Posted: 30 Mar 2016 06:27 PM PDT
By Jeffrey K. Shapiro & Charlene Cho –
In the emerging world of regenerative medicine, there is a stark dichotomy in the level of regulation applied to products derived from human cells and tissues, or what FDA calls “human cell, tissue or cellular or tissue‑based products” (HCT/Ps).
If an HCT/P meets certain requirements, it is eligible for regulation solely under section 361 of the Public Health Service (PHS) Act. A “361 HCT/P” does not undergo any premarket review by FDA prior to marketing. Once marketed, under 21 C.F.R. Part 1271, such products must comply with certain donor screening and eligibility requirements, and labeling, adverse event / manufacturing deviation reporting to FDA and product handling (Good Tissue Practice) requirements.
To qualify as a 361 HCT/P, a product must meet the following requirements in 21 CFR 1271.10(a):
This regulatory framework has inhibited innovation by creating regulatory uncertainty as to whether products are regulated as 361 or 351 HCT/Ps. The applicability of the 361 HCT/P requirements are often debatable, with the outcome of said debate leading either to extreme outcomes: no premarket review at all versus full IND/BLA review. Additionally, many products that arguably do deviate from the 361 HCT/P requirements simply do not pose a level of risk that would justify the high regulatory hurdle imposed in the IND/BLA process.
Congress is now considering a legislative solution, the “Reliable and Effective Growth for Regenerative Health Options that Improve Wellness” or the “REGROW Act.” With rare bipartisan support in both the House and Senate, the REGROW Act was introduced on March 16, 2016 by Senators Mark Kirk (R-IL), Joe Manchin (D-WV) and Susan Collins (R-ME) in the Senate (S. 2689) and by Representatives Mike Coffman (R-CO), Mark Takai (D-HI) and H. Morgan Griffith (R-VA) in the House (H.R. 4762). The House Bill is identical to the Senate Bill, so for convenience, the discussion below refers only to S. 2689.
The REGROW Act would allow FDA to grant a five year conditional approval of a cellular or tissue therapeutic product that demonstrates preliminary clinical evidence of safety and a reasonable expectation of effectiveness. The firm is required to use this time to initiate an IND study and, ultimately, to submit a BLA for FDA review.
There is no definition of what a “cellular or tissue therapeutic product” is, but it seems likely from the criteria that apply (described below) that this category corresponds to what FDA defines as HCT/Ps in 21 C.F.R. § 1271.10(a). (The bill refers to both “cellular” and “tissue” products, but some provisions and headings refer to “cellular” products while others refer to “cellular and tissue” products. And sometimes the word “therapeutic” is included and sometimes it is not. The inconsistencies appear to be unintentional.)
The conditional approval would cover the manufacture, distribution and sale as well as use of a cellular or tissue therapeutic product, provided that a BLA is submitted within five years. Additionally, the bill says FDA “may” continue the conditional approval during review of the BLA. (Given the length of BLA review, the bill should make it mandatory unless a significant safety concern exists.)
A number of requirements would apply in order for a product to qualify for conditional approval:
The manufacture, distribution and sale as well as use of the cellular or tissue therapeutic product must be consistent with the current regulations, including good manufacturing practices (GMPs).
The cellular or tissue therapeutic product also must satisfy all of the following criteria:
During the five year conditional approval period, the sponsor must submit a BLA as well as annual reports and adverse event reports, which must contain all information generally required for approved biological products.
The sponsor must have submitted an IND for treating the patients with the cellular therapeutic product during the five year conditional approval period.
And finally, the sponsor must not have obtained a conditional approval for the cellular therapeutic product for the same indication.
If all the above-described conditions are satisfied, the cellular or tissue therapeutic product would be permitted to remain on the market unless and until FDA denies BLA approval.
The notion of applying conditional approval is not as novel as it might seem. For many years, when an HCT/P has been found by FDA to have stepped outside the 361 requirements, the firm has been required to initiate an IND/BLA process, but has been in some cases also allowed to continue marketing under enforcement discretion if there is not a serious public health risk. In a sense, this statute would codify that approach but in a manner that provides greater regulatory certainty.
The last part of the bill addresses devices involved in the recovery, isolation, processing and delivery of cellular therapeutic products used in regenerative medicine. It includes language that does not alter the general regulatory scheme for devices, but seems intended to nudge FDA toward regulating with a lighter touch, focusing premarket review and classification of the devices based upon their functional performance in handling and preserving cells, as opposed to the specific clinical uses to which the cells are being put.
All in all, the REGROW Act deserves serious consideration. It holds out hope that the young regenerative medicine industry will be allowed to continue developing beneficial therapies in a way that is commercially viable, but with appropriate public health assurances. Whatever the shape of the final legislation, this draft is a good first step in the right direction.
In the emerging world of regenerative medicine, there is a stark dichotomy in the level of regulation applied to products derived from human cells and tissues, or what FDA calls “human cell, tissue or cellular or tissue‑based products” (HCT/Ps).
