CDRH Issues Final Guidance on Research Use Only and Investigational Use Only In Vitro Diagnostics Products

By Allyson B. Mullen & Jeffrey N. Gibbs –

On November 25, 2013, CDRH issued the Final Guidance “Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions” (the “RUO Guidance”) (see our previous posts on the draft guidance here and here).  The draft guidance significantly limited the sale and distribution of “Research Use Only” (RUO) and “Investigational Use Only” (IUO) products.  76 Fed. Reg. 31615 (June 1, 2011).  As we discussed in our previous blog posts on the draft guidance, most of the restrictions set out in the policy were consistent with the current practices of many IVD companies, but in several key areas the agency’s proposals would have substantially curbed the sale of RUO and IUO labeled products.

Most significantly, in the draft guidance, FDA departed from the well-established practice of determining intended use based on the manufacturer’s conduct, by also considering how a customer uses a product.  FDA stated in the draft guidance that a manufacturer must stop sales of its RUO or IUO product to a customer once the manufacturer knows – “or has reason to know” – that the customer is using the product for a diagnostic use, even if the manufacturer makes no diagnostic claims or statements.  In Hyman, Phelps & McNamara, P.C.’s comments to the draft guidance, we recommended that this concept be removed from the final guidance (see here and here). 

In the draft guidance, FDA defended this approach by stating that cessation of sales was necessary since use of RUO and IUO products in clinical diagnostic tests “presented[ed] a serious potential risk to the public health.”  Draft Guidance at 11.  However, in a recent FDASIA Hearing before the House Energy and Commerce Committee’s Subcommittee on Health (the “Committee) Dr. Jeffery Shuren, Director of CDRH, did not defend this position.  USHR21 Energy and Commerce Committee, November 15, 2013, available here (last visited Nov. 17, 2013).  When asked by Congressman Michael C. Burgess, M.D., Vice Chair of the Committee, whether Dr. Shuren had any evidence of patient harm caused by use of RUO products, Dr. Shuren said that while he was aware of companies putting RUO products on the market and then promoting them for clinical diagnosis, there was no evidence of harm.  Id.

With no known harm to patients or the public health, and a questionable legal basis for equating known use with intended use, the agency clearly could not justify the change in policy proposed in the draft guidance.  (Indeed, one could make a stronger argument that heavy restrictions on RUO sales actually would have an adverse impact on public health).   Dr. Shuren testified that the agency received the message loud and clear that the “reason to know” standard needed to come out of the final guidance.  Issued just 8 days later, the final guidance did just that.

With this background, FDA significantly modified the guidance before issuing the final version.  Some of the key differences between the draft guidance the RUO Guidance are:

• The final guidance introduces the concept of a certification program as evidence that the manufacturer is ensuring its customer are using the RUO or IUO product in accordance with its intended purpose.  RUO Guidance at 11.  The concept of a certification program for RUO products was originally introduced in the early 1990s in a draft Compliance Policy Guide (CPG) document issued by FDA.  After many companies implemented such programs, FDA never finalized the CPG and had seemed to move away from this concept in recent years, including having excluded such a concept from the draft RUO guidance.  However, unlike the earlier drafts of the CPG, the final RUO Guidance gives little weight to certification programs.
• The final guidance does not include the concept of registration and listing for foreign manufacturers, which was previously included in the draft guidance.  Draft Guidance at 7.
• The final guidance does not expressly address whether RUO and IUO products are subject to the Quality System Regulation like the draft guidance did.  Id. at 9.  This could suggest that for mislabeled RUO and IUO products FDA will subject them to the requirements in the QSR. 
• As discussed above, the final guidance does not include the concept that if the manufacturer of an RUO or IUO “knows, or has reason to know” that the product is being used in clinical diagnosis that it must take action and cease selling to that customer.  Id. at 10-11.  On the other hand, it does say “a manufacturer who produces only products labeled RUO whose sales force makes routine calls to clinical laboratories that do not perform research or clinical studies may be viewed as demonstrating its intent that its products be used for clinical purposes.”  RUO Guidance at 9.  This sentence may cause some RUO manufacturers to think more carefully about their customer lists.
• The Guidance puts some limits on the support RUO manufacturers can provide laboratory customers.  The guidance says, “provision of certain types of specialized technical support (e.g., assistance in performing clinical validation) to clinical laboratories” would be in conflict with the product’s RUO or IUO labeling.  Id.  However, FDA clarifies in Footnote 10 that specialized technical support “is not referring . . . to generic maintenance support or software updates for an RUO or IUO IVD product.”

