- Email: [email protected]
The Accelerated Drug Approval
Pipeline GARY D. NOVACK, PHD, EDITOR
The Accelerated Drug Approval GARY D. NOVACK, PHD
nacted by the U.S. Congress in 1962, the Kefauver-Harris amendment to the food and drug laws requires “substantive evidence of safety and efficacy” of a new pharmaceutical in well-controlled studies.1 This is generally interpreted to mean that two large controlled, pivotal (ie, Phase 3) trials are required for marketing approval of a drug. Prevalent chronic conditions, such as diabetes or glaucoma, might eventually provide the product revenue to justify the cost and time required to develop a product. However, revenues from treatments of rarer diseases, such as posterior uveitis, vernal keratoconjunctivitis, or retinitis pigmentosa, may not be adequate to offset the cost of development. Thus, in 1983, the U.S. Congress passed the Orphan Drug Act to provide financial incentives and consulting support for development of such drugs.2 But, when drugs are being developed for life-or sight-threatening conditions, should patients have to wait for Phase 3 trials to be completed? What about a drug that showed efficacy on a potential biomarker that is predictive of longterm efficacy?4 The U.S. Congress approved a pathway for accelerated approvals for such clinical situations. In 1992, the FDA instituted the Accelerated Approval regulation, allowing earlier
E
Gary D. Novack, PhD, consults with numerous pharmaceutical firms. He owns stock in Inspire Pharmaceuticals. ©2010 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack GD. The accelerated drug approval. 2010;8(4):205-207.
approval of drugs to treat serious diseases. This regulation, called “Subpart H,” allows for accelerated approval of a drug based upon a surrogate endpoint (21 CFR 314.510). FDA may grant such marketing approval if the surrogate endpoint is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence to predict survival or irreversible morbidity. Consistent with the Kefauver-Harris amendment, the Sponsor would have to provide “adequate and well-controlled” studies to support the application. Approval could be granted with the condition that the Sponsor study the drug further to verify and describe its clinical benefit (typically called “Phase 4 confirmatory trials”). FDA gives the example of a novel oncology therapy. Instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the FDA might now approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than the time it would take to learn whether patients actually live longer. The drug company would still need to conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer. As reviewed in a recent article in this journal, we, unfortunately, do not have good predictive biomarkers in ophthalmology.3 The FDA, ARVO, and the National Eye Institute have been sponsoring a series of symposia to discuss outcomes in ophthalmology.4,5
There was discussion of the possibility that macular thickness as measured by ocular coherence tomography (OCT) could be predictive of visual acuity in chronic retinal diseases such as diabetic macular edema (DME). If this is valid, then a Sponsor evaluating a new treatment for DME might be able to submit an application for approval based upon OCT data at 6 months, rather than visual acuity data at 3 years. Regrettably, to date, data supporting this relationship have not been strong enough to allow such a regulatory approach. When a prescription drug is approved by the FDA, its use is open to all physicians. For example, any physician may use the Vitrasert™ (ganciclovir intravitreal implant), which is approved for the treatment of cytomegalovirus retinitis and requires intravitreal implantation. FDA does not restrict its use to retinal subspecialists or even to ophthalmologists. However, there is another type of accelerated “restricted” approval (21 CFR 314.520), whereby FDA concludes that a drug can be marketed only if its distribution or use is restricted. For instance, the drug may be distributed only to certain facilities or physicians with special training or experience, or it may be used only in the performance of specified medical procedures. “Restricted” approval may also require post-marketing studies at the time of approval. There are similar pathways for therapeutic biological agents (“Subpart E,” 21 CFR 601.41 and 21 CFR 601.42, respectively). Since the enactment of this law in 1992, scores of products have been approved using
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
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ACCELERATED DRUG APPROVAL / Novack
