Just before the new year 2017, it was reported that new legislation was approved to speed up Food and Drug Administration (FDA) approvals. This was designed to enable faster and more industry-friendly drug and medical device approvals that could bring innovation and treatments to patients who desperately need them. It also hoped to achieve greater innovation and competition – especially among generic drug manufacturers.
Even before the new legislation, one area that has seen expedited FDA approvals is for drugs seeking Orphan Drug status. For small populations with an imminent need for certain drugs, the regulatory approval process can move more quickly, with smaller clinical trials. According to the FDA, “the Orphan Drug Act (ODA) provides special status to a drug or biological product to treat a rare disease or condition upon request of a sponsor. for which the drug was designated.”
While its questionable about how quickly swifter approvals are occurring across the board, it in no way means FDA guidelines and restrictions are simple or less time-consuming for drug manufacturers. In fact, the FDA approval process is one of the most time-consuming, complex processes for Contract Manufacturing Organizations (CMOs) everywhere – and rightly so. According to a recent study, among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 of them were affected by a post-market safety event.
FDA scrutiny ensures the safety of drugs and those that consume them. So how does the FDA determine approval of new drugs entering the market and why is it still a complex process?
What is the FDA Looking For?
There really are two major concerns that the FDA requires be proven during clinical trials: That the drug won’t hurt anyone, and that the efficacy of the drug is sound. While most products that go through clinical trials are deemed safe by the FDA, there are also plenty of watchdogs, such as patient advocacy groups, politicians and medical professionals who work to ensure that any issues with both brand-name drugs and generics are documented and addressed – this results in drug warning labels that can prevent serious side effects or worse.
Tighter FDA Restrictions Key to GDUFA
Contrary to easing restrictions, tighter restrictions for FDA approval were established as part of the Generic Drug User Fee Amendments (GDUFA) in 2012. These were designed to speed access to safe and effective generic drugs to the public and reduce costs to the industry.
As part of GDUFA, the FDA requires regulatory filing of new entities be completed electronically in order to be more efficient, reduce costs to the government and eliminate manual, error-prone processes. While all submissions are done electronically, the ability to navigate the FDA electronic submission process alone, including using the Electronic Common Technical Document (eCTD) standard, has become increasingly time-consuming and difficult. Additionally, filing each chemical entity can cost from $41,000 to $46,000 per Drug Master File (DMF), the primary document in support of an Abbreviated New Drug Application (ANDA).
Complex Reporting Requirements
Aside from inspections and other FDA regulations, reporting alone is a time-consuming and costly process. A critical piece of technical documentation CMOs must provide is the analytical methodology used to test the drug substance. Validation reports for the methods for assay, impurities and residual solvents are included in the open portion of the DMF, along with reports on forced degradation studies performed on the drug substance. These reports demonstrate that the methodology possesses stability indicating properties.
The DMF also includes reports on various scientific studies essential to the applicant’s preparations. The first essential scientific document is a chemical description of the API impurity profile, which includes raw materials and intermediates that have the potential to carry through into the final product, as well as all possible degradants and products of side-reactions that may occur during the process. The second essential document in this category is a well-articulated and scientifically sound rationale for the manufacturing process, with special attention to the selection of the API Starting Material. A third important report is a justification for the drug substance specifications, especially those for assay, impurities and residual solvents.
Gathering this information must be handled by the CMO, yet given the time and costs involved in submitting the data in-house, many outsource the actual formatting into the FDA-required structure to a third-party. FDA approval through e-filing doesn’t end there. Under GDUFA, on the anniversary of a submission, the developer must e-file an annual report each year with updated information on their products.
So, while there may be talk of easing FDA requirements for new chemical entities to spur greater innovation and better meet demand, the process is by no means an easy one. Securing FDA approvals may soon be a swifter process, but CMOs and their sponsors understand that for most products seeking approvals, it will continue to be a time-consuming, costly and complex process, but necessary to ensure safe and effective drugs.
Ed Price is President of PCI Synthesis (www.pcisynthesis.com), a pharmaceutical development CMO based in Newburyport, MA and the largest small molecule drug substance manufacturer in New England. PCI Synthesis is also a commercial manufacturer of NCEs, generic active pharmaceutical ingredients (APIs), and other specialty chemical products for the medical device industry. As a CMO, PCI Synthesis provides emerging and mid-sized pharmaceutical companies access to the expertise needed to develop and manufacture complex small molecules.