One other interesting change between the draft and final RUO Guidance relates to use of RUO and IUO products in pre-market submissions to FDA.  The draft guidance affirmatively stated that a manufacturer could obtain 510(k) clearance for an IVD which used RUO or IUO products as part of the submission.  Draft Guidance at 12.  This language is not in the final guidance.  The significance of that omission is unclear.  However, the timing of the release of this Guidance interestingly coincided with two other important IVD developments.  On November 22, FDA issued a highly publicized Warning Letter to 23andMe, a provider of direct-to-consumer FDA sequencing service.  Also, FDA recently cleared Illumina MiSeqDx Platform for high-throughput DNA sequencing.  One could infer that FDA is signaling through the RUO Guidance and its clearance and enforcement actions that it wants manufacturers of laboratory instrumentation (e.g., sequencers) and reagents, and providers of at least certain laboratory developed tests to obtain FDA pre-market clearance. 

Even with some of the key changes in the RUO Guidance compared to the draft guidance, it is clear that FDA expects commercially available RUO and IUO products to be an area of focus for FDA enforcement.  The RUO Guidance emphasizes that FDA will review the totality of the circumstances when it comes to assessing whether an IVD is properly labeled as RUO or IUO.  This approach is consistent with FDA’s traditional approach to enforcement, although we do not yet know which restrictions may trip up some RUO manufacturers.

• FDA views the RUO and IUO labeling statements as warnings and anything done by a manufacturer or distributor to undercut those warnings may be viewed as problematic. RUO Guidance at 8.
• FDA will be looking at the “objective intent” of the manufacturer to determine if the product is a true RUO or IUO.  Id. at 9. 
• The manufacturer should ensure that all presentations and talks are appropriately labeled with the RUO or IUO statement as applicable.  Id.
• The manufacturer should carefully review its current sales practices, including who the company solicits RUO and IUO business from.  Id. If an RUO/IUO manufacturer is soliciting business primarily from diagnostic laboratories, FDA would consider this off-label promotion.
• The manufacturer should ensure that it is not providing specialized support (e.g., beyond generic maintenance support or software updates) or LDT validation support for its RUO and IUO products.  Id.

During Dr. Shuren’s testimony before the Committee, he stated that the concern with RUO products being used in clinical diagnosis is that a determination (we should say an FDA determination) has not been made as to whether the RUO product is accurate or not.  Dr. Shuren went on to testify that in the instances where the agency has taken action against a manufacturer of an RUO product for clinical diagnostics promotion, it has been where there is an alternative test that has been cleared or approved for the same intended use.  This is helpful insight for industry into FDA’s thinking as it relates to the marketing of RUO and IUO products.

With the issuance of the RUO Guidance FDA’s policy is now articulated.  Of course, the RUO Guidance is just that: guidance.  It is not legally binding.  Still, we expect the agency to be keeping a close eye on RUO and IUO manufacturers and their marketing and sales practices.  The agency says it will take enforcement action based on the totality of the circumstances.  What that actually means remains to be seen.  As with most things with FDA, we will simply have to wait and see.  Thus, 21 years after FDA first proposed an RUO/IUO guidance document; the process has come to an end.  A final RUO/IUO guidance is now in effect.  Yet the original 1992 CPG proposal did spawn an issue that lives on: FDA has the power to regulate LDTs.  And that is an issue that will not be definitively resolved any time soon.