Statement from FDA Commissioner Scott Gottlieb, M.D., and Director of FDA’s Center for Drug Evaluation and Research Janet Woodcock, M.D., on the FDA’s continuing efforts to maintain its strong oversight of generic drug quality issues domestically and abroad

FDA Statement

• For Immediate Release: February 22, 2019
• Statement From: Scott Gottlieb, M.D.

At the FDA, protecting patient and consumer health is our highest priority. Assessing and mitigating risks is at the heart of everything we do across our vast portfolio. Sometimes the actions we take are visible, like warning letters or recalls. At other times, our actions to protect consumers are less discernable, but equally vital. Analyzing and addressing potential risks is a complex effort based on data and grounded in science. These activities are at the center of our consumer protection mission and underpin our efforts to ensure the quality and safety of medical products.

Recently, there have been reports in the press calling into question the quality of our nation’s drug supply and specifically, asserting that certain generic drugs are of a lesser quality than brand drugs. Some of these reports claim to be based on data analysis. We believe these interpretations are seriously flawed and do not account for the full picture of our global vigilance over generic drug manufacturing.

Today, we want to explain some of the fundamental steps we take to protect the quality and effectiveness of generic medicines that consumers and patients rely on every day and address what we believe are shortcomings in the analyses that have been performed by some news outlets. We recognize that our statement, in part directly responding to a news report, is not customary; we nonetheless feel obligated to provide a substantive response given the public health issues at stake.

Consumers must have confidence in the safety and quality of generic medicines. Generic drugs provide affordable access to critical treatments. They are just as safe and effective as their brand counterparts and we stand behind the regulatory efforts that go into ensuring the safety and quality of all generic drugs. Our rigorous standards and inspections apply equally to generic and brand drugs – whether the medicines are being manufactured in Shandong, India, or Indiana.

We welcome discourse about our process through public comment and a constructive dialogue with all partners and stakeholders, including the press. We welcome the scrutiny of our programs. We welcome the accountability inspired by a free press. This dialogue is part of how we advance our public health mission. We also welcome here, the opportunity to lay out our case for our high confidence in our generic program.

To address recent questions raised about the scope and effectiveness of our oversight of generic manufacturing, we’ve asked our teams of experts in pharmacovigilance, pharmaceutical quality, compliance, and enforcement to look into a few specific, critical observations that were made.

FACT: Generic drugs are just as safe and effective as their brand drug counterparts

Generic medicines use the same active ingredients as brand-name medicines and work the same way. So, they have the same risks and benefits as the brand-name medicines.

The FDA’s generic drugs program conducts a rigorous assessment before a generic drug is approved to ensure generic drugs meet these requirements. In addition, the FDA conducts inspections of manufacturing plants, ensuring compliance with the agency's requirements on good manufacturing practices.

The FDA’s staff also continually monitors brand and generic drug products to make certain the medicines at all levels of the supply chain, from active pharmaceutical ingredients (API) to drug products being sold to consumers, are safe, effective, and high quality. In the event that reports of negative patient side effects or other concerns suggest a problem with a drug, the FDA investigates and, when appropriate, may require changes in how a medicine (both brand-name and generic versions) is used or manufactured.

FACT: We closely analyze reams of data to ensure the quality and safety of manufacturing throughout a product’s lifecycle

The FDA monitors many sources of data to ensure the safety and quality of generic manufacturing. One of the fundamental elements of overseeing the quality and safety of generic and brand drugs is having a clear understanding of the specific processes and technologies used to manufacture drugs throughout their lifecycle. This starts before a drug is even approved and brought to market, with the FDA’s premarket (or preapproval) review of drug applications, including a robust review of manufacturing information, which is a cornerstone of our current regulatory framework. This manufacturing information allows the FDA to perform a careful analysis and assessment of the drug product and manufacturing quality. We also, where needed, conduct premarket inspections of manufacturing facilities for the product to ensure compliance with good manufacturing practice regulations and other quality requirements before it is ever marketed. For generic drugs in particular, this includes all the assessment activities conducted by our Office of Generic Drugs as part of their multidisciplinary review of all generic drug applications. As a result of the FDA’s rigorous review of manufacturing information, many drugs are not allowed to be marketed because, based on our careful review and analysis, they do not meet the standards for approval.

