On October 26, Senator Cruz introduced the “Reciprocity Ensures Streamlined Use of Lifesaving Treatments Act of 2017” (S. 2022), which is interesting from an FDA law perspective as well as an administrative law perspective.  We have seen this proposal before — in 2015 (S. 2388, introduced by Senator Cruz) and in 2016 (H.R. 6241, introduced by Congressman DeSantis).  Rachel Sachs wrote about it from a policy perspective in December 2015, and Zach Brennan offered more details in his own piece the same month.  I am going to dig into the details a bit more than they did and explain why I call it the “Send All the FDA Employees Home Act of 2017.”

The General Idea

S. 2022 would amend the Federal Food, Drug, and Cosmetic Act (FDCA), creating a new provision (in section 524B) entitled “Reciprocal Marketing Approval.” The general idea is to force FDA to recognize marketing authorization decisions from certain foreign countries if there is a “public health or unmet medical need” for the products in question.

Process and Standards

The “sponsor” of a drug, biological product, or device would submit a “request for reciprocal marketing approval.”  The bill doesn’t specify the form or contents of this request, leaving the details to FDA.  But, to be approved, such a request would have to demonstrate that:

• The product in question is authorized to be marketed in one of the countries listed under section 802(b)(1) of the FDCA — meaning Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, South Africa, or the United Kingdom.
• The product is not otherwise cleared for marketing under section 505(c), 510(k), or 515 of the FDCA or section 351(a) of the Public Health Service Act (PHSA). These are the provisions that govern new drug applications (NDAs), device premarket notifications (known as “510(k)s”), device premarket approval applications (PMAs), and biologics license applications (BLAs).  Notice that this doesn’t include approval as a generic drug or biosimilar biologic; in other words, apparently the product could be approved in the U.S. under one of those provisions.
• FDA hasn’t withdrawn or rescinded such approval or clearance (i.e., under 505(c), 510(k), 515, or 351(a)) due to concerns about the product’s safety or effectiveness.
• Authorization to market in one of the listed countries hasn’t been rescinded or withdrawn due to concerns about the product’s safety or effectiveness. (This should probably say “authorization has not been rescinded or withdrawn in any of the listed countries due to concerns . . . .”)
• It’s not a banned device under section 516 (meaning it’s not prosthetic hair fiber or powdered gloves).
• There is a “public health or unmet medical need” for the product, which is not defined.

Approval of a request would not be discretionary; FDA would be required to grant the request if these criteria were met.  Once the agency granted the request, the product would  be “deemed” approved or cleared under the relevant provision of law (i.e., 505(c), 510(k), 515, or 351(a)).

The bill would permit (but not require) FDA to decline the request for a drug if the agency “affirmatively” found the drug not safe and effective.  It would also permit (but not require) FDA to decline the request for a device if the agency “affirmatively” found there was not a reasonable assurance of safety and effectiveness.  The fact that this is discretionary troubles me.  Under current law FDA may not approve a new drug if the drug is not shown to be safe and effective, and it may not approve a device without a reasonable assurance of safety and effectiveness.  Under this bill, the agency could approve a drug or device for U.S. patients that it knew was not safe and effective.

The bill does give the agency the discretion to refuse to approve the products.  But how on earth would the agency affirmatively find that the drug was not safe (or not effective) or that there wasn’t a reasonable assurance of the device’s safety or effectiveness?

• It’s not clear the agency would have enough information to make this call.  The application would have to contain an English translation of the “dossier issued” by any country in the 802(b)(1) to authorize marketing in that country.  I have no idea what this means.  I would have thought the bill would require an English translation of the “dossier submitted” to the foreign regulatory authority, asking for permission to market.  But instead, it sounds like the company would provide something akin to the approval letter and professional labeling (sometimes called the “summary of product characteristic,” at least in European countries).  I suppose because the agency has the discretion to specify the form and content of the request for reciprocity, it could require a translation of the foreign marketing application.  But it is a bit alarming that the sponsor of this bill doesn’t think submitting original research on the drug or device is sufficiently important to be spelled out in the legislation.
• More concerning, the bill would require affirmative findings of non-safety and non-effectiveness before the agency could exercise this discretion.  Compare current law.  Today, FDA must deny approval of a drug if (for example) there is “insufficient information to determine whether” the drug is safe.  It must deny approval if the applicant has not shown effectiveness.  In other words, under current law, the burden is on the applicant to make its case.  Under this bill, the burden would be flipped; there would be an implicit presumption in favor of the drug.  The agency would have to find the drug wasn’t safe, in order to have the option of denying the request to market.
• Most concerning, FDA would have only 30 days to make a decision.  FDA reports that in 2016, median review time for priority new drug applications was 8 months, and median review time for standard new drug applications was 10.1 months!  Even if FDA asked for a translation of the foreign marketing application, it could not conduct anything close to the kind of close review of the studies, the data, and the analyses that it ordinarily conducts.  And, during that 30 days, FDA is also supposed to negotiate the final labeling for the product (without having studied the underlying data).  In the case of a device, it’s supposed to classify the device and figure out whether the device would ordinarily need a 510(k) or a PMA.

The bill adds that FDA could “condition reciprocal marketing approval” on the conduct of postmarket studies, though the drafters refer to “studies pursuant to a risk evaluation and mitigation strategy under section 505-1.”  This makes no sense, because section 505-1 of the statute doesn’t actually authorize studies.  Maybe the drafters meant section 505(o) (here and here).

