NCHR Testimony at 2016 FDA GDUFA Regulatory Science Meeting

Thank you for the opportunity to speak today. My name is Tracy Rupp and I’m speaking on behalf of the National Center for Health Research. I’m a pharmacist and Director of Public Health Policy Initiatives at NCHR. Our research center analyzes scientific and medical data and provides objective health information to patients, providers and policy makers. We do not accept funding from the drug or medical device industry and I have no other conflicts of interest.

Manufacturer Inspections

The first GDUFA regulatory science priority I would like to discuss is the inspection of manufacturing plants. We have heard today that patient and prescriber confidence in generics is disproportionately shaped by the recalls and quality issues that occur so increased attention to manufacturing quality control is critical. And importantly, we have heard how bioequivalency for complex generic drugs is highly dependent on quality control of the manufacturing process.

In 2012, Congress passed the FDA Safety and Innovation Act (FDASIA), which among other things, requires the agency to inspect foreign facilities that make drugs sold in the U.S. as frequently as it inspects domestic plants. In addition to achieving parity in the frequency of inspections, FDA also committed to ensuring that domestic and foreign inspections are conducted with “comparable depth and rigor.”

A 2015 report from the Office of the Inspector General found that FDA has made progress on oversight and inspection of manufacturers of generic drugs but gaps remain.[1] For example, FDA increased its preapproval inspections by 60 percent between 2011 and 2013. However, it did not conduct all of the preapproval inspections requested by its own generic drug application reviewers during this time period. And, most unfulfilled requests were for inspections of foreign manufacturers. FDA staff attributed outstanding preapproval inspections to a lack of resources. In addition to improving drug quality and improving consumer confidence in generics, timely conduct of preapproval inspections may help reduce delays in the availability of new generic drugs.

In recent years, FDA has sent warning letters about violations to companies with plants in foreign countries such as India and China. The number of warning letters sent to Chinese and Indian firms for violations nearly quadrupled from 2012 (4 letters) to 2015 (15 letters).[2] Most of the warning letters raised concerns about data integrity. Many of the observations were for egregious problems like altering official documents in front of an inspector, falsifying dates of quality control testing, or documenting important manufacturing data on scrap paper in pencil.[3] These are the types of issues that impact consumer confidence in generic drugs.

Despite the increased resources from the GDUFA provisions of FDASIA in 2012, it’s difficult to keep up with the increasing production of drugs and devices in foreign countries. Imports of drugs and medical devices from China alone increased by nearly five-fold from 2007 to 2013.[4]

The 2015 OIG report recommended that FDA use its inspection resources more efficiently by making greater use of authority granted by FDASIA to request records in lieu of or in advance of an inspection. This authority could increase FDA’s capacity for preapproval inspections; record reviews could be completed in advance, rather than using up the inspection staff’s time during an onsite inspection. The inspector’s time onsite could be prioritized to address the tasks that must be conducted in person rather than on reviewing paperwork. Two important questions are:  has FDA implemented this recommendation? And if so, what impact has it had?

Additional related regulatory science research questions include:

  • Has this new authority improved the quality of inspections? Has it helped FDA hone in on the issues posing the greatest risk to public health?
  • Can a more focused onsite review help improve drug quality and reduce the risk of patient harm from unsafe drugs?
  • Does this new authority reduce approval delays?
  • Do more frequent preapproval inspections result in fewer recalls?
  • Are problems identified and fixed earlier as a result?

Registering with the FDA

Another important GDUFA regulatory science research question is how to improve compliance with the requirement for manufacturers of generic drugs to register with FDA.  FDA uses the registration database to help determine which facilities to inspect, using its risk-based approach. The OIG report found that of the 432 generic drug manufacturers listed on ANDAs approved in 2013, 10 percent did not match entries in FDA’s registry of generic manufacturers. It’s worth noting that 62 percent (28 of 45) of the manufacturers that couldn’t be located in the registry were foreign. FDA can’t inspect facilities if it doesn’t know they exist.

