drives the manufacturers and distributors of such adulterated drugs, the current state of technology for detection of these falsified and substandard drugs and the emerging standard code of practice for falsified and substandard drugs.

A key IOM observation relates to the role of national regulatory authorities. The report correctly observes that international quality standards for drug manufacture depend on the competence of the national regulatory authority.

Role of the Health Regulator in India:

In May 2012, a Standing Committee on Health and Family Welfare of the Indian Parliament produced an exhaustive report on the structure and functioning of the Indian Regulator, Central Drugs Standard Control Organization.² This Report focuses on the manner in which regulatory approvals are sought for marketing of drugs for the Indian market and how the Drugs Controller General of India (DCGI) and the Central Drug Standards Control Organization (CDSCO) allegedly have failed to enforce the law, either through collusion or blatant negligence.

There are many serious observations in the Standing Committee report. However, one stands out: namely, the allegation that there is sufficient evidence of collusion between drug manufacturers and some officials at the CDSCO. It further states that it is difficult to believe that these irregularities merely were due to poor oversight or that they were unintentional.

The entire report is accessible online and makes for great reading. It is interesting to note that, as of almost one year after release of this report, no public action has been taken by the Ministry of Health on any recommendation made in this report. In fact, the only action noteworthy in this context is the public interest litigation filed by two non-governmental organizations in the Supreme Court of India alleging flaws in the regulatory framework governing clinical studies in India. As a consequence, the Supreme Court has imposed a temporary hold on any new approval of clinical studies for two months, effective January 22, 2013.

Response to the Ranbaxy case:

In the wake of the news about Ranbaxy pleading guilty to several criminal charges in the U.S., there have been demands for greater accountability from Indian regulator. There were reports in the Indian media that the Indian regulatory body is examining documents submitted by Ranbaxy to gain approval for marketing its drugs in India. It remains to be seen if there is any actionable outcome from this review.

In a recent interview with the media,³ the DCGI said Indian law governing marketing of drugs purely is based on science, while laws of other countries (unfortunately he did not name which ones) may be influenced by commercial interests. Having observed and participated in the work of the U.S. FDA for more than eight years in the prosecution of my case against Ranbaxy, this insinuation is totally false. The U.S. FDA is a science-based and data-driven organization, and the outcome of my case proves it.  I wish this were true of other regulators across the world.

Equally absurd is the assertion there are differing standards when it comes to cGMPs. The amount of stability data needed to support a filing varies considerably among different countries. For example, some countries accept three months of initial stability data, while others require six or more months of data. This doesn’t mean the process by which they expect the manufacturer to study the shelf life, or the standards by which they expect the data to be analyzed to determine shelf life of their product are somehow different. It is exactly this type of approach that encourages manufacturers to have two different set of processes and quality standards: a stringent set of specifications for what they call “regulated markets” – which includes the U.S. and western Europe – and a “less stringent” set for what they call “rest of the world,” which, unfortunately, sometimes includes India. An interesting analysis of the current state of drug regulation in India was published earlier this year by Amir Attaran and Marvin Shephard in BMJ.⁴

Why do we care about the Drug Regulator in India:

It is the stated policy of the U.S. FDA to work collaboratively with national regulators of other countries to ensure product quality and safety. It is noteworthy that the U.S. FDA has no information-sharing agreement, confidential commitment or any other cooperative agreement with their regulatory counterpart in India. The question therefore to ask is what confidence do we have in a national regulator that has such a checkered past and that is tasked with overseeing the manufacture of medicines for domestic and international distribution? What do you think?

References:

¹http://www.nap.edu/catalog.php?record_id=18272

²http://164.100.47.5/newcommittee/reports/EnglishCommittees/Committee%20on%20Health%20and%20Family%20Welfare/59.pdf

³http://economictimes.indiatimes.com/news/news-by-industry/healthcare/biotech/pharmaceuticals/dcgi-working-on-policy-to-respond-to-safety-alerts-by-foreign-regulators/articleshow/20284107.cms

⁴http://blogs.bmj.com/bmj/2013/01/24/amir-attaran-and-marvin-shepherd-denialism-and-indias-risky-medicine/?utm_source=%20feedburner&utm_medium=feed&utm_campaign=Feed%3A+bmj%2Fblogs+%28Latest+BMJ+blogs%29&g=widget_default

My eight-year journey for truth and justice came to an end on May 13. On that day, I stood in a U.S. courtroom as Ranbaxy pleaded guilty to multiple criminal felonies and agreed to pay $500 million to resolve criminal and civil allegations of falsified drug data and systemic manufacturing violations. It is the largest settlement of its kind against a generic drug manufacturer.

Although the past eight years have been difficult, the occasion offers a moment to reflect on the broader meanings, particularly with regard to India’s place in the world.

As I read the comments on various news sites, blog posts and personal email messages after the announcement last month, a common theme emerges which characterizes my actions as “unusually courageous.”  While I am humbled by such characterization, I must say my actions are neither unusual nor courageous to me. They are the result of three important factors that led me to act when my conscience said I ought to.

My parents taught me well. My father always said, it is a bigger sin to be indifferent and not act than to commit the crime. Secondly, Dr. Rajinder Kumar, who was my manager at Ranbaxy, personified integrity. He was and still is my role model. When many in his place chose to look away, he took a principled stand for what he believed in, namely protecting patients. Lastly, my work in the pharmaceutical industry has always been rooted in a desire to help people. I saw what happened at Ranbaxy as a threat to public health. When you put these three things together, it is hard to see my actions as either unusual or courageous. They were, quite simply, the right thing to do.

And I believe my actions are consistent with my Indian heritage. While I am now a citizen of the United States, I am from India and am proud of my Indian ancestry.  We are an honest and hard-working people. We are rooted in an ancient civilization and culture that values truth and integrity.

Despite this noble tradition, recent headlines have highlighted corruption, fraud, nepotism and depravity in India. This is not who we are—and we need to prove that to the world.

As India continues to grow in global prominence, it becomes more important than ever for parents to instill in their children a sense of duty to be individually and socially responsible and to stand up for what is right—even when it is difficult to do so. We need to elevate role models like Dr. Abdul Kalam, who push us to dream big. We need corporate leaders like Narayana Murthy, Ratan Tata and Azim Premji, who show us how good governance is good business. Finally, we need transparent public systems and processes that work for the people, not for the protected elite.

Achieving this vision requires each of us to act and to lead by example. I tried to do that through my actions to help expose the wrongdoing at just one company. There were many hardships along the way. But in hard moments, we draw comfort from the simple truth so prominently displayed on our national symbol—the quote from Mukunda Upanishad, Satyamev Jayate: Truth alone triumphs.

Cradled in this simple truth, we must redouble our resolve to show the world the greatness of our country.

I have strong respect for the FDA and its dedicated staff.  My eight-year effort to expose fraudulent activity at Ranbaxy has given me unique insight into how the FDA works and how it stacks up to regulatory agencies in other countries.  My assessment is that the agency truly is the “gold standard” by which all national regulators should be measured.

However, in today’s complex regulatory arena, even the best can improve. Based on my experience, I have several suggestions for how the agency can better meet the challenges of regulating drugs produced overseas and sold in the U.S.  The ideas below are just the start of what will become recurring themes on this blog.

How FDA Stacks Up