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FDA Requiring many Amnion Fluid Injectables to be Withdrawn by May 31, 2021.

As of May 31, 2021, many amnion fluid and membrane injectables must be withdrawn from the market. Here is a (non-exhaustive) list of suppliers/products affected:

Flower – https://flowerortho.com
FlowerAmnioFlo – Amnion Fluid from Micronized Membrane – Not FDA Compliant

MiMedx – https://mimedx.com
AmnioFix Injectable – Amnion Fluid from Micronized Membrane – Not FDA Compliant

Amnio Tech – https://amniotechnology.com
PalinGen InovoFlo, PalinGen Flow – Amnion Fluid from Micronized Membrane – Not FDA Compliant

Applied Biologics – https://appliedbiologics.com/product-showcase/flograft/
FloGraft – Amnion Fluid from Micronized Membrane – Not FDA Compliant

Amniox – https://amnioxmedical.com/clarix-injectable/
CLARIX® Injectable – Amnion Fluid from Micronized Membrane – Not FDA Compliant

Predictive Biotech – https://www.predictivebiotech.com/products/
AmnioCyte, AmnioCyte Plus – Amnion Fluid from Micronized Membrane – Not FDA Compliant

The following have NOT been affected by this action:

Biolab Sciences – https://www.biolabsciences.net/
Fluid FlowTM, Amnio Restore – Amniotic Liquid Allograft derived from the amniotic liquid within the placenta. 100% Pure Amniotic Fluid – FDA 2020 Compliant

Regulatory Background:

The FDA’s 2017 regenerative medicine policy framework1 was developed to help facilitate and support the innovation of regenerative medicine therapies. The policy allows use of “certain human cell, tissue, and cellular and tissue-based products (HCT/Ps)”. All placental-based products are currently defined by the FDA as HCT/Ps.

The agency had originally expressed its intent to exercise enforcement discretion for these products with respect to the FDA’s IND and premarket approval requirements, to give manufacturers time to understand and meet the applicable requirements and engage with the agency. This discretion was to last until November 2020, but was extended2 until May 31, 2021 due to the pandemic.

In a recent (May 12, 2021) Contractor Advisory Committee (CAC) meeting led by Noridian on the topic of Amniotic Product Injections for Musculoskeletal Indications, Non-Wound, the CAC confirmed that there would be no further extension of the enforcement discretion. As a result, letters were sent to many if not most amniotic product suppliers requiring them to withdraw certain products from the market.

Why?

Many if not most of the amniotic products injectables used (off label) for pain and inflammation are made using lyophilized and micronized placental membrane. In the simplified description, placental membrane is freeze-dried, reduced to a powder, then turned into an injectable form by addition of saline. The agency defines products processed this way as ‘more than minimally manipulated’. The affected products had previously been authorized under section 361 the Public Health Service Act, but that section requires minimal manipulation. With the enforcement discretion ended, the producers are required to withdraw those products. Some may choose to apply for authorization under section 351 instead, but that will take time. Many of these products will not return to the market.

More detail on the relevant regulatory sections:

Placental derived and amniotic fluid based products are regulated under either section 361 or section 351 of the Public Health Service Act. Section 361 allows use of amniotic products for homologous use only3, meaning they can be used only for repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues when applied using implantation, transplantation, infusion, or transfer into a human recipient. Producers under section 361 must also adhere to particular requirements on how the tissues are handled and treated. Furthermore, (and of particular importance to this action) under 361, amniotic products must be ‘minimally manipulated’3.

Section 351 covers products which have undergone more than minimal manipulation. These products are allowed for non-homologous use but will require a Biologics License Application as well as phase I, phase II and phase III studies.

Methodology:

It would be most helpful if the FDA published a list of products which are affected by these changes and a list of those unaffected. Unfortunately, the FDA does not work that way. For each of the affected products, the FDA sent a letter to the offending producer requiring them to a) remove the product from further availability, and b) inform their existing customers to return to them any unused product for a refund, both with a May 31, 2021 deadline. No letters were sent to those unaffected.

The first step to confirm who was affected was to search each company’s website. With one exception, the websites listed either no longer mention the liquid injectable products or they state that they are committed to pursuing FDA approval. (The exception is FlowGraft, which has a user-only site. The open part of the website does mention the product, but with no detail.)

The next step was to search the web using product and company name, for more information on the type of product. In several cases, it was easy to find confirmation that the product was processed from amniotic tissues, and therefore ‘more than minimally manipulated’. In one case, the product is described as “comprised of amnion and amniotic fluid”. This could have a shorter time back to market if they only use amniotic fluid going forward, but they could not do that without a new FDA application.

FDA References:

1. Framework for the Regulation of Regenerative Medicine Products
2. FDA Extends Enforcement Discretion Policy for Certain Regenerative Medicine Products
3. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use

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