Thank you for tuning into my blog. I am taking some time off for the next few months but look forward to re-engaging with you all in the fall.
On February 25, 2009, the U.S. FDA imposed on Ranbaxy what is akin to a death penalty if you are a pharmaceutical manufacturer: it invoked the Application Integrity Policy1. It cited numerous instances where the FDA said “These and other findings indicate a pattern and practice of submitting untrue statements of material fact and other wrongful conduct, which raise significant questions regarding the reliability of the data and information contained in applications (pending and approved) that your firm has filed with the Agency and which contain data developed at the Ranbaxy Laboratories, Paonta Sahib site.” Consequently, it banned the import of 30 drugs, which were manufactured at this site from entering the U.S. healthcare system2. However, if you look at the list of products that were manufactured at that site, one stood out, which was not banned from import into the U.S.: Ganciclovir Sodium.
The reason why the FDA exempted this antiviral drug, which is used to treat or prevent viral infections, was because Ranbaxy was the sole generic manufacturer of this drug sold it the U.S. It is used to prevent viral infections in patients who receive solid organ transplants among its other uses. If the FDA had included this drug in the import ban list, despite overwhelming evidence that the manufacturer’s systems and processes were violating cGMP and its application for marketing was most probably based on fraudulent data, it would have created a shortage of this drug in the US.
Over the last 10 years, there has been an increase in shortage of medications, which impact both acute and chronic care in the U.S. Data tracked by the University of Utah show that there were 267 cases of drug shortages in the U.S. in 2011, with the majority of the drugs falling into the following therapeutic areas: Oncology, anti-infectives, Cardiovascular and central nervous system. The common characteristics across all of these shortages are that they are mostly sterile injectables and generic drugs.
What causes drug shortages?
There are diverging opinions on what causes drug shortages. Potential reasons include lack of manufacturing capacity, lower profit margins leading to de-prioritization of their manufacture, price-gouging and overzealous regulations. FDA’s own data show that product quality-related issues are the primary drivers of drug shortages in 54% of the cases. In fact, if you look at the reasons behind the shortage of sterile injectable products in 2010, the lion’s share (>50%) of these were due to problems related to product quality.
This brings the focus back on effective cGMP inspections. Given that the majority of the drug shortages are for generic drugs, which are primarily manufactured overseas using active ingredients (API) which are also made overseas, it is critical that the inspectorate responsible for ensuring cGMP compliance at these overseas manufacturing facilities is provided with adequate resources to ensure that the largest source of these shortages, product quality is addressed effectively. One of the stated performance goal for the FDA in the Generic Drug User Fee Act (GDUFA) is to bring parity between domestic and foreign manufacturing plant inspections in five years. It is in our all our interest to advance this timeline significantly to close to two to three years.
How do we prevent drug shortages going forward?
It is in all our interests to have a list of “vulnerable” drugs, most of which are generic, that are susceptible to shortages. There needs to be continuity plans to ensure supply of these vulnerable drugs to protect public safety. The FDA sought input and comments on this topic by March 14, 20133.
While communications and information sharing are at the top of the agenda to address shortages, raw material sourcing and manufacturing issues also need to be highlighted in our comments to this request. Standard risk management techniques like the Failure Mode and Effects Analysis (FMEA) presented two recent articles4,5 focused on managing the risks caused by these shortages in hospitals could be extended to help identify steps of high risk within the overall supply chain. This will help us focus on large subsystems which drive such shortages, be it challenges within the distribution system, quality of raw material/manufacturing compliance, regulatory/legislative control or market factors dealing with business incentives for low margin products. The agency will then be in a better position to address these risks proactively.
3 FDA Docket Number: FDA-2013-N-0124, Federal Register, Volume 78, Number 29, Page 9928, 2-12-2013.
4Drug Shortages: Process for evaluating impact on safety, Elyse A. MacDonald et al., Hosp. Pharm 2011; 46(12): 943-951, Thomasland Publishers, Inc.
5Managing risks arising from medicine shortages in hospitals; David Cousins, Mary Evans & Kevan Wind, The Pharmaceutical Journal, 11th September 2012; 289:306
Compliance today is continuous process of assessing and eliminating or minimizing risks associated with the manufacture of pharmaceutical product. The key objective of Current Good Manufacturing Practices (cGMPs) is to provide patients with a product that has an equivalent identity, safety, strength, quality and purity to the one which was used to establish the clinical efficacy during product development (bio-equivalence in the case of generic drugs).
