Legislators Want GAO Studies on Non-Biologic Complex Drugs & FDA Inspections, and Want a Raft of Documents as Questions are Raised About ANDA Review Efficiency

By Kurt R. Karst –      

Congress has been busy in the lead-up to the holiday!  In addition to the recently-enacted 2016 Consolidated Appropriations Act, which saddles FDA will meeting myriad requests and new requirements, a host of lawmakers from the U.S. House or Representatives recently sent out three letters (here, here, and here) seeking answers and documents on various generic drug review and FDA inspection issues. 

Complex Generics

The first letter, dated December 10, 2015, requests that the Government Accountability Office (“GAO”) conduct a study to assess the FDA approval pathway for reviewing generic versions of so-called Non-Biologic Comples Drugs (“NBCDs”).  A similar request was made earlier this year as part of the “Generic Complex Drugs Safety and Effectiveness for Patients Act of 2015” (H.R. 1576) (see our previous post here). 

NBCDs, like sodium ferric gluconate and liposomal doxorubicin hydrochloride, “are drugs of non-biological origin with an active ingredient that has molecular diversity,” where “scientific analytic methodologies are unable to fully identify the molecular structures and physiochemical properties of the active ingredient,” and where “the natue of the active ingredient is not understood sufficiently to identify all the molecular components that produce the therapeutic effect of the drug, and the mechanisms of action that produce such effect,” says the letter.  NBCDs are approved under Section 505 of the FDC Act instead of under Section 351 of the PHS Act, but the lawmakers suggest that FDC Act regulation may not be sufficient.  “The current regulatory pathway used for generic approval of small molecule drugs is being used for the evaluation of NBCDs.  Given the complex natures of these large molecule drugs, we seek GAO’s input on whether the current statutory pathway for generic NBCDs is adequate to guarantee patient safety,” says the letter.

If GAO’s study concludes that meeting FDC Act approval standards presents unique challenges for generic NBCD products, then the lawmakers request that the GAO address certain questions in consultation with appropriate public and private entities, including:

1. 1.What degree of characterization of the proposed generic version and the reference product should be required in order to determine the safety and effectiveness of the generic version;
2. 2.What degree of similarity should be required to deem that the active ingredient of the proposed generic version is the same as the active ingredient of the reference product;
3. 3.What types of evidence should be required to demonstrate that the proposed generic version is bioequivalent to the reference product;
4. 4.What requirements should be established with respect to the comparability of the manufacturing process for the proposed generic version and the manufacturing process for the reference product;
5. 5.Whether and to what extent clinical evidence is needed to demonstrate that there is no difference in immunogenicity between the proposed generic version and the reference product; and
6. 6.Whether and to what extent other clinical evidence is needed to demonstrate that the proposed generic version is as safe and effective for patients as the reference product.

If GAO has to answer the questions above, then the lawmakers request that GAO assess whether the FDC Act’s ANDA process is sufficient and to recommend “whether and when FDA should develop a public policy document offering comprehensive, general principles on the evidence necessary to obtain the FDA’s approval of generic drug applications that use such reference products.” 

Interest in the approval of generic versions of NBCDs has been increasing over the past several years, and such products have been the topic of numerous Citizen Petitions and research (see here).  Under the Performance Goals and Procedures FDA agreed to as part of the 2012 Generic Drug User Fee Amendments (“GDUFA”), the Agency said that it would look into complex drug substances as part of the Agency’s Regulatory Science Plan.  Each Fiscal Year thereafter, FDA has outlined Regulatory Science Priorities including complex generics.  For example, FDA’s GDUFA Regulatory Science Priorities for Fiscal Year 2016 include the following:

Equivalence of complex drug products includes research into making generic versions available in all product categories, including complex drugs with unique characteristics.  FDA spends an increasing amount of time reviewing and developing policy for complex drug products, and future generic products will need to demonstrate equivalence to increasingly complex RLDs.  This scientific research supports the development of guidance and policy that clarifies the Abbreviated New Drug Application (ANDA) pathway for complex products, such as drug-device combinations, transdermal systems, implants and parenteral microspheres, nanomaterials (e.g. liposomes and iron colloids), and products that contain complex mixtures and peptides.  New FY 2016 priorities include transdermal irritation studies and research into human factors studies that will aid in evaluation of product substitutability and robustness for drug-device combinations.

