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In the News: November 2020 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

Remote Document Review Leads to CRL: Be Careful What You Wish for?

The FDA’s halt of onsite inspections has created a wealth of problems. Camargo is currently involved with no less than three product applications that are stalled because the FDA is requiring inspections before the application can be approved (assuming a satisfactory outcome). Needless to say, the sponsors of these applications are anxious to pursue all possible alternatives to simply waiting for an indeterminate period for inspections to take place, especially since these delays sometimes result in Complete Response Letters (CRLs), which can be hard to explain to board members and investors.

The August edition of In the News discussed recent FDA guidance detailing the approach to inspections during the COVID-19 pandemic, including the proposed use of various “remote” inspection methods—such as document review—to allow inspections to progress without physical access to the facilities involved. Biopharma and manufacturing company Alkermes was recently able to participate in a remote document review for its ALKS 3831 product. The firm supplied all the requested documentation, and the outcome was . . . a CRL.

What took place? Camargo’s past experience with FDA inspections suggests that, while there may have been problems that could have been better addressed in the documents, the critical issue was likely Alkermes’s inability to address the FDA’s concerns as they arose (as would typically happen in an on-site inspection). Inspections need to be actively and carefully managed by the inspected company to ensure that the FDA does not draw conclusions hastily or with insufficient context. This type of misunderstanding may have easily occurred in this “remote review,” and we advise caution to others who will be in similar circumstances. If you are facing an FDA remote review, Camargo can help design a comprehensive approach in order to avoid such pitfalls.

Approval of the Month: Alnylam to Use Value-Based Agreements for Ultra-rare Disease Treatment

On Nov. 23, Alnylam announced the FDA approval of Oxlumo®, a treatment for primary hyperoxaluria type 1 (PH1), which is an ultra-rare disease impacting between 1,000 and 1,700 patients in the US and Europe. PH1 is characterized by the buildup of calcium oxalate in the kidneys and urinary tract and can occur in both pediatric and adult patients. Patients with PH1 are typically diagnosed at the time of kidney failure and undergo daily dialysis treatment, which can last 10-12 hours per day, to manage the condition. The only solution currently available for patients with PH1 is a dual or sequential liver and kidney transplant.

Along with the FDA approval of Oxlumo®, Alnylam announced its pricing and access strategy for the treatment, which is based on value-based agreements (VBAs) with insurers and integrated delivery networks (IDNs). While Oxlumo® will be an expensive therapy (the list price is expected to be $493,000 per patient per year), Alnylam’s VBA framework provides a thoughtful, strategic approach to pricing that is designed to maximize patient access and address payer concerns about the possible disproportionate economic burden for a disease that may impact 1,000 patients per year.

Since PH1 is likely underdiagnosed as a disease, and since Oxlumo® will be dosed based on individual patients’ weights, insurers could easily be in a position to bear a disproportionate economic burden based on unique factors within their covered populations. Alnylam’s VBAs are designed to address variability and risk for insurers by offering them rebates if (a) a covered patient requires more than a pre-specified number of vials of Oxlumo® each year or (b) the number of patients diagnosed with PH1 in an insurer’s covered population exceeds epidemiologic estimates.

By addressing insurers’ concerns, the VBAs should expedite coverage, remove barriers to uptake, and increase access to and adoption of a much-needed medication for patients suffering from a debilitating disease who have limited or no alternatives.

As Alnylam and others gain traction with this approach, we expect to see broader adoption of creative and value-based contracts going forward. Camargo can help you to develop the right pricing and access strategy for your product; contact us for more information.

Evergreening Orphan Drugs May Be Over

The Orphan Drug Act of 1983 provides market exclusivity for drugs intended to treat conditions affecting fewer than 200,000 patients in the US. A lesser-known provision also grants the same seven-year market exclusivity if the sponsor demonstrates that it does not expect to recover the development costs from selling the drug. Some pharma companies have used a loophole in the latter provision to make changes to their drug products and obtain a further seven years of exclusivity, without having to demonstrate that they cannot recoup the R&D costs. This effectively “evergreens” the product, preventing generic competition.

The U.S. House of Representatives passed the “Fairness in Orphan Drug Exclusivity Act” to require proof from pharma companies introducing improved versions of orphan drugs that they do not expect to recoup R&D costs through US sales in 12 years. For those with existing orphan exclusivity, the House bill gives sponsors 60 days to show that, at the time of approval, it could not reasonably expect to recoup the R&D costs within 12 years of first marketing the drug. Without that showing, the FDA is directed to revoke the exclusivity.

Practically, this act (which still must be considered by the Senate) will mainly apply to orphan drugs granted exclusivity prior to 2017. In that year, a new rule (21CFR §316.34(c)) took effect which blocks such serial exclusivity for improved drugs unless a sponsor can demonstrate that a new drug is clinically superior to the previously approved version.

Camargo has followed this issue closely. Our previous blog post provides background information on this loophole and presents examples of when industry and consumer groups have cried foul.

Unapproved Drug Initiative Ends

In November, the FDA ended its Unapproved Drug Initiative. The program was launched in 2006 with the goal of either removing marketed drug products which do not have FDA-approved applications or motivating the firms marketing the products to go through the application approval process. The primary driver for the initiative was safety; unapproved drugs do not have an application associated, so there is no mechanism for reporting adverse drug reactions.

The initiative had both “carrot” and “stick” provisions, the most notable being “de facto exclusivity” for the first sponsor to receive approval for an unapproved product being sold by multiple firms. Following approval of the first application, the FDA required that the remaining products be removed. The primary reason offered for ending the program was the claim that, when this exclusivity was in effect, prices for the product increased, sometimes dramatically.

So, what now for the still-considerable number of marketed unapproved drugs? The FDA will still encounter these products in various ways, during regular surveillance inspections (when they become truly regular once more) for example. Enforcement actions will likely follow, now that the program encouraging cooperation with the FDA to gain approval has been removed. Rather than lose the products, companies that are marketing unapproved products can work with Camargo to find solutions to gain product approval in the most cost-effective manner.

Guidance Published on Formal Meetings for Complex Generics with the FDA

The pharma industry has had meetings with the FDA for new drugs, biologics, and devices for decades. In fact, PDUFA made many of these meetings mandatory for both parties. In stark contrast, meetings for ANDAs with the Generic Drug Division have been few and far between, inconsistently granted, and, if held, poorly documented. GDUFA has changed this picture, at least for complex drug products.

The FDA has published a new guidance document called “Formal Meetings Between the Food and Drug Administration and Abbreviated New Drug Application Applicants of Complex Products Under Generic Drug User Fee Amendments.” This document outlines information on requesting and conducting product development meetings, pre-submission meetings (with details on the contents of the meeting submission package), and mid-review cycle meetings with the FDA. Not surprisingly, it contains requirements similar to the PDUFA-mandated FDA-industry meetings for NDAs.

Camargo conducts dozens of pre-IND and other PDUFA-mandated and optional meetings each year, meeting with every FDA division concerning complex drug products. We look forward to extending our expertise to the complex drug meetings for ANDAs.


Robb Lawrence
Senior Vice President, Commercial Strategy

Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations