Laboratory Products for “Research Use Only” (RUO) – Often a Dangerous Claim

Definition in Europe

In Europe, the MEDDEV 2.14/2 guidance document (IVD Guidance: Research Use Only products – A guide for manufacturers and notified bodies) provides clues as to the definition of RUOs. This guidance was written within the framework of the now obsolete Directive 98/79/EC on in vitro diagnostic medical devices (IVDD) and, in the absence of an up-to-date replacement, it can still be considered the state of the art.

MEDDEV 2.14/2 states:

This means that an RUO product must not have even a rudimentary medical purpose.

However, in the case of tests developed in-house by a laboratory (LDTs), this restriction does not apply provided that the products are not sold to other companies. The guidance gives the following specific examples of LDTs that may be designated “research use only” under this requirement:

• PCR enzymes
• Gel component agars
• Primers

The IVDR also addresses RUO products.

Thus, the IVDR, like MEDDEV 2.14/1 (IVD Medical Device Borderline and Classification issues), draws a distinction between RUO products and “devices for performance studies.”

Again, the key aspect of the definition is the RUO product’s lack of medical purpose.

Definition in the USA

In 2013, the FDA published a guidance document on RUOs entitled “Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only.”

This guidance defines RUO products as follows:

Some examples of products that the FDA believes fall into this research phase of development are:

• Tests that are in development to identify test kit methodology, necessary components, and analytes to be measured
• Instrumentation, software, or other electrical/mechanical components under development to determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods
• Reagents under development to determine production methods, purification levels, packaging needs, shelf life, storage conditions, etc.

Therefore, according to the FDA, a clearly visible RUO label must be affixed specifically to products that are in a research phase.

c) What are the consequences of using the “Research Use Only” label?

Normally, IVDs are subject to regulatory requirements (for example, according to the IVDR or FDA) based on their risk class.

However, RUO products do not fall within the definition of “in vitro diagnostic medical devices” given by the IVDR or the relevant FDA regulations. This means that these regulations do not apply to RUO products.

Therefore, the requirements of the IVDR do not apply to RUO products. In the USA, they are exempt from cGMP and the FDA's quality regulations.

Depending on the product, they may still have to comply with requirements that are not specifically intended for IVDs (such as the REACH regulation for chemicals or the Machinery Directive).

Since RUO products are thus subject to considerably fewer controls than IVDs, it is necessary to severely restrict their use.

Therefore, in particular they may not be used to:

• Make diagnoses
• Conduct performance studies

2. Use and misuse of “Research Use Only” labels

a) What should RUO products be used for?

As the name “research use only” indicates, products with RUO labeling are intended for research purposes only. RUO products are particularly attractive for the research sector due to the simplified process and lower hurdles for placing them on the market.

MEDDEV. 2.14/2 rev.1 provides a precise list of areas where RUO products may potentially be used:

• Basic research
• Pharmaceutical research
• Better identification and quantification of individual chemical substances or ligands in biological specimens
• In house manufacturing of so called “home brew kits” for research purposes

And of areas where the use of RUOs is expressly not permitted:

• Use of raw materials which are labeled “for “research use only” but which are incorporated into a finished product
• So called “research use” products being tested against a comparator IVD product that bears the CE mark
• Products for market studies/ feasibility studies

b) What RUO products are often used for

However, the low hurdles are also the reason why RUO products are often used for purposes they are not intended for. This poses significant dangers for manufacturers, operators and patients.

Sale of RUO products to medical laboratories

RUO products are sold by manufacturers to medical laboratories. Although doctors sometimes also conduct research, this is not really the main purpose of a medical laboratory. Therefore, when discussing sales with doctors, it should always be assumed that there is a medical reason behind the use of the product.

This means that anyone who knowingly sells RUO products to medical laboratories is potentially under suspicion of using the pretext “for research use only” to ignore an intended medical purpose and thus avoid responsibility for a medical device.

There are certainly laboratory products that clearly have no specific medical purpose, e.g.:

• Chemicals
• Nutrient media
• Reaction vessels
• Buffers
• Washing solutions

These products are best labeled as “general laboratory supplies” rather than “RUO”.

The issue with analyte specific reagents

Whether an RUO product contains analyte specific reagents, e.g., primary antibodies, FISH probes, PCR primers and probes, and sequencing panels, can be critical. In some cases, a medical purpose can be inferred just from the description of the product's performance.

Example:

This would be the case if a manufacturer of a RUO-labeled kit for the detection of viral genes specifies a number of copies per ml of blood that the kit can detect.

ASR in the USA

The FDA abbreviates the term “analyte specific reagents” to “ASR” and defines it as follows:

In other words, US law says that, by definition, ASRs have a diagnostic purpose.

Exception:
The sale of ASRs to IVD manufacturers as components for manufacturing kits or to non-clinical laboratories for research and development without compliance with regulatory requirements is permitted.

ASR in the EU
EU law does not contain this exception. Nor does the term “analyte specific reagent” does appear in any of the applicable EU regulations. Therefore, such products may have a general laboratory purpose in the EU, depending on the justification. This means they do not fall under the IVDR if the manufacturer defines the intended purpose accordingly.
 
However, if the manufacturer assigns a medical or diagnostic purpose to these products, the regulatory hurdles will very high once the IVDR comes into full effect (currently scheduled for May 26, 2022).

This means that the crucial factor is whether manufacturers have clearly defined the intended purpose and whether communication with customers (e.g., in advertising materials) is in line with this purpose.

3. Consequences of incorrect classification

Lack of controls can have a negative effect on quality. As a result, the relevant bodies (e.g., authorities during inspections) take a closer look at whether a product is actually intended for “research use only”.

Manufacturers should also be aware that simply sticking an RUO label on a product does not on its own mean that the product no longer has to comply with requirements for IVDs that would otherwise apply.

In its guidance document on RUO, the FDA writes that only the actual intended use qualifies a product as RUO – or doesn’t. The FDA also uses marketing materials or other general factors as evidence of the intended purpose.

Manufacturers and operators who misuse the RUO label could face severe penalties, as such behavior can cause serious harm to patients or even the general public.

a) Consequences for manufacturers and operators

Improperly selling IVDs with an RUO label or using RUO products for purposes other than research is not a trivial offense.

Manufacturers who demonstrably hide or aim to hide a diagnostic purpose behind the RUO label should expect legal consequences in Germany. The same applies for operators who misuse RUO products. There is the possibility of a fine or even prison sentences. In addition, there is potential liability for harm suffered by patients.

b) Consequences in the USA

There are also severe penalties in the USA. If an RUO label is deemed to have been incorrectly used for a product, the product would be considered misbranded under sections 502(a) and 502(o) of 21 US Code, 352(a), 352(o) [A1] and would be considered adulterated under section 501(f) of 21 US Code 351(f).

c) Consequences for patients

However, the consequences can be even worse for patients. After all, the regulatory requirements for IVDs aren’t just plucked out of thin air to annoy manufacturers and operators. The regulations are intended to protect patients against incorrect results and subsequent wrong decisions. False-negative results can lull patients into a false sense of security and an existing disease may worsen undetected. One example would be the metastasis of an undetected cancer due to a test not performing as intended.

Some incorrect diagnoses could even be so severe that they can cause the death of a lot of people: an undetected viral infection can cost many lives in the early stages of an epidemic or pandemic, as the coronavirus pandemic sadly demonstrated.

4. Alternatives to “research use only” products

To avoid legal problems and risks for third parties, manufacturers and users should use alternatives to RUO products in borderline cases.

These alternatives don’t always have to be CE-IVDs. Depending on the specific situation, the following alternatives can be considered based on the intended purpose:

a) Products for general laboratory use

According to the MEDDEV 2.14/1 (IVD Medical Device Borderline and Classification Issues) guidance, it is a product's characteristics that determine whether it can be classified as a product for general laboratory use or not.

• If, based on its characteristics, a product is not specifically intended to be used for in vitro diagnostic examinations, it is not an IVD.
• Manufacturers cannot label products for general laboratory use as IVDs.

Such products must have a general use. However, use as an IVD does not have to be ruled out, provided the product is not made specifically for a particular test. According to MEDDEV 2.14/2, even the aforementioned analyte specific reagents (ASRs) without a medical purpose fall into this category.