Before and after marketing of a drug product, manufacturers are also required to notify the FDA of any changes they make to their manufacturing process or facilities. Moderate and significant changes require a supplemental application to be submitted to the FDA and significant manufacturing changes require the FDA’s approval before the manufacturer can distribute the drug product. Overseeing how drugs are produced is a key component of ensuring their ongoing quality and safety.

After marketing of a drug, we also maintain active safety pharmacovigilance, particularly to identify and evaluate previously unreported adverse events (more commonly known as side effects). In most cases, one cannot draw a causal relationship from adverse event reports alone. It’s also generally not possible to determine whether a particular manufacturer’s product is causing more adverse events than another manufacturer’s product, just from adverse event reports. Additionally, analyses of voluntary, spontaneous adverse event reports from the FDA Adverse Event Reporting System (FAERS) – whether using the public database, or reports received through a public records request – cannot provide the actual rate of an adverse event (AE) for any drug.

The FAERS database includes reports regardless of whether AEs are attributable to the drug (vs. an underlying condition, for example). Moreover, reports typically have limited information for fully analyzing causality. Numerous biases influence whether AEs are reported in the first place. For example, some patients and providers may have negative expectations about generic products, and there may be a bias to report AEs with generic products, particularly early during their marketing. The AE severity and publicity about a drug or AE can also influence reporting.

Atorvastatin has recently been cited in some press accounts. Looking at this drug as an example, the FDA pharmacovigilance experts reviewed data from our FAERS database along with drug utilization data from January 1, 2012 through December 31, 2018 and did not find evidence that any single generic atorvastatin was more likely to be associated with adverse events than another (or that any generic was more likely to be associated with adverse events than the innovator product).

The FDA has no concerns regarding the safety or efficacy of any generic atorvastatin at this time, including the Mylan product which was cited in the recent press accounts.

We are aware that AE reports in FAERS often refer to the brand name product and manufacturer (rather than to the specific generic products and corresponding manufacturers) as the “providing manufacturers,” and those reports can far exceed the brand products’ percentage of prescriptions dispensed when compared with generic products.

But this is not surprising. This type of discrepancy has been noted before in AE reporting, and likely represents health care professionals’ familiarity with and use of the brand name. This mismatch suggests the identification of the manufacturer in these reports is unreliable.

The differences in reporting among generic manufacturers are difficult to compare given the small numbers, known misclassification of product manufacturers in FAERS, and other biases. Additionally, reports typically involve more than one product, and other comorbidities, which makes drawing a causal relationship to one particular manufacturer very difficult.

So, how does the FDA identify and track potential safety signals with a specific drug?

When the FDA investigates a possible drug safety concern, a multidisciplinary team reviews the data. Interpreting postmarket safety data is complex. It involves analysis of a wide range of information, including spontaneous reports of adverse drug events, controlled clinical trials and epidemiologic studies, electronic healthcare databases, estimates of drug usage and adverse drug experience reporting rates, estimates of background rates of the adverse events, the pharmacology of the drug in relation to the identified safety concern, and other relevant information.

If a potential safety concern is identified in FAERS, further evaluation is performed. This might include conducting studies using other large databases, such as those available in the Sentinel System, which comprises payer claims data. Based on an evaluation of the potential safety concern, the FDA may take regulatory action(s) to improve product safety and protect the public health, such as updating a product’s labeling information, restricting the use of the drug, communicating new safety information to the public, or, in rare cases, removing a product from the market.

FACT: FDA’s inspectional footprint is robust, particularly in China and India

The FDA maintains global vigilance through a risk-based inspection strategy to focus inspectional resources on higher risk facilities and works closely with our international regulatory partners in Europe to avoid duplication of inspections. For instance, while surveillance inspections declined slightly in China from 2017-18, inspections in India have increased substantially. Among other things, the number of inspections in any given country reflects our risk-based prioritization of our inspections and improvements in our targeting; our increasing ability to leverage inspectional work done by trusted partners, especially in Europe; and a higher number of pre-approval inspections.

Our policy for prioritizing and scheduling drug manufacturing inspections at higher risk facilities for quality-related surveillance is based on a facility’s compliance history, recall trends, time since last inspection, inherent risk of the drug being manufactured, processing complexity, and other factors, which are all carefully weighed and considered. When you look at the full force of our inspectional resources, the FDA is maintaining global vigilance by concentrating inspections on higher risk facilities. As global compliance trends change – and standards in some sectors improve – we should expect to see an evolution in these trends.

