Table 3.

History of regulatory action, preapproval and postapproval clinical evaluation of autologous human cells and tissue products in the US, the EU, and Japan.

Generic name (trade name)	History of regulatory action	Preapproval evaluation	Postapproval evaluation
US
Autologous cultured chondrocytes (Carticel™)	•Began marketing in 1995 due to not to be regulated for autologous cell therapy •Submitted BLA in 1996 •Issued guidance regarding MAS cellsa on May 28, 1996 (FDA determined to be regulated) •Approved on August 22, 1997 for accelerated approval •Approval of narrow indication (second line therapy) on March 2, 2000	Nonclinical studies •Rabbit studies of improved healing at 52 weeks •Dog study of improved healing at 13 and 26 weeks Clinical studies •Swedish Clinical Experience of 153 patients with retrospectively generated CRF •US registry data of 191 patients repairing of femoral condyle in 241 patients treated	Nonclinical studies •Goat studies of histological healing at 16 weeks •Horse study of histological healing at eight weeks Clinical studies •Registry-based study (RBS) of 97 US patients in which 44 were part of subset of 191 patients in preapproval clinical evaluation •Study of the treatment of articular repair (STAR) of 154 patients in which 136 and 115 patients were completed 24 and 48 months follow-up, respectively
Cultured epidermal autografts (Epicel®)	•Commercialized from 1988 to 1996 as banked human tissue •Issued guidance regarding MAS cells on May 28, 1996 (FDA determined to be regulated) •Filed as Humanitarian Device Exemption (HDE) application on February 5, 1997 •Designated as Humanitarian Use Device (HUD) on November 30, 1998 •Approved as HDE on October 25, 2007	Nonclinical studies •In vitro and in vivo efficacy studies Clinical studies •Clinical experience of 552 patients for 1989–1996 and 734 patients for 1997–2006 •Physician-sponsored study of 44 patients with and without Epicel® followed for seven years	Nonclinical studies •Not conducted Clinical studies •Not conducted (No registry of ClinicalTrial.govb)
Sipuleucel-T (Provenge®)	•Submitted IND on December 22, 1996 •Submitted BLA on August 21, 2006 •Approved as Biologic Products on April 29, 2010	Nonclinical studies •In vitro study for PAPc expression in human tissues •Five in vivo studies for immunogenicity and generation of PAP and efficacy model in mice and rats •No toxicology studies Clinical studies •Randomized clinical trial (RCT) as pivotal study of 512 patients to compare Provenge® (341 patients) to placebo (171 patients) •Other phase three, two RCTs of 225 patients to compare Provenge® (147 patients) to placebo (78 patients) •Other phase three, a RCT of 176 patients and phase two, an open-label trial of 113 patients	Nonclinical studies •Not conducted Clinical studies •A Registry of Sipuleucel-T therapy in men with advanced prostate cancer (PROCEED)d of estimated enrollment 1500 patients, NCT01306890
Azficel-T (Laviv®)	•Marketed as cosmetic treatment from December 1995 to February 1999 •Submitted IND on October 12, 1999 •Submitted BLA on March 6, 2009. •Approved as Biologic Products on June 21, 2011	Nonclinical studies •No preclinical studies conducted due to applicable five published articles of various in vitro and in vivo studies Clinical studies •Of 7 clinical trials, two randomized clinical trial studies of phase 3 with 421 patients to compare Laviv® (210 patients) to vehicle-control (211 patients) and phase two an open-label trial of 50 patients •Other indication for four trials of 436 patients •Commercial experience of >9077 patients in the US and UK from 1995 to 2007	Nonclinical studies •Not conducted Clinical studies •Proceeding pharmacovigilance activities of estimated enrollment 2700 patients (No registry of ClinicalTrial.govb website)
EU
Characterized viable autologous cartilage cells expanded ex vivo expressing specific marker proteins (ChondroCelect®)	•Submitted through the centralized procedure on June 1, 2007 •Approved as ATMP on October 5, 2009	Nonclinical studies •Goat study of improved repair at 52 weeks •Single dose toxicity of nude mice and sheep •Carcinogenicity assay after serial passaging Clinical studies •Randomized clinical trial of 144 patients to compare ChondroCelect to microfracture •Compassionate use of 334 patients	Nonclinical studies •Not conducted Clinical studies •Proceeding pharmacovigilance activities (No registry of ClinicalTrial.govb and EU Clinical Trials Registere website)