Research is needed to determine what strategies are most effective for ensuring registration, including incentives for registering and effective penalties for those that don’t.

Generic Labelling of New Risks

Another important regulatory science question is the effect of generic drug labelling updates on patient safety. FDA has issued a proposed rule that would allow manufacturers of generic drugs to update their label as new information becomes available. We strongly support that proposed rule. Currently, generic manufacturers have little incentive to monitor drug safety and they aren’t required to update the label with new risk information. As a result, safety monitoring basically stops when generics enter the market. This puts patients at risk since the FDA found that the median time from initial approval of the drug product to the time of making a safety-related labeling change was 11 years, past the market exclusivity period for many branded drugs.

The proposed rule will give generic drug manufacturers the authority to initiate safety labeling changes through the Changes Being Effected (CBE) process. The result will be to give patients access to the most up-to-date product labeling information regardless of whether they choose a brand-name or generic drug. It would be helpful if the FDA could conduct or support research to determine the impact of the current situation, where labels for generic drugs are not updated unless the branded version is updated. It’s especially important to compare the current situation with previous policies. For example, prior to the Supreme Court decision Pliva v. Mensing in 2011, generic drug companies were responsible for updating their labels. Now that they are not required to update their labels, an interesting question is how many labels for generic drugs were updated in the 5 years prior to the Supreme Court decision compared to how many have been updated in the years since.

And, when and if the proposed rule is implemented in the future, an important regulatory science question is how will this affect the timeliness, accuracy, and completeness of drug safety labeling? And will it protect patients from harm?

Patient Co-Pay Coupons

The third and last regulatory science question I will mention today is related to patient co-pay coupons. Like we heard earlier today, as drug costs continue to rise, brand name manufacturers are more likely to use coupons to entice consumers to fill their prescriptions, since coupons defray or eliminate copay costs. In 2009, coupons were available for fewer than 100 prescription medicines, but the number exceeded 700 by last year, according to a recent analysis by the Tufts Center for the Study of Drug Development.[5] These coupons are more common just prior to generic competitors coming on the market. The goal is to establish brand loyalty and reduce the number of patients switching to generic versions. As we heard earlier today, a 2013 New England Journal of Medicine analysis found that 62 percent of coupons were for brand-name drugs for which lower-cost options existed.[6]

Important regulatory science questions related to copay coupons are:

  • How do coupons affect prescribing of generic drugs?
  • What impact do coupons have on patient outcomes such as adherence to therapy and treatment success?
  • What is the impact on cost for patients, for Medicare, and for private insurers?


In summary, generic drug research and policies have an enormous impact on the health and safety of millions of Americans and impact patient and prescriber confidence in generic drugs. We urge you to consider research that will improve drug quality through rigorous manufacturer inspections, increase patient safety through the communication of important drug information on generic drug labels, and promote the uptake of generic drugs where they have the potential to reduce cost and improve outcomes.

Thank you for this opportunity to share our recommendations and I’ll be happy to answer any questions.


  1. FDA has made progress on oversight and inspections of manufacturers of generic drugs. HHS Office of the Inspector General, May 2015. Available at:
  2. International Pharmaceutical Supply Chain Imperiled Like Never Before. FDA Law Blog. February 29, 2016. Available at:
  3. Brennan Z. FDA Form 483s from India: a deep dive into the problems. Regulatory Affairs Professionals Society. November 9, 2015. Available at:
  4. Are generic drugs like Apotex medication made in India safe? Consumer Reports. April 25, 2014. Available at:
  5. Expected Growth in PBM Exclusion Lists Poses a Challenge to Drug Developers. Tufts Center for the Study of Drug Development. May 10, 2016. Available at:
  6. Ross JS, Kesselheim AS. Prescription-drug coupons–no such thing as a free lunch. N Engl J Med. 2013 Sep 26;369(13):1188-9.