There are several advantages to using products for general laboratory use instead of RUO products:

1. The product does not fall under the IVD Directive or the IVDR, which saves you a lot of time and money.
2. Laboratories that use these products for in-house procedures are not in danger of being accused of using RUO products in routine diagnostic procedures.

However, the disadvantage is that the medical laboratory is responsible for ensuring that the examination conforms with the IVDR. This can make the product less interesting because the regulatory requirements entail a lot of work.

b) Lab developed tests with class A CE-IVDs
Manufacturers may sell general laboratory reagents, which can be authorized as IVDs under the IVDR, to medical laboratories.

In combination with the ASRs developed in-house, laboratories can validate and use these products as lab developed tests (LDTs).

Read our article on lab developed tests to find out what laboratories should be aware of.

c) “For performance evaluation only” as a preliminary stage for certified IVDs

The IVDR defines "device for performance studies” as follows:

These devices must already be safe, as far as possible, and meet the relevant general safety and performance requirements.

5. Ways to protect yourself

Manufacturers, operators and patients can take the following steps to avoid legal and other negative consequences when using RUO products:

a) Manufacturers

In the case of manufacturers, it is particularly important that they narrowly define the intended purpose of their product.

Analyte specific reagents should only be labeled as RUO products for specific non-medical purposes.

Example:
SARS-CoV-2 and its mutations: a test kit that uses specific primers and probes to distinguish the variants B.1.1.7 (alpha variant) and B.1.351 (beta variant) from the initial variant following a positive result may be an RUO product if it is only intended to be used to determine the prevalence of the variant in the population.
A specific intended purpose in this case would be: “Intended solely for epidemiological research for the purpose of surveying the prevalence of SARS-CoV-2 variants in the general population.”
If a medical laboratory subsequently, based on new findings, used this test to provide the best possible treatment for infection by a specific variant, this would be an off-label use. The laboratory would then be responsible for the test's conformity.

b) Operators

Operators should record exactly what they use IVDs and RUO products for.

Medical laboratories are operators of medical devices and IVDs and, therefore, are responsible for only using medical devices according to their intended purpose and in accordance with the generally accepted rules of the technology. This is stipulated in Section 4 of the German Medizinprodukte-Betreiberverordnung (MPBetreibV (German)).
To be on the safe side, laboratories should keep a record of which medical devices and IVDs are in operation and routine use. This record should include a reference to the applicable test procedure and the intended purpose of the IVD.

This record can also be used to identify investigational procedures for which there are no adequate CE-IVDs available on the market. The lack of alternatives would justify the use of RUOs (as lab developed tests) in validated processes it has developed in-house, provided that the laboratory checks and can demonstrate that the general safety and performance requirements and the additional requirements of Article 5(5) of the IVDR are met.

c) Patients

Patients lack the knowledge to recognize what is and isn’t an RUO on their own. They are often given little to no information about the test they are undergoing. So, patients should follow this basic rule: ask your doctor or pharmacist!

• Patients can ask for the complete test report from the laboratory so that they can get a second opinion in case of doubt. The report should also indicate which specific test was performed.
• Patients should inform themselves about how “well” or “poorly” a test works, as well as the benefit-risk ratio.
• In the future, patients and doctors will also be able to get information about medical devices from EUDAMED and use this information to decide whether or not the test was performed with certified and thus legally compliant IVDs.

6. Conclusion

In the opinion of the EU Commission and the FDA, products “for research use only" have no place in diagnostics. To be used for diagnostic purposes, products have to go through the necessary controls. But these controls do not apply to RUO products.

Anyone who ignores this prohibition and uses or sells RUO products for purposes other than pure research is playing with fire. Manufacturers and operators run the risk of legal trouble and could even endanger patients’ health. Therefore, RUO products should only be used for research purposes. For other uses, manufacturers and operators should use the alternatives mentioned.

Our tip is: if you, as a manufacturer or medical laboratory, find that an RUO product is particularly well-suited for in vitro diagnostics, consider whether further development and conformity assessment to make it an IVD is worthwhile. We will be happy to help you work out which of the three alternatives to RUOs mentioned above is the best alternative to your product as part of our IVD authorization strategy consultation. If necessary, we can also help you ensure your product development conforms with the regulations.