Risk-based assessment of compliance with cGMPs focus on control of critical points in the manufacturing process that are needed to ensure that the finished product meets the quality attributes required for the patient use. Here is a rundown of key objectives of cGMPs and how they accomplish them:
- To asssure the patient that the product prescribed has equivalence to the one tested and for which market authorization was obtained. This means that the product weight, volume, dosage strength, potency and stability are identical to that which was used during clinical development.
- The active drug in the product must be bioavailable to the patient in a manner that was shown and tested in clinical studies. This leads to the requirements for dissolution and contributes to the requirements for stability. These two criteria form the basis of what the regulators call “adulterated” drugs.
- Foreign substances, cross-contaminants and any other extraneous materials that may impact the patient in an adverse manner must be prevented from being a part of the product through effective quality-control procedures. This leads to requirements for adequate maintenance and calibration of equipment in the manufacturing plant.
- The process by which the drug product is manufactured must be monitored and controlled so that there is consistency and repeatability of above characteristics to meet set standards of control. This leads to establishment of key outcomes, called “specifications” which qualify the process and the output product that can be tested to make sure the process is working as intended.
- The raw material that is used to prepare the final drug product is also a key area of control. Lately, sources of Active Pharmaceutical Ingredient (API), excipients and other chemical/biological substances used in the manufacturing process are located all the way across the globe. Majority of bulk API now comes from China and a lion’s share of formulation into the final drug product is done in India. Ensuring high standards of quality of input into the manufacturing process as it relates to the raw material is a key risk to overall product quality.
- Finally, the documentation associated with the entire manufacturing process must be adequately detailed to demonstrate that the process is sufficiently controlled. Good documentation is key to training new operators, providing guidelines for handling unanticipated situations and for assuring quality inspectors that the process consistently produces a quality product. It also helps identify any trends and provide traceability in conducting investigations when things go wrong.
While the above six areas of control may be commonsense, it is surprising to see how often they are not properly implemented. External inspections often focus on identifying discrepancies in the implementation of these processes; and as I have said in an earlier blog post, the geographical location of overseas manufacturing facilities present a more challenging scenario to ensure their implementation.
The recently released report on Countering Falsified and Substandard Drugs from the Institute of Medicine1 correctly articulates the following:
- Failure to adhere to good manufacturing practices is the root cause of substandard drugs.
- While any one test may suffice to label a drug substandard or falsified, no single analytical technique provides enough information to confirm that a drug is genuine.
- Neglect of good manufacturing practices, both accidental and deliberate, drives the circulation of substandard drugs, while falsification of medicines has its roots in crime and corruption.
- The cost of active ingredients is by far the largest fraction of overall cost. A small reduction in active ingredient can vastly increase the profit margin.
- Good quality comes at a price, either from equipment costs, better ingredients or the higher process cost of quality assurance.
It behooves us, therefore, to ensure that every manufacturer that supplies its product to our healthcare system is consistently following cGMPs. Beginning July 2013, the European Medicines Agency (EUMA) now requires a cGMP certification for all active pharmaceutical ingredients (APIs) imported into the EU. The certification should be issued by competent authority of the exporting country.
According to Directive 2001/83/EC, the Qualified Person (QP) of the finished product manufacturing authorization holder needs to sign a declaration stating that the active substance is manufactured in compliance with the detailed guidelines on good manufacturing practice for starting materials. This is a good first step. The challenge, as I have learned from my experience in the Ranbaxy case, will be to have an effective inspection program to verify the authenticity of the cGMP certification. As we now know, this is easier said than done.
With the renewed focus on cGMP compliance and the significant gaps that I have seen in the implementation of the above controls in overseas manufacturing facilities, it is critical that pharmaceutical manufacturers pay special attention to this area and tighten up controls so that the patients who use their products are assured of the highest quality.
The discussion in India following the resolution of my case against Ranbaxy has been primarily focused on violations of processes that the U.S. Food and Drug Administration (U.S. FDA) requires pharmaceutical companies to follow. The general theme of the discussion is that, while the U.S. FDA requires compliance with detailed processes for manufacturing drugs and establishing drug stability, Indian regulators do not have such strict requirements. Others have stated that violations of detailed processes do not necessarily result in poor quality drugs.
In response to this discussion, the Indian Health Ministry offered an assurance to the public that it considers products manufactured by Ranbaxy – and other generic manufacturers – to be of high quality. This response from the Ministry of Health (and others in the medical field) is understandable. Any statement to the contrary would have created a panic in the delivery of healthcare in India. Indeed, one incident with Ranbaxy should not be used to paint the entire Indian generic industry with a broad brush.
Having said that, there are two important aspects of this discussion that need closer attention.