Role of Congress

This is the part that administrative law junkies may find interesting.  If this bill passed, FDA would send a monthly report to the House Committee on Energy and Commerce and the Senate Committee on Health, Education, Labor and Pensions, listing any denials in the prior month.  Congress would have the authority to overrule any denial, pursuant to a joint resolution of disapproval, following the procedures of 5 U.S.C. § 802 (“Congressional disapproval procedure”).  This is part of the Congressional Review Act, enacted in 1996.  In this case, reciprocal marketing approval would be immediately effective.

Subjecting denial of reciprocity decisions to the disapproval procedures laid out in the Congressional Review Act is curious, because that statute is intended and was drafted to apply to rules (as defined in section 551 of the Administrative Procedure Act, with a specific exception for rules of particular applicability).  It requires that all rules be reported to Congress and gives Congress 60 legislative working days to introduce a special joint resolution of disapproval of the rule.  It was barely used for the first 20 years, but has been used repeatedly in the 115th Congress.  (See the tracker from George Washington University, here.)  Although I haven’t searched exhaustively, I am not aware of any law enacted by Congress that would subject an “order” (like denial of permission to market) to Congressional disapproval procedures.

I Don’t Even Know Where To Start

The Congressional override is very troubling.  Suppose a company failed to satisfy the standard for reciprocal approval, for instance because the product wasn’t lawfully marketed in one of the listed countries.  The bill would require FDA to deny the request for marketing approval.  Or suppose the company satisfied the standard, but the agency was able to conclude in the 30-day window that the drug wasn’t safe or effective, so it exercised it discretion to deny the request.  In either case Congress could overrule FDA and simply approve the decision on its own.  Joint resolutions of disapproval must be signed by the President to become law, so there would still be a role for the executive branch before all was said and done.  But no one should be under any illusion that either the legislature or the White House would conduct its own thorough review of the product, engaging (in the case of a drug) statisticians, chemists, pharmacologists, toxicologists, and physicians to examine the studies and data, the way FDA does.  This would be a political decision.  The bill would turn approval of drugs and medical devices into a political decision rather than a scientific and regulatory decision.

I also worry about unintended consequences . . . about aspects of FDA’s regime the drafters may not have thought through.

• For instance, the bill provides that FDCA will apply to one of these products, just as if the product had been approved or cleared under the appropriate provision of the statute.  That’s reassuring.   But consider this.  Section 505(e) of the FDCA requires the agency to withdraw approval of a new drug if scientific data show that the drug is unsafe for use under the conditions of use upon the basis of which the application was approved.  So the new section 524B would allow the agency to grant reciprocal marketing approval to a drug that it found not safe (discretionary, remember?) and then 505(e) would immediately require it to rescind approval because the drug is not actually safe!  How is this a rational process (or good use of taxpayer money)?

Indeed, pretty much all of FDA’s regulatory scheme for new drugs assumes the existence of a new drug application.  It’s hard to see how the scheme will work, if the company hasn’t actually submitted a marketing application under section 505 that complies with its regulations.

• If the company submitted adverse events (the pharmacovigilance regulation is authorized by section 505(k)), how would FDA review and contextualize them, if it doesn’t have the initial safety database from the premarket trials in the first instance?  How would it know whether the information required a change in the labeling or a postmarket study?
• How would FDA conduct a good manufacturing practices inspection under section 704, if it didn’t have the chemistry, manufacturing, and controls section of the marketing application?

Other aspects of the drafting could have consequences the drafters haven’t thought through.  Suppose a drug or biologic still has patent protection or exclusivity in the United States, but in a foreign country (let’s say South Africa) there is a generic or biosimilar.  This foreign product doesn’t have U.S. approval yet.  If FDA found a “public health need” for the foreign product, it appears to me that the standards for reciprocal marketing approval would be met.  Circumventing U.S. patents and exclusivity may actually be one of the things the drafters intended, and in my view this is reason enough to be very concerned about the bill.  But consider also this.  Under the bill, once a product has “reciprocal marketing approval,” it is deemed approved under section 505(c) of the FDCA or 351(a) of the PHSA.  In other words, it is deemed an innovative product.  A biosimilar in South Africa would be deemed an innovative biologic in the United States.  It could therefore serve as a reference product for biosimilars, leading to copies of copies, something that Congress rejected when it passed the biosimilar law in 2010.

And then there are other bodies of law to consider.  Consider a products liability case involving a medical device.  The FDCA contains an express preemption provision. Under the Lohr decision, negligent design claims are not preempted when the device is cleared under section 510(k), because the clearance process focuses on equivalence rather than safety and effectiveness.  But tort claims involving approved devices are handled differently.  Would “reciprocity marketing approval” preempt some claims from injured patients? Maybe so, since the product would be deemed approved under the PMA provisions.  But FDA won’t have actually focused on the device’s safety and effectiveness.  I have no idea how this would shake out, but I can’t imagine preemption would sit well with patient groups or the personal injury bar.

Finally, and most importantly, if this were law, why on earth would anyone ever file a new drug application or premarket approval application again?  It seems like the cheaper and easier solution would be to get approval in a country like Latvia first.  Then you would use this provision, which basically requires FDA to accept the Latvian approval.  It seems to me that no one would bother with the U.S. process anymore.  And this means all of those physicians, statisticians, chemists, pharmacologists, and toxicologists would have nothing to do.  The agency has more than 16,000 employees.  You have to wonder how many would keep their jobs.  That’s why I call this the “Send All the FDA Employees Home Act.”