Understanding 505(b)(2) Drug Development & API Supply Issues

Situated between the NDA and the ANDA is an increasingly popular drug commercialization pathway – the 505(b)(2) – and it potentially offers pharmaceutical companies clear advantages.

Situated between the NDA and the ANDA is an increasingly popular drug commercialization pathway – the 505(b)(2) – and it potentially offers pharmaceutical companies clear advantages.

We’ve been working with clients for years on 505(b)(2) drugs. At present, we are working on well over 100 API projects using the 505(b)(2) pathway.

But why is there increased attention, and is it a good fit for your drug candidate?

Some History: Hatch-Waxman & 505(b)(2)
The 505(b)(2) application pathway was created in 1984 as part of the Hatch-Waxman Act, as it has become known, in order to rectify the scarcity of generic approvals in the U.S. at the time. [Its official name is the Drug Price Competition and Patent Term Restoration Act, which created new sections of the Federal Food, Drug and Cosmetic Act.]

Hatch-Waxman, in Section 505 of the act, defined a number of different types of drug applications (aside from an OTC drug relying on an existing monograph):

The NDAs - LGM PharmaA 505(b)(1) new drug application (NDA) requires comprehensive safety and efficacy studies for a new, unapproved chemical entity. The NDA pathway requires evidence of both safety and efficacy demonstrated through controlled clinical trials.

An ANDA (“Abbreviated NDA”), defined in section 505(j) of the act, is an application intended to demonstrate “equivalence” (meaning an identical API, in the same  dosage form, with identical strength, efficacy, route of administration, quality,  therapeutic use and more) to a previously approved NDA product.

The “Paper NDA,” as the 505(B)(2) has been branded, is essentially an existing approved product with some novelty. It might be a new therapeutic application, new delivery mechanism, a different strength, or something else, but it relies on an existing approved product and its attendant studies – sometimes performed by others. A 505(b)(2) application will typically contain full safety and efficacy studies, but some portion of the data comes from an external, existing source.

ANDA versus 505(b)(2): What About Cost and Exclusivity?
A 505(b)(2) is more expensive than a typical ANDA, but it is still vastly cheaper than an NDA.

What accounts for the higher cost? The applicant typically must conduct some clinical studies to bridge the difference between its proposed product and the reference brand product.

This higher cost confers some benefits – including a period of post-launch exclusivity. The duration of exclusivity depends on the compound and the indication. For example, orphan indications can receive up to 7 years, while a drug compound requiring only phase I studies will not receive any marketing exclusivity period.

How Long Does a 505(b)(2) Filing Typically Take?
A traditional NDA, in which you are developing a novel therapeutic, requires lead identification, formulation, toxicology and further development, followed by efficacy & safety research and ultimately phases I through III of clinical studies. The pathway for a traditional NDA is usually 10 to 12 years. Even with a fast-tracked compound, less than seven years would be considered incredibly fast.

At the other end of the spectrum, generic drugs usually move through the ANDA process in 18 months or so.

The 505(b)(2) can be fast – 18 months is not unheard of. More realistically, it requires 2-3 years – placing it closer on the spectrum to an ANDA than to a full NDA.

Which Drug Projects are Suitable 505(b)(2) Candidates, and What Are Some of the Benefits?

Pic 1 - LGM Pharma

For those in the pharma industry, there is a clear-cut distinction between the two primary drug approval pathways: the 505(b)(1) NDA and the 505(j) ANDA generic pathway. NCEs, for which no clinical safety or efficacy data exists follow the 505(b)(1) pathway. Generics, which are essentially duplicates of an existing, approved drug, almost exclusively use the ANDA approval process. The midpoint between these two, however, is a bit fuzzier – and there are often advantages and disadvantages as to which pathway a drug developer should follow.

There are a number of situations in which the 505(b)(2) really shines. Companies with a novel device, delivery system, or delivery technology can take advantage of the pathway to use it for existing approved therapeutics.

In our experience, projects involving a modified mode of drug delivery are excellent candidates for the 505(b)(2) regulatory route.

For example, a new transdermal system can be introduced for a compound that has only been previously used via inhalation. The new drug uses the same therapeutic compound – and perhaps even targets the same indication – but it also solves a problem. In this case, the transdermal delivery system could replace a complex inhalation device which delivered poor efficacy due to dosing inaccuracies.

Likewise, a new delivery coating that allows a compound to survive the intestine can enable an oral dosage form, improving patient compliance and efficacy.

These are two examples of cases in which the 505(b)(2) pathway would prove its worth, allowing companies to take advantage of an existing therapeutic and get the new form to market very quickly.

Pic 2 scaled - LGM Pharma

Supply Chain Challenges Along the 505(b)(2) Pathway
Because timelines are compressed, drug makers need to quickly establish robust supply chains. At LGM, we’ve found this is where companies often get tripped up. Here are 3 ways supply chain issues can impact a 505(b)(2) filing:

  • Finding the Right Quality APIs and Intermediates
    Chemically, an API may be identical to an existing, approved product – yet its performance turns out to be anything but. We’ve seen cases where different suppliers provide an identical compound, but the variances in particle size are sufficient to impact drug performance.In many cases, companies purchase R&D materials from an inexpensive, ready source in order to get started working with the API. Their early indications are that their novel drug delivery system work well with the material. Then – after the shift to a new API manufacturer with high quality GMP material – they may find the product is slightly different. We’ve seen cases where the particle size distribution, or the bulk and tapped density, are different – and the changes in performance force the company to redevelop the product.
  • Regulatory Supply Chain Risks
    Finding the right pharma API manufacturer ultimately comes down to compliance. CMOs and CDMOs which already have a US DMF, for example, are preferable to those who have yet to file. How quickly they can file must also be considered, but risks are still measurably greater with a manufacturer who doesn’t have an existing DMF for the API. Remember: if a DMF is rejected, your product can potentially be delayed by years.
  • Matching Scale Expectations
    As companies race along the 505(b)(2) pathway, the process of selecting an appropriate manufacturing partner becomes condensed, and criteria can fall by the wayside. We’ve seen companies needing 10 kilos/year of a product sign up manufacturers who produce 50 or 500 metric tons. Suffice it to say, a customer that small takes the risk of not receiving service or being treated as a priority.

An Effective Option for Some Drug Candidates
The 505(b)(2) pathway’s popularity can be attributed to the benefits an ANDA and full NDA could offer – namely, a shorter, less expensive, lower risk process which still confers a period of market exclusivity. But while drug development & clinical risks may be mitigated, there are supply chain and manufacturing challenges your company must address in order to maximize the value of the pathway.

Learn more – contact us today!

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