this accelerated approval mechanism.* For the most part, these are agents to treat HIV infection (where HIV viral loads are the surrogate for survival), anthrax infection, various cancers and pain in advanced cancer. However, there are also approvals for other indications such as subtypes of pulmonary arterial hypertension, transfusiondependent anemia and infertility. Note that for all approval routes, there is either an explicit or implied commitment to conduct further research on the predictive nature of the surrogate, the actual clinical outcome, and the safety of the product. In 2000, Mylotarg® (gemtuzumab ozogamicin) was approved for the treatment of acute myeloid leukemia. A confirmatory, post-approval clinical trial was begun by the Sponsor in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. In 2010, the trial was stopped early when no improvement in clinical benefit was observed and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. Consistent with the regulation, the accelerated approval was withdrawn. Thus, hand-in-hand with the conditional approval is the potential for subsequent withdrawal. To date, there are no Subpart H or Subpart E approvals for ocular surface disease therapies or for any ophthalmic agent. It is hoped that, in the future, this approval route will provide the potential for ophthalmologists to provide treatment with novel therapies for patients with life- or sight-threatening disease. REFERENCES 1. Kaufman B, Novack GD. Compliance issues in manufacturing of drugs. Ocul Surf 2003;1:80-5 2. Novack GD. Pipeline: Orphan drugs. Ocul Surf 2008;6:52-5 3. Novack GD. Pipeline: Just a small, proof-
of-concept study. Ocul Surf 2009;7:111-4 4. Csaky KG, Richman EA, Ferris FL, III. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 2008;49:479-89 5. Weinreb RN, Kaufman PL. The glaucoma research community and FDA look to the future: a report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 2009;50:1497-505
NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES Ophthalmic Products Related to the Ocular Surface ⦁ EyeGate Pharma has begun a Phase 3 trial of dexamethasone phosphate delivered to the eye by iontophoresis in patients with dry eye syndrome (June 2010). ⦁ International Stem Cell Corporation and Sankara Nethralaya are collaborating to develop ISCO’s stem cell-derived corneal tissue to treat corneal disease (July 2010). ⦁ International Stem Cell Corporation created a new business unit, Cytovis™, focused on protective, transparent corneas (CytoCor™) and light-sensitive retinal tissue (CytoRet™, [August 2010]). ⦁ Vistakon Pharmaceuticals announced that the FDA approved Lastacaft® (alcaftadine ophthalmic solution) for the prevention of itching associated with allergic conjunctivitis (July 2010).
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⦁ Ophthalmic Products Not Related to the Ocular Surface ⦁ Advanced Cell Technology continues its plans to initiate a Phase 1/2 multicenter study using embryonic stem cell-derived retinal cells to treat patients with Stargardt’s macular dystrophy (July 2010). ⦁ Alimera Sciences announced that the FDA has accepted for filing and granted Priority Review status for their pending new drug application (NDA) for Iluvien® (fluo-
* http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/DrugandBiologicApprovalReports/ucm121597.htm
206
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cinolone acetonide intravitreal insert) for the treatment of diabetic macular edema (August 2010). Allergan announced that the Medicines and Health Care Products Regulatory Agency in the U.K. has approved injectable Botox® (botulinum toxin type A) for the treatment of chronic migraine headaches (July 2010). Allergan announced that the Committee for Orphan Medical Products of the European Medicines Agency has adopted a positive opinion and recommends the granting of orphan medicinal product designation for its intravitreal dexamethasone implant (Ozurdex®) for the treatment of noninfectious uveitis (August 2010). Allergan has received FDA approval for a new, lower concentration of Lumigan® (0.01% bimatoprost) for the treatment of glaucoma (August 2010). Genentech announced that the FDA has approved Lucentis® (ranibizumab injection) for the treatment of macular edema following retinal vein occlusion (June 2010). Glaukos’ iStent Trabecular MicroBypass Stent was given approval by the FDA ophthalmic devices advisory panel (July 2010). InNexus Biotechnology has developed IXS312(VEGF), an antibody fragment with activity against the growth factor VEGF for planned use in ocular treatments (June 2010). InSite Vision started a Phase 1/2 clinical trial of ISV-303, a formulation of bromfenac in its DuraSite® technology, for the indication of reduction of the pain and inflammation associated with ocular surgery (August 2010). Lux Biosciences announced that, at the request of the FDA, they will conduct an additional clinical study for oral voclosporin for the treatment of non-infectious uveitis involving the intermediate or posterior segments of the eye (August 2010). MorphoSys has started a phase 1 clinical trial of a HuCAL-derived,
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
ACCELERATED DRUG APPROVAL / Novack
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fully human antibody in the therapeutic area of ophthalmology (August 2010). Omeros has started enrollment in a Phase 2b trial of OMS302 in patients undergoing cataract surgery for the maintenance of mydriasis (July 2010). Otsuka Pharmaceutical Co. Ltd. has further extended its funded research collaboration with MethylGene for the development of novel, small molecule kinase inhibitors for the local delivery and treatment of ocular diseases (June 2010). OXiGENE is continuing to develop combretastatin for topical ocular use in the treatment of retinal vasculature disease (June 2010). Sylentis has completed a Phase Ia study in normal volunteers of SYL040012, an siRNA agent, intended for treatment of elevated intraocular pressure and glaucoma (July 2010).