FDA Inspections

In a second letter, dated December 18, 2015, a group of four lawmakers from the House Energy and Commerce Committee ask the GAO to take a look at and assess FDA’s foreign inspectional activities.  A 2010 GAO report concluded that while FDA was making efforts to improve the Agency’s inspectional activities, more progress was needed (see our previous post here).  Since then, FDA has formed the Office of Global Regulatory Operations and Policy and has looked to partner with other agencies and organizations to strengthen inspectional activities.  In 2012, the FDA Safety and Innovation Act gave FDA new authorities to improve the drug supply chain and directed FDA to take a risk-based approach to domestic and foreign inspections.  Despite these changes, however, the lawmakers remain sceptical and concerned about FDA’s progress in addressing global supply chain issues.  “[W]e are concerned that there is still inadequate oversight with regards to these foreign drug plants, not to mention an unequal playing field compared to U.S. drug manufacturers that are subjected to more frequent and rigorous inspections,” write the lawmakers, who also note that only two FDA drug inspectors are reportedly assigned to oversee 700 drug manufacturing facilities in China. 

Given these lingering concerns, the lawmakers ask the GAO to “revisit these issues [from the 2010 report] and assess FDA’s activities and accomplishments” in certain areas, including:

• Foreign Drug Inspections – How has FDA implemented the risk-based inspection frequency in selecting foreign drug manufacturing facilities for inspection as required in Section 705 of FDASIA?  Has it finalized the development of the risk-based schedule?  In addition to the risk factors outline in the statute, what other criteria, if any, did FDA identify as necessary for establishing the risk-based schedule?  When did FDA begin to use the risk-based schedule?  How many surveillance inspections of foreign establishments has the agency conducted over the last 5 years?  How does the rate of inspections of foreign drug manufacturing establishments compare to domestic drug manufacturing establishments?  What is the average inspection frequency for domestic drug manufacturing establishments and foreign drug manufacturing establishments?  What is the status of FDA’s cadre of staff dedicated to foreign drug inspections – how many staff members and how many inspections have they conducted?

• FDA’s Foreign Offices – What are the specific accomplishments of these offices?  How many inspections of drug manufacturing establishments have these offices conducted?  In what ways have the offices improved relationships with foreign regulators and manufacturers?  Why has FDA closed some of these offices, which only opened a few years ago?  What is the agency’s plan to fill the many vacancies in the remaining offices?  Does it continue to experience difficulties in obtaining visas for its staff.  Any what accounts for the agency’s delay in implementing recommendations made by your office five years ago?

ANDA Review Efficiency

In a third letter, dated December 15, 2015, a group of 12 lawmakers ask Acting FDA Commissioner Stephen Ostroff, M.D., for a trove of documents relating to ANDAs.  The request is apparently related to recent price increases for certain generic drugs that have captured the attention of Congress as of late, as well as to reports of alleged declining market competition.  We also suspect that Congress wants the information as the generic drug industry gears up for creation of the second iteration of GDUFA.

The list of requested documents is long.  There are 15 general requests, some of which have multiple subparts.  (The folks in FDA’s Office of Generic Drugs almost certainly have to feel like Rodney Dangerfield’s Thornton Melon in that famous examination day scene from “Back to School.”)  The lawmakers want, among other things, information on median ANDA approval times, Refuse-to-Receive decisions (including rescissions), ANDA Target Action Date assignments, industry communications, documents and communications concerning barriers to generic drug entry, user fee funding accountability, and on and on. 

FDA is supposed to respond to the request no later than 5PM pn January 6, 2016.  It’s not quite the the present anyone from FDA had hoped for this season. . . . But, like Thornton Melon, we know the Agency will pull through.