Orders of Magnitude

I am often asked to explain the regulatory pathway DiscGenics is pursuing in the U.S. with IDCT and how our injectable disc cell therapy differs from the guy down the street who claims he can inject stem cells into my body today.

The short answer is that IDCT is an allogeneic (donor-derived) cell therapy produced through a proprietary cell culture manufacturing process that is regulated as a biologic by the U.S. Food & Drug Administration (FDA). This categorization requires DiscGenics to generate preclinical data, conduct clinical studies under an investigational new drug allowance (IND), and apply for a biologics license application (BLA) that will allow us to introduce IDCT to the market once we’ve proven that our product is safe and bioactive.

Figure 1. Understanding Cell Therapy Regulations

In contrast, companies and clinics that claim they can inject your stem cells, or other minimally manipulated cells, into your body today, are merely required to submit to FDA a list of each product they’re processing. They do not need to demonstrate how the product is made or that it meets cGMP manufacturing standards, whether or not it has a therapeutic effect, or that it’s even safe.

Simply put, developing a manufactured allogeneic cell therapy requires orders of magnitude of increased rigor over minimally manipulated cells when it comes to not only proving that the product has a therapeutic effect, but also that it meets critical safety standards and is manufactured consistently from lot to lot, adhering to cGMP standards for a cell therapy [see Figure 1].

The longer answer requires a bit of background…

FDA’s Center for Biologics Evaluation and Research (CBER) regulates “human cells, tissues and other cellular and tissue-based products” or “HCT/Ps” through two different pathways, which are described in 21 C.F.R. Part 1271, to reflect what it considers to be relative risk.(1)

Minimally Manipulated Cells

The first pathway is for HCT/Ps regulated under Section 361 of the Public Health Service Act (PHSA) that meet very specific criteria set forth in 21 CFR 1271.10(a).(2) These products do not require premarket review or approval by the FDA, as regulation of these products is exclusively concerned with product safety, and more specifically transmission of infectious disease.

According to the FDA, in order to be regulated as a Section 361 HCT/P, the following requirements must be met:

1. It is minimally manipulated, meaning processing does not alter the relevant characteristics of the cells or tissues;

2. It is intended for homologous use only, meaning the product performs the same basic function(s) in the recipient as in the donor;

3. Manufacturing of the product does not involved the combination of the cells or tissues with another article except for a few identified agents that do not raise new safety concerns; and

4. Either:

   1. The product does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or

   2. It has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: (i) is for autologous use; (ii) is for allogeneic use in a first-degree or second-degree blood relative; or (iii) is for reproductive use.2

A few examples of products that are regulated as Section 361 HCT/Ps are skin grafts, bone grafts, ligament grafts, tendon grafts, cartilage grafts, amniotic membrane (without added cells), and hematopoietic stem cells derived from umbilical cord blood.

As previously stated, these products are not required to be licensed or approved by the FDA, but the product’s manufacturer must submit to FDA a list of the products they’re producing, ensure appropriate donor-eligibility measures are in place, and engage in good tissue practices.

While such products certainly play an important role in our healthcare system, recent actions by the FDA suggest that some companies are inaccurately self-designating themselves as Section 361 products and marketing manufactured cell-based products without going through the necessary steps to ensure patient safety and product characterization.

See:

• FDA warns of significant deviations related to unapproved stem cell product

• FDA seeks permanent injunctions against two stem cell clinics

• FDA warns of illegally marketing an unapproved cellular product manufactured in a facility with significant manufacturing violations, putting patients at risk

• FDA sends warning to company for marketing dangerous unapproved stem cell products that put patients at risk and puts other stem cell firms, providers on notice

Manufactured Cell Therapies

The second pathway is for products that do not meet the criteria in 21 C.F.R. Part 1271.10 and are regulated under Section 351 of the PHSA. IDCT and other engineered cell therapies, both allogeneic (derived from donor tissue, like IDCT) and autologous (from the patient for the patient), fall into this category and are thus regulated by the FDA like biologics.

In addition to meeting the premarket review and approval requirements described above (e.g. IND, BLA), manufactured cell therapy developers must comply with current good manufacturing practice (cGMP) regulations for drug and biological products (21 CFR 210/211) issued by FDA.(3)

To comply with these requirements, DiscGenics:

1. has conducted preclinical studies to ensure the product’s safety and bioactivity;

2. obtained an IND from the FDA;

3. is conducting an ongoing Phase I/II multicenter clinical trial to demonstrate safety and initial efficacy of IDCT in patients with mild to moderate degenerative disc disease;

4. is developing a fully cGMP compliant manufacturing facility and process to support future clinical trials and commercial use; and

5. intends to apply for and achieve a BLA that will allow us to introduce IDCT to the market.

These requirements are plentiful but critical, as they place the burden on us as developers of manufactured cell therapies to ensure the product we’re producing has been extensively tested for potency, identify, purity and safety. At DiscGenics, we believe this is the best and only way to deliver a product to market that promotes patient safety and quality healthcare.

References

1. 21 C.F.R. Part 1271; see also Human Cells, Tissues, and Cellular and Tissue-Based Products (Dec 2018).

2. 21 C.F.R. Part 1271.10(a); see also FDA Guidance, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (Dec. 2017).

3. 21 C.F.R. Part 210; see also Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General (Dec 2018).