ICH Generic Drug Harmonization May Be Another Cost-Lowering Opportunity

The international group will work on harmonizing scientific and technical standards for generic drugs, which could reduce duplication and development costs.

The US FDA may be able to use the International Conference on Harmonization to align generic drug standards around the world and by extension potentially lower development and patient costs.

ICH, which comprises representatives of many international regulators and is focused on creating common drug development standards, wants to move into the generic drug space. The organization has previously released guidelines that apply to generics, but has not specifically targeted the products in the past.

The effort would begin by convening a discussion group that would meet over a year to prioritize areas of interest, according to a reflection paper released Feb. 6. FDA plans to join the discussion group, and could use it as an opportunity to not only increase generic quality, an issue that the industry continues to battle, but also reduce development costs.

"This is not a lowering of standards but a convergence"  - AAM's David Gaugh

In the paper, ICH officials cite the lack of common standards as a potential cause of "monopolies or limited sources of drugs in those markets in which approval is not sought due to additional development burdens."

"Harmonization may increase the size of generic drug markets and thereby attract more competition from developers, lower costs by increasing the number of market entrants, and expand patient access in jurisdictions in which developers otherwise may have decided not to pursue marketing authorization due to differences in scientific and technical standards that require additional expensive studies in each jurisdiction," ICH said in the paper.

ICH wrote that common scientific and technical standards could make generic drug development "more cost effective" by reducing the duplicative studies necessary for varying regulatory requirements, as well as by lowering the number of human subjects needed for clinical trials.

"Duplicative bioequivalence studies may place participants at additional risk and delay patient access to more affordable medicines," ICH said in the paper. "For some studies requiring patients with certain specific diagnoses, duplicative studies can exhaust the available human subjects or may require extended recruitment periods which leads to delays in completion."

Costs can prevent some manufacturers from entering markets. David Gaugh, senior VP of sciences and regulatory affairs at the Association for Accessible Medicines, said that now it is not cost effective to develop a generic for some regional markets because they are not large enough to recoup the investment.

AAM supports harmonizing all standards, including bioequivalence, clinical and stability requirements, Gaugh said.

HHS Secretary Alex Azar did not reference the ICH effort specifically in a recent speech at the AAM annual meeting, but indicated that FDA was considering areas where standards harmonization could help increase competition. (See sidebar.)

Azar embraced harmonization's potential for lowering drug costs, which is a focus of the White House as well as FDA. The agency's primary task has been to increase competition through more generic approvals, however not all of the approved products are reaching the market. (Also see "Is Bloom Gone From Rosy ANDA Approvals Figures?" - Pink Sheet, 12 Nov, 2018.)

ICH is not interested in advocating changes to any regulator's legal or regulatory requirements. FDA already has said it will not change either and told the Pink Sheet that harmonization would not relax agency standards.

"FDA is committed to pursuing opportunities to harmonize international standards for generic drugs while maintaining FDA’s standards for rigorous, science-based regulation," the agency said.

Gaugh also told the Pink Sheet that the effort will not "relaxing" any FDA standards. "This is not a lowering of standards but a convergence," he said.

Another Chance To Elevate Quality

Harmonized standards also may present an opportunity to improve generic drug manufacturing, such as by encouraging "a globally consistent culture of quality and moving compliance standards in a common direction," according to the paper.

ICH suggested in the paper that drug makers today may have two or more manufacturing lines, "one that is subject to domestic regulatory standards and others that are subject to different foreign regulatory standards."

"This potentially results in greater cost, an increase in the likelihood of error in applying the correct regulatory and scientific standards, and in the complexity of recordkeeping," the group wrote.

Gaugh added that the idea would avoid multiple quality formats that force a company to pivot between them depending on the destination of the products it is making.

FDA for years has pushed generic companies to improve their manufacturing operations, in part to maintain consumer confidence that generics are as safe and effective as their brand counterparts.

However, high-profile problems with data integrity (Also see "Why Data Integrity Concerns Led Fresenius To Back Away From Akorn Deal" - Pink Sheet, 14 May, 2018.), as well as tainted ingredients (Also see "Drug Safety Announcement Blitz Highlights Gottlieb's PR Savvy As Shutdown Drags On " - Pink Sheet, 9 Jan, 2019.), continue to plague the industry.

The agency also has argued that generic companies should invest in new manufacturing technology, in part to reduce costs, but also to improve quality. (Also see "FDA Highlights Advanced Drug Manufacturing Approaches In Budget Plan" - Pink Sheet, 13 Feb, 2018.)

Multi-Arm Studies To Accommodate Multiple Regulators

ICH recommended a guideline on BE studies for immediate-release oral dosage forms be tackled first, including BE study design and data analysis, since the products are a substantial portion of existing regulatory submissions.

ICH wrote in the paper that harmonized BE study designs could allow for trials accommodating more than one reference product for bridging purposes and allow for submissions to multiple regulators.

US law does not permit non-US reference products, but FDA said the multi-arm trials enabled by common BE standards "may allow developers to use the data submitted in support of a generic drug marketing application, for example submitted to FDA for review, to meet multiple jurisdictions’ regulatory requirements for marketing authorization."

Other guidelines may address modified-release oral dosage forms, pharmaceutical equivalence and BE standards for products with complex active pharmaceutical ingredients, complex formulations, locally acting products, and drug-device combinations.

"Harmonization might reduce the need for comparative clinical endpoint bioequivalence studies and improve the sensitivity and reproducibility of bioequivalence determinations," the group wrote.

Complex generic approvals in the US remain elusive for many sponsors, although FDA has made an effort to streamline the process. The agency recently approved the first generic version of GlaxoSmithKline PLC's Advair Diskus (fluticasone propionate and salmeterol inhalation powder), which Mylan NV expects to launch in late February. (Also see "Keeping Track: FDA Approves First Generic Advair, But Alkermes And Sunovion Land CRLs" - Pink Sheet, 2 Feb, 2019.)

[Editor's Note: This story has been updated to include comments from FDA that were received after press time.]