If an HCT/P meets certain requirements, it is eligible for regulation solely under section 361 of the Public Health Service (PHS) Act. A “361 HCT/P” does not undergo any premarket review by FDA prior to marketing. Once marketed, under 21 C.F.R. Part 1271, such products must comply with certain donor screening and eligibility requirements, and labeling, adverse event / manufacturing deviation reporting to FDA and product handling (Good Tissue Practice) requirements.
To qualify as a 361 HCT/P, a product must meet the following requirements in 21 CFR 1271.10(a):
- Be minimally manipulated;
- Be intended for homologous use (as reflected in labeling and advertising);
- Not be manufactured by combining cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent;
- Not have a systemic effect and not dependent upon the metabolic activity of living cells for its primary function, with certain limited exceptions.
This regulatory framework has inhibited innovation by creating regulatory uncertainty as to whether products are regulated as 361 or 351 HCT/Ps. The applicability of the 361 HCT/P requirements are often debatable, with the outcome of said debate leading either to extreme outcomes: no premarket review at all versus full IND/BLA review. Additionally, many products that arguably do deviate from the 361 HCT/P requirements simply do not pose a level of risk that would justify the high regulatory hurdle imposed in the IND/BLA process.
Congress is now considering a legislative solution, the “Reliable and Effective Growth for Regenerative Health Options that Improve Wellness” or the “REGROW Act.” With rare bipartisan support in both the House and Senate, the REGROW Act was introduced on March 16, 2016 by Senators Mark Kirk (R-IL), Joe Manchin (D-WV) and Susan Collins (R-ME) in the Senate (S. 2689) and by Representatives Mike Coffman (R-CO), Mark Takai (D-HI) and H. Morgan Griffith (R-VA) in the House (H.R. 4762). The House Bill is identical to the Senate Bill, so for convenience, the discussion below refers only to S. 2689.
The REGROW Act would allow FDA to grant a five year conditional approval of a cellular or tissue therapeutic product that demonstrates preliminary clinical evidence of safety and a reasonable expectation of effectiveness. The firm is required to use this time to initiate an IND study and, ultimately, to submit a BLA for FDA review.
There is no definition of what a “cellular or tissue therapeutic product” is, but it seems likely from the criteria that apply (described below) that this category corresponds to what FDA defines as HCT/Ps in 21 C.F.R. § 1271.10(a). (The bill refers to both “cellular” and “tissue” products, but some provisions and headings refer to “cellular” products while others refer to “cellular and tissue” products. And sometimes the word “therapeutic” is included and sometimes it is not. The inconsistencies appear to be unintentional.)
The conditional approval would cover the manufacture, distribution and sale as well as use of a cellular or tissue therapeutic product, provided that a BLA is submitted within five years. Additionally, the bill says FDA “may” continue the conditional approval during review of the BLA. (Given the length of BLA review, the bill should make it mandatory unless a significant safety concern exists.)
A number of requirements would apply in order for a product to qualify for conditional approval:
The manufacture, distribution and sale as well as use of the cellular or tissue therapeutic product must be consistent with the current regulations, including good manufacturing practices (GMPs).
The cellular or tissue therapeutic product also must satisfy all of the following criteria:
- The cells or tissue are adult human cells or tissues;
- The cells or tissues do not provoke a significant immunogenic response;
- The cells or tissues are either minimally manipulated and for a non-homologous use or more than minimally manipulated and for either a homologous or non-homologous use but in either case, not genetically modified;
- The cells or tissues are for a specific indication;
- The cells or tissues are produced exclusively for a use that performs, or helps achieve or restore, the same, or similar, function in the recipient as in the donor.
During the five year conditional approval period, the sponsor must submit a BLA as well as annual reports and adverse event reports, which must contain all information generally required for approved biological products.
The sponsor must have submitted an IND for treating the patients with the cellular therapeutic product during the five year conditional approval period.
And finally, the sponsor must not have obtained a conditional approval for the cellular therapeutic product for the same indication.
If all the above-described conditions are satisfied, the cellular or tissue therapeutic product would be permitted to remain on the market unless and until FDA denies BLA approval.
The notion of applying conditional approval is not as novel as it might seem. For many years, when an HCT/P has been found by FDA to have stepped outside the 361 requirements, the firm has been required to initiate an IND/BLA process, but has been in some cases also allowed to continue marketing under enforcement discretion if there is not a serious public health risk. In a sense, this statute would codify that approach but in a manner that provides greater regulatory certainty.
The last part of the bill addresses devices involved in the recovery, isolation, processing and delivery of cellular therapeutic products used in regenerative medicine. It includes language that does not alter the general regulatory scheme for devices, but seems intended to nudge FDA toward regulating with a lighter touch, focusing premarket review and classification of the devices based upon their functional performance in handling and preserving cells, as opposed to the specific clinical uses to which the cells are being put.
All in all, the REGROW Act deserves serious consideration. It holds out hope that the young regenerative medicine industry will be allowed to continue developing beneficial therapies in a way that is commercially viable, but with appropriate public health assurances. Whatever the shape of the final legislation, this draft is a good first step in the right direction.
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