Improving the Drug Quality and Safety Net

Abstract

When large quantities of contaminated, subpotent, or superpotent drugs are introduced into the medical supply pipeline, injury or death of hundreds or thousands of patients can occur. Tracing the origin of substandard and dangerous products and tracking across regions and countries where shipped is quite costly in both money and time. From patients’ perspective, timely access to quality product is paramount. Receiving deficient product threatens their survival and creates huge sums of financial cost to both them and the medical system. With the passage of HR 3204 the FDA must now find a way to be proactive in policing the global medical product supply line without restricting market availability. Without a comprehensive, world-focused implementation plan these new regulations will fail to protect the public.

Recent legislation, the Drug Quality and Security Act (HR 3204), passed by the US Congress and signed into law to bestow on the Food and Drug Administration (FDA) legal parameters to address custom drug compounding issues and create a track-and-trace program to be applied to all drugs manufactured under good manufacturing practice (GMP) and United States Pharmacopeia (USP) guidelines, has potential to create more problems than it solves. HR 3204 was conceived as a compromise solution to address recent product safety disasters in the United States from sterile compounded medications provided by pharmacies operating as unrecognized manufacturers, from registered manufacturers who failed to follow GMP/USP guidelines and counterfeit or diverted products. Once large quantities of contaminated, subpotent or superpotent drugs are introduced into the medical supply pipeline injury or death of hundreds or even thousands of patients can occur very quickly. Tracing the origin of these fraudulent and dangerous products and tracking across regions and countries to whom they may have been shipped is quite costly in both money and time.

From patients’ perspective, timely access to quality product is paramount. Receiving substandard product threatens their survival and creates huge sums of financial cost to both them and the medical system. With the passage of HR 3204 the FDA must now find a way to be proactive in policing the global medical product supply line without unnecessarily restricting market availability. Without a comprehensive, world-focused implementation plan these new regulations will fail to protect the public as intended.

HR 3204 has drug compounding regulations based primarily on voluntary participation. Compounding pharmacies will have the option to submit to FDA oversight but are not required to in order to remain in business. In theory, legitimate compounding pharmacy operations will register with the FDA to reassure clients that their products are safe to use, but that assurance (FDA guarantee?) will likely come at a price. Given the free-market, for-profit system and constant pressure to utilize the lowest cost service and product, it’s only a matter of time before consumers look for alternate suppliers (who may or may not volunteer to have FDA oversight).

While specialty compounding is a concern, compounded drug product utilization is not a substantial percentage of medication use and does not represent a large numerical threat to patient safety. Counterfeit and substandard manufactured drug products, both branded and similar generics, present a much larger and potentially more dangerous threat to the health care consumer.

As currently understood the track-and-trace provisions of HR 3204 will require as of January 1, 2015, that all manufacturers and wholesalers provide a transaction history in the form of paper documentation for each individual unit of a drug shipped. Pharmacies can still accept product without accompanying paperwork until July 1, 2015, then every unit must be accompanied by a paper transaction history. Sounds simple but the pharmacy must keep each individual unit transaction history paper on file for a minimum of 6 years to be retrieved and returned with the product if the product is still usable. Given the thousands of drug units received each week by a busy pharmacy, there is simply not enough storage space to keep the paper records as dictated. Electronic tracking is proposed to be developed and implemented by the FDA within 10 years, but no specific technology is identified. In the interim the supply chain will overflow with potentially meaningless paper.

Compromise legislation and rule making without consideration for the logistics of implementation often results in loopholes that, at best, reduce the effectiveness of intent, at worst, increase the potential for abuse/manipulation of the system. Paperwork for the track-and-trace system could be counterfeited and supplied with adulterated, counterfeited, substandard, and/or diverted products to gain entrance of “lower cost” products into the supply pipeline. Pharmacies are supposed to quarantine any suspect product for destruction and report details to FDA, but if the paperwork looks legit, how are they to know? Forgery of product transaction history records would create a false sense of supply system security and delay meaningful investigation of product quality. Unfortunately it appears to this author that the FDA will maintain their reliance on individual adverse event reporting as their primary investigative tool even with these recent efforts to close regulatory gaps. Without FDA implementation of a more comprehensive pharmacovigilance/risk management plan the number of consumers affected could become exponentially larger as authorities try to determine what paperwork may be forged and what is not. A properly designed and implemented plan would not only help the FDA identify substandard products earlier it could also assist in long-term evaluation of patient outcomes when utilizing multiple source products.

An effective pharmacovigilance/risk management plan could be implemented by coupling the track-and-trace provisions of HR 3204 with independent evaluation of product quality and composition by comparing samples randomly drawn from the supply pipeline and compared to the original FDA approved originator data. Random samples would help “front load” the product track-and-trace database with baseline information the FDA is now required to collect and evaluate. Periodic random sampling from the supply pipeline and evaluation of suspect quality samples reported by pharmacies and through consumer MedWatch programs could be compared to initial data standards in the system. This method would close the information loop by helping pinpoint lots, dates and origin of shipment, potential duplicate tracking (serial) numbers, packaging differences, and other product discrepancy allowing for more accurate and timely recall. Prosecution of intentional malfeasance would be greatly assisted as well.

With the exception of narrow therapeutic range medications, oral solid and liquid medications can vary slightly in concentration and absorption between manufacturers without greatly affecting patient outcome or response. Sterile injection medications should be more precise in concentration and formulation from batch-to-batch but will also provide very similar outcome from different manufacturer sources. In general most of these products are considered bioequivalent and freely substituted with the lowest cost product available.

As we migrate to a global supply chain for raw materials and finished product it becomes much more difficult to monitor quality after initial approval of a supplier for release to market. Bioengineered biosimilar “generic” products, not to be confused with bioequivalent products, pose an even greater patient risk from poor quality control than the currently recognized safety deficiencies. These biosimilar medications will never be bioequivalent, just bioclose, and must be monitored postapproval for unexpected adverse events. In the case of bioengineered, biosimilar insulin known differences in protein fragments, desamido insulin forms and foreign protein contaminants constitute a potential risk for allergic reaction, insulin resistance, absorption rate differences and other yet to be identified impact on patient outcome. Insulin is temperature sensitive, shouldn’t be shaken vigorously, and becomes unstable once opened. Variance in manufacturer bioengineering process will change the composition and/or stability of the final product that may affect patient response. Manufacturers of innovator bioengineered products have shown themselves to be vigilant in quality control. Alternate manufacturers will have a slightly different product and may not be able to maintain the same batch-to-batch quality assurance as their better funded competitors. Changing from one manufacturer product to another will likely change patient response even with outstanding quality control, so additional clinical outcome results tracking should be instituted as part of an ongoing FDA postmarketing review process.

Bioengineered biosimilar products and diabetes testing supplies offer a huge savings opportunity only as long as the quality is monitored and maintained. Perhaps HR 3204 provides us with a framework to develop a comprehensive pharmacovigilant/risk management plan to assess all drug products and supplies for safety and efficacy among industry, researchers, regulators, and the patients we serve that’s mutually beneficial for all.