Matrix-applied characterized autologous cultured chondrocytes (MACI)	•Available in certain European countries, and Australia in accordance with national legislations since 1998 •Submitted through the centralized procedure on September 1, 2011 •Approved as ATMP on June 27, 2013	Nonclinical studies •Rabbit, sheep, and horse of repair at 53 weeks •Single dose toxicity of mice and horse •Chromosomal stability testing with lack of tumorigenic findings Clinical studies •Randomized clinical trial of 144 patients to compare MACI to microfracture •Supportive data of approximately 800 patients from 19 studies •Safety reports from post-market experience	Nonclinical studies •Not conducted Clinical studies •Proceeding pharmacovigilance activities (5-year long term safety and efficacy; EudraCT: 2009-016970-33) •Planned retrospective and prospective study of pediatric patients
Autologous peripheral-blood mononuclear cells activated with prostatic acid phosphatase granulocyte- macrophage colony-stimulating factor (Sipuleucel-T) (Provenge)	•Submitted through the centralized procedure on December 30, 2011 •Approved as ATMP on September 6, 2013	Nonclinical studies •In vitro study for PAPd expression in human tissues •Five in vivo studies for immunogenicity and generation of PAP and efficacy model in mice and rats •No toxicology studies Clinical studies •Randomized clinical trial (RCT) as pivotal study of 512 patients to compare Provenge (341 patients) to placebo (171 patients) •Other phase three, two RCTs of 225 patients to compare Provenge (147 patients) to placebo (78 patients) •Other phase three, a RCT of 175 patients, and phase one and two, eight open-label trials of 301 patients •Two salvage studies of 169 patients •Post-marketing experience of 28 patients as of July 29, 2011 (PROCEED)	Nonclinical studies •Not conducted Clinical studies •A Registry of Sipuleucel-T therapy in men with advanced prostate cancer (PROCEED)d of estimated enrollment 1500 patients, NCT01306890 •Proceeding phase 2 study with immunosuppressant therapies •Proposed post-approval study and EU registry study
Japan
Other surgical/orthopedic materials; autologous cultured epidermis (JACE)	•Submitted New Medical Device Application on October 6, 2004 •Approved as New Medical Device on October 29, 2007	Nonclinical studies •Biological safety studies Clinical studies •Clinical trial of two patients	Nonclinical studies •Not conducted Clinical studies •Completed post-approval clinical trial with 30 patients •Proceeding post-market survey for all patients treated with JACE for 7 years
Human autologous cells and tissues (JACC)	•Submitted confirmatory application on September 7, 2001 and confirmed on February 19, 2004 •Submitted New Medical Device Application on August 24, 2009 •Approved as New Medical Device on July 22, 2012	Nonclinical studies •Biological safety studies •Rabbit and Dog studies for graft treatments Clinical studies •Open clinical trial of 32 patients •Follow-up study for safety after clinical trial	Nonclinical studies •Not conducted Clinical studies •Proceeding post-market survey for all patients treated with JACC for 7 years

BLA, Biologics License Application; MAS, Manipulated Autologous; the FDA, the Food and Drug Administration; ND, Not determined; AMTP, Advanced Therapy Medicinal Products; EU, European Union. IND, Investigational New Drug application; PAP, Prostatic acid phosphatase.

The US, The United State; The UK, The United Kingdom.

^aUS Food and Drug Administration. Guidance on application for products comprised of living autologous cells manipulated ex vivo and intended for structural repair or reconstruction; availability. Fed. Regist. 61,26523–26254 (1996).

^bhttp://clinicaltrials.gov/.

^cPAP is an anigen expressed in prostate cancer tissue.

^dhttp://clinicaltrials.gov/ct2/show/NCT01306890?term=PROCEED&rank=4.

^ehttps://www.clinicaltrialsregister.eu/.