- How do we establish quality when the processes by which drugs are manufactured are not sufficiently described and documented?
- What kind of data do regulators need in order guarantee drug quality to the public?
Comparing Indian and U.S. Standards
The U. S. FDA has a Quality Systems Model that represents a framework for compliance with the Current Good Manufacturing Practices (cGMPs) (21 CFR Parts 210 and 211). Its prime directive is: “Quality should be built into the product; testing alone cannot be relied [upon] to ensure product quality.” This is the U. S. FDA’s stated approach to compliance and is available online.
In India, however, there is no such policy to define what constitutes “standard quality.” Drug The Controller General of India (DCGI) tests commercial samples following complaints, known as an adverse events, from consumers. The Central Drugs Standard Control Organization (CDSCO) publishes a list of products that are tested by the central laboratories, which are found to be “not of standard quality.”
It also is instructive to compare how regulations are framed in both countries to understand minimum expectations of high-quality products. In India, cGMP standards are described in Schedule M; in the U.S., the Code of Federal Regulations, Title 21, Volume 4 governs these standards. For example, in the area of training and skill of personnel employed in the manufacturing facilities, India’s Section 6 of Schedule M describes the role of the management, operators, staffing and training in general terms. There are more stringent and defined requirements in the U.S. Subpart B of Part 211 of the CFR, which governs organizational and personnel standards, states that:
There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.
Such detailed expectations are missing in the Indian regulations. Although there are additional clauses elsewhere in Schedule M that govern the rejection of products that fail tests, there is nothing as explicit as what is the law in the U.S. on how the process ought to work. There are many such examples in Indian regulations.
Why Processes and Standards Matter
Why is this important? Inspectors generally check compliance with stated regulations to establish variance from standard processes. If there is no explicit expectation of independence of the personnel and management in the quality-control unit, why should anyone be surprised if records, documents, and final products released to the public haven’t gone through rigorous checks for quality?
Violations of such processes result in significant penalties in the U.S. Historically, the same cannot be said about India.
Rigorous compliance with detailed and established processes and systems is a key determinant of the quality of the product. Business process excellence requires definition of the process in detailed steps, its dependencies and associated decision criteria so that the process can be executed consistently by a trained operator.
By way of comparison, the Indian information technology (IT) industry has used this approach as a key differentiator in its growth. SEI CMM is a standard that most Indian IT companies adhere to. ISO 9001 and other certifications require clear definition and adherence to detailed process. The reason these frameworks and certifications require adherence to a well-defined, detailed process is because consistency and repeatability across each step of the process leads to a better quality of the overall product. I believe this adherence to detailed process is why the IT industry from India is proving so globally competitive.
Improving Adverse Event Reporting
In safeguarding drug safety, compliance with processes and standards is particularly important when it comes to adverse event reporting—which is how regulators learn of problems with drugs already in the market. The U.S. has a well-established system to collect and analyze adverse event data. It is easily accessible to the consumer, and regulations require compliance with reporting both individual cases and annual aggregate reports that provide an analysis of trends for a particular drug product. The systems and processes needed to collect such data are still nascent in India.
Historically, reporting of adverse events for generic products lags behind that for branded products in the U.S. This needs to change. The U. S. FDA continues to educate consumers of the need to report adverse events. However, the frequency of reporting adverse events for the same products (generic formulations) in India is significantly lower compared to the U.S. Although the Indian regulator requires submission of periodic aggregate safety data, it is not clear what actions result from the analyses of such data. Regulatory actions seem to be driven more by international incidents (recalls, judgments etc.) than the results of analysis of aggregate safety data.
It’s worth noting that safety is a good surrogate for product quality, a case that I have made before on this blog. There are many such sources of data that are key to a sound scientific decision-making process used by the U. S. FDA. Unless the regulatory framework makes it a priority to collect and analyze such safety and adverse event data, assertions to the superior quality of products dispensed in the Indian market will remain subjective.
FDA Has Approved Only a Fraction of India’s Drug Manufacturers
According to the DCGI, there are 169 manufacturing facilities in India approved by the U.S. FDA, 160 facilities approved by European regulators, and approximately 1,300 certified by the World Health Organization. Overall, the DCGI estimates there to be about 8,000 manufacturing units across the country. Industry estimates put that number as high as 20,000.
The facilities that are inspected by the U.S. FDA and European Regulators have to comply with detailed processes and standards that govern the manufacture of medical products sold in those countries. Can we say the same about the other manufacturing facilities that cater primarily to the local market? Do we really have the confidence that the drugs manufactured in these facilities are in-fact of high quality?
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.
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?
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.