FACT: FDA takes strong compliance and enforcement action when issues are observed

While the numbers of inspections have varied over the past few years, compliance actions, including warning letters, have increased. Warning letters to human drug manufacturers regulated by the FDA’s Center for Drug Evaluation and Research (CDER) have steadily increased over the past four years. In fact, in FY 2018, CDER issued nearly five times as many warning letters to human drug manufacturers as it did in FY 2015.

• 19 in FY 2015;
• 43 in FY 2016;
• 67 in FY 2017; and
• 94 in FY 2018.

But it’s important to note that we don’t believe this reflects a growing problem in drug quality. On the contrary, the FDA’s improvements to targeting inspections and in evaluating recommendations for enforcement action mean more attention is being given to higher risk facilities than ever before. By better focusing our inspectional resources on higher risk facilities, we can identify potential quality problems that have the most impact on consumers. Then, we can take appropriate action to address our public health concerns.

Overall, our inspections find that most companies are in compliance with good manufacturing practices and other regulations. But the reality is that we’re looking in the riskiest places. So, we’re better able to spot problems and take action when needed. Our approach appropriately allows for companies to provide a plan for how they’ll address issues identified during an inspection, which encourages a culture of quality within manufacturers, supported by smart and efficient regulation.

Findings from inspections are evaluated and classified according to a defined process agreed upon by the CDER and our investigators and staff in the field who work for the FDA’s Office of Regulatory Affairs (. Recommendations from field investigators are an important factor in the evaluation and classification process, but we also consider other important factors: the manufacturer’s prior inspection history; how issues identified during the investigation relate to the quality and safety of drugs being produced; the manufacturer’s response to the inspectional findings, including any proposed corrective actions by the manufacturer; and other factors that may arise. Final decisions about what action to take based on an inspections’ findings reflect a careful analysis of all relevant information.

In the great majority of cases, (about 75 percent of the proposed surveillance inspection classifications from the field), experts in CDER concur with the inspection classification recommendation from the field investigators. Per the agreed upon process and procedure, CDER makes the final decision regarding the issuance of warning letters following an inspection.

To guide this process, there are standards that we follow for classification and violations must meet a certain level to be classified as OAI, or “Official Action Indicated.” While one publicly visible measure of FDA action, it’s important to understand that warning letters are not the FDA’s only course of action with a manufacturer following an inspection. The FDA can also have regulatory meetings with companies; issue an untitled letter; conduct a follow-up inspection; and take other regulatory and compliance measures depending on the situation – and we often do much of this behind the scenes in the interest of patient safety, while also working to prevent potential drug shortages, for example.

FACT: Drugs manufactured outside the U.S. meet the same standards as drugs made domestically

The FDA’s standards and inspections for generic manufacturers are the same around the globe. Pharmaceutical manufacturers, no matter where they’re located, are responsible for ensuring that high quality products reach U.S. patients. The FDA’s role is to provide sufficient oversight – through application reviews and inspections – to ensure that companies fulfill their responsibilities and to take appropriate action when they do not. In addition to our pre-market steps, this oversight also includes testing selected finished drug products and APIs after they’re on the market. This testing affirms that the potency, quality, and consistency of generic medicines meets the standards established for the specific drug.

For example, the FDA labs tested 323 products from around the world – including more than 100 from India – to determine if foreign manufacturers had a higher incidence of product failure. All 323 samples met U.S. market quality standards using testing standards set by the United States Pharmacopeia (USP) or submitted in marketing applications.

We recognize that the U.S. market for pharmaceuticals has changed dramatically in recent years. In 1990, generic medicines only accounted for 33 percent of retail prescriptions. Today, generics account for 90 percent. Supply chains have also expanded globally. This has created new complexities, and new opportunities for novel risks. Our program has evolved to meet these new challenges, and we continue to implement policy measures to address emerging threats.

By maintaining global vigilance over the generic manufacturing industry, in close collaboration with our international regulatory partners, we’re maintaining the quality of these medicines while helping patients and payers realize more of the benefits from high quality, low cost generics. We continue to take new steps to address the challenges posed by a global supply chain and encourage the adoption of new advanced manufacturing methods. These actions are key parts of our commitment to ensure high-quality manufacturing, and to make sure Americans have confidence in the quality of products in their medicine cabinets – regardless of where they were manufactured.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.