HCT/Ps Get Support from Congress but Benefits are Limited
[Posted on: Friday, 8 April , 2016]

Last month in a rare bipartisan move, a new bill was introduced in the Congress to provide conditional approval to regenerative medicine products intended primarily to affect how FDA regulates the Human Cell, Tissue or cellular or tissue-based Products (HCT/Ps). The proposed bill, called the “Reliable and Effective Growth for Regenerative Health Options that Improve Wellness”, or the “REGROW Act” will create a pathway to market approval for HCT/Ps. However, a close review of the proposed regulation shows that this law, if passed, will codify the current practice rather than requiring FDA to make any significant changes to its process. The overall impact will, in effect, be a deferment to a later date of FDA’s requirement for the highly onerous IND and BLA process for such products without any guidance for regulatory expectations for such programs. The act will require most HCT/P manufacturers to file an IND, conduct clinical trials and file a BLA within 5 years and risk rejection by FDA while providing an artificial relief of conditional marketing of the HCT/P product being tested during the clinical trial in parallel. Since the BLA approval is not guaranteed, any HCT/P product failing to get approval for its BLA would need to get off the market, presumably immediately upon the decision. The risk to the manufacturers is increase in several ways such as liability of all patients who were “treated” with a supposedly unapproved product, losing the investment made for the IND and BLA filing, cost differences for the product before and after approval leading to legal issues, and FDA setting unreasonable standards on HCT/Ps equating them equal to other cell-therapies such as transformed cells and biological products. FDA has not announced any differentiators in its clinical and non-clinical requirements for HCT/Ps compared to other cell therapies. HCT/Ps is a different class of therapy and such differences are not addressed in the proposed law. And FDA does have a history of confusing policies for regulation of HCT/Ps. Cell-based therapies are regulated in two ways. The first way is to conduct clinical trials under an IND followed by a BLA for market approval. This process is similar to other biological products and conducted under PHS 351. This applies to all biological products containing live cells which are grown in culture, transformed, or manipulated in other ways to create a therapeutic product. However, if the cells meet certain criteria, they do not require a formal IND or BLA but can be marketed under PHS 361 codified in 21 CFR 1271. Such products only need to comply with donor screening, and Good Tissue Practices (GTP) to assure good quality of the cells. The regulations under 21 CFR 1271 were intended to allow cell therapies under traditional medical practice whereby a physician could isolate cells from a donor and use those cells in a recipient without any major changes to the cells and for the same purpose as naturally intended for such cells. For example, a cornea can be use for corneal transplants, stems cells from blood can be used to enrich stems cell population in a donor. One major condition for products to be regulated under 21 CFR 1271 is that the isolated cells and tissues must be “minimally manipulated”; FDA has published a couple of guidance documents to describe what it believes to be such case. This is where it gets confusing. In its guidance documents FDA lists a few examples of its definition of minimum manipulation which are not all inclusive and confusing for the industry. For example a skin tissue can be mechanically and chemically processed to remove cells and some connective tissue components, freeze-dried and packaged as sheets as a decellularized dermal graft and still be considered minimally manipulated. On the other hand, isolating stem cell fraction from fat tissue harvested during liposuction by low speed centrifugation and suspension in saline without any processing what so ever is termed as major manipulation. Similarly isolation of stem cells from blood is considered minimal manipulation while isolation from bone marrow is considered major manipulation. Since 1271 products do not require pre-approval by FDA, most manufacturer of such products self-assess applicability of this regulatory pathway and have been using such products for decades in some cases. With the FDA’s interpretation of science behind HCT/Ps, there is ample confusion and distress in the industry. FDA’s last draft guidance on adipose derived stem cells received about 100 comments from the industry with almost none agreeing with FDA’s interpretation. FDA called off its public hearing on the guidance in mid-April possibly expecting a very robust opposition to its proposed guidance. It would probably not want pretty much every scientific leader in the field publicly challenge it in an open meeting. The REGROW Act does raise the awareness for the importance of regenerative therapies in healthcare. However, it has major limitations. While it is undeniable that all therapies must be supported by robust science and quality control, it is imperative that regulations be built around current science. No one debates that GTP is an essential requirement for HCT/Ps but application of such therapies should follow principles of risk-benefit assessment where risk to patients governs its availability in market. There is little evidence that HCT/Ps manufactured under GTP increase the risk to a patient. But there are published case studies of patients benefiting from such. Hence the REGROW Act justified keeping them in market. Why stop there?