Although a complete response letter (CRL) is not an official rejection letter, it can result in approval delays by listing out shortcomings in an application and giving companies an opportunity to respond. In his latest column, Sarfaraz K. Niazi, PhD, goes over how companies can avoid these approval postponements.
Although a complete response letter (CRL) is not an official rejection letter, it can result in approval delays by listing out shortcomings in an application and giving companies an opportunity to respond.
Most biosimilar developers, including Amgen, Pfizer, Mylan, Alvogen, Biocon, Coherus, Kashiv Biosciences, Celltrion Healthcare, Sandoz, and Viatris, have received CRLs, a regulation the FDA implemented in 1998 for biologics and in 2008 for drugs to replace “approvable” and “not approvable” letters, and to prevent entire resubmission. The sponsor who receives a CRL has 1 year to re-submit the necessary supplemental information based on the recommendations in the letter.
Unfortunately, each CRL takes a 9 to 12 month hit in the development timeline, adding high cost and thus, the cost of goods sold. So, why did all of these developers receive a CRL? How could it have been avoided? How should biosimilar development be changed to avoid these significant delays for approval? This is the topic of my discussion today. These suggestions are based on first-hand experience in securing approval of biosimilars, meeting with the FDA in an advisory role, and scientific investigation to rationalize the development of biosimilars.
The most common reason for a CRL is data analysis and integrity of analytical similarity testing because approvals are based mainly on this evaluation. This issue is of more significance to smaller or new-to-biosimilars companies. However, the issue arises for established companies because they submit much more data than necessary. The cardinal principle is to submit data to support the claim, not impress the FDA. For example, a company submitted 95 tests for analytical similarity in one case, mostly claiming to be orthogonal but not required. The more data submitted means more chances of finding mistakes. So, submit only what is needed.
Data integrity and quality assurance are other objections. Companies may not realize that having 21 complaints for part 11 of Title 21 of the Code of Federal Regulations is not required, but if it is instituted, it must be enforced. Electronic record keeping is an option. If a third party conducts the final analytical assessment, it will remove much of the FDA concern. I strongly advise it, regardless of your confidence.
Many clinical research organization (CROs) are now available to deliver this requirement. Since the CRO also collects the reference samples, it reduces the integrity question, and the FDA is least likely to question such data. Besides, the CROs are expected to be compliant to stay in business, and your contract should include this compliance clause. Besides, the ‘‘Further Consolidated Appropriations Act, 2020’’, widely known as CREATES, makes available a pathway for potential drug and biological product developers to obtain samples of brand products that they need to support their applications.1 Let the CRO invoke these rights; plan to pay at least 20% wholesale acquisition cost and secure it through your CRO.
Analytical profile-related observations are widespread. For example, an unmatched impurity cannot be justified, regardless of the efforts, so removing it at the risk of losing the yield is best. Know that "animal toxicology" testing is no longer a part of Biologics Price Competition and Innovation Act.
Significant issues also arise if the formulation is not the same as the reference product to demonstrate that aggregation or structure change during the shelf-life will not alter immunogenicity. The best way to avoid it is to use the reference product formulation, and if it is under intellectual property, then only use components that have already been in use for the specific drug or class of that drug. Do not forget the pure red-cell aplasia issue with erythropoietin.
The compliance issues identified in the CRLs were avoidable if the companies had conducted third-party FDA-simulated audits before submitting the biologics license application (BLA). The assurance given by the internal team to the leadership should always be taken with a grain of salt, if not lack of trust. It is a matter of perspective, not a hard rule. I strongly urge all companies, regardless of size, to conduct multiple third-party audits before submitting a BLA; these audits should include good manufacturing practice compliance and data compliance (for sufficiency).
Other common findings relate to procedure follow-up, the presence of standard operating procedures and environment monitoring, which should be caught in the pre-BLA filing audits.
Another delay in filing BLA, regardless of the company's size, are the bottlenecks in moving the portfolio. This situation can be quickly resolved by engaging qualified contract manufacturing organization (CMOs) to create the dossier details. This is how you can take more than 100 molecules awaiting entry as biosimilars. There is a misconception that the cost of development is higher when working contract development and manufacturing organization (CDMOs).
A decade ago, there were few qualified CDMOs, but now there are many choices. One should differentiate between cost and price. The price you pay to CDMOs should match the depreciation of capital expenditure, added operating expenditures, CRLs, and other delays incumbent on internal development. Moderna understood it well and got its COVID-19 messenger RNA vaccine through a CDMO. There is less likelihood of getting a CRL if a CDMO compiles the dossier.
Newer CDMO models include compliance as a deliverable. Further, launching a biosimilar sourced from a CMO and then transferring the manufacturing in-house (if needed) is the ICH Q5E compliance that is readily doable. The work can begin early, but the technology transfer should only come after BLA approval.
You can have dozens of biosimilars without taxing your internal systems and human resources. But there is 1 requirement: you should have more substantial scientific and regulatory support. You should tell them, not ask, how to develop the product.
One source of delay in bringing biosimilars to patients has been the patent dance that has blocked the entry, such as adalimumab. If you are developing molecules already present as a biosimilar, your risk of litigation is minimized because it is no longer worth the effort by the originator company. I suggest not sharing your dossier and letting the originator wonder what to do. When you are the first to file, litigation is inevitable. In this case, share the dossier and force the originator to choose only 2 patents to litigate.
Finally, much of the delay comes from developers making repeated use of the FDA meetings that are allowed free of charge when a program is registered. Each meeting takes a 6-month hit. Type 3 meeting is required, but others can be avoided if there is an understanding of what the FDA expects. A Type 2 meeting after completing a clinical pharmacology study will be needed to assert that "no residual uncertainty" allows BLA submission. Waiver of clinical efficacy testing in patients is just around the corner, and qualifying for it should be a significant effort to reduce the time to approval. The common belief is that getting a biosimilar approved takes 7 to 8 years, and $100 million to $300 million dollars is no longer a challenge if the development is planned correctly.
 Niazi SK. Molecular biosimilarity—An AI-Driven paradigm shift. Int J Mol Sci. 2022; 23(18):10690. doi:10.3390/ijms231810690
 Niazi SK. Biosimilars: A futuristic fast-to-market advice to developers. Expert Opin Biol Ther. 2022;22(2):149-155. doi:10.1080/14712598.2022.2020241
 Chiu K, Racz R, Burkhart K, et al. New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science. Front Med (Lausanne). 2022;9:1109541. doi:10.3389/fmed.2022.1109541