⦁ VisionCare Ophthalmic Technologies announced that the FDA has approved the company’s implantable miniature telescope to improve vision in patients with endstage age-related macular degeneration (July 2010). ⦁ XOMA Ltd. completed an openlabel pilot study of XOMA 052, a therapeutic antibody candidate that inhibits the inflammatory cytokine interleukin-1 beta (IL-1 beta) in patients with uveitis of Behcet’s disease. This agent received orphan status from the European Medicines Agency (June and July 2010). NEWS FROM THE FDA AND OTHER REGULATORY AGENCIES ⦁ The FDA announced that it would propose stronger regulations for pharmaceutical companies that outsource manufacturing, putting more responsibility on the compa-
nies to ensure the purity and safety of products made by contractors (June 2010). ⦁ The FDA proposed withdrawal of midodrine HCl (ProAmatine), an oral α1-adrenoceptor agonist used to treat orthostatic hypotension approved in 1996, because required post-approval studies did not verify the clinical benefit of the drug (August 2010). MISCELLANEOUS NEWS NOTES ⦁ ARVO has withdrawn its 2009 mandate to register Phase 1 clinical trials by July 1, 2010 (July 2010). (For additional information, see Novack GD. Clinical trial registry update. Ocul Surf 2009;7:212-4.) ⦁ The University of Michigan Medical School announced that, effective January 2010, it will no longer accept any money from drug and device makers to pay for continuing medical education (June 2010). ●
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
207
The Accelerated Drug Approval GARY D. NOVACK, PHD
nacted by the U.S. Congress in 1962, the Kefauver-Harris amendment to the food and drug laws requires “substantive evidence of safety and efficacy” of a new pharmaceutical in well-controlled studies.1 This is generally interpreted to mean that two large controlled, pivotal (ie, Phase 3) trials are required for marketing approval of a drug. Prevalent chronic conditions, such as diabetes or glaucoma, might eventually provide the product revenue to justify the cost and time required to develop a product. However, revenues from treatments of rarer diseases, such as posterior uveitis, vernal keratoconjunctivitis, or retinitis pigmentosa, may not be adequate to offset the cost of development. Thus, in 1983, the U.S. Congress passed the Orphan Drug Act to provide financial incentives and consulting support for development of such drugs.2 But, when drugs are being developed for life-or sight-threatening conditions, should patients have to wait for Phase 3 trials to be completed? What about a drug that showed efficacy on a potential biomarker that is predictive of longterm efficacy?4 The U.S. Congress approved a pathway for accelerated approvals for such clinical situations. In 1992, the FDA instituted the Accelerated Approval regulation, allowing earlier
E
Gary D. Novack, PhD, consults with numerous pharmaceutical firms. He owns stock in Inspire Pharmaceuticals. ©2010 Ethis Communications, Inc. The Ocular Surface ISSN: 1542-0124. Novack GD. The accelerated drug approval. 2010;8(4):205-207.
approval of drugs to treat serious diseases. This regulation, called “Subpart H,” allows for accelerated approval of a drug based upon a surrogate endpoint (21 CFR 314.510). FDA may grant such marketing approval if the surrogate endpoint is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence to predict survival or irreversible morbidity. Consistent with the Kefauver-Harris amendment, the Sponsor would have to provide “adequate and well-controlled” studies to support the application. Approval could be granted with the condition that the Sponsor study the drug further to verify and describe its clinical benefit (typically called “Phase 4 confirmatory trials”). FDA gives the example of a novel oncology therapy. Instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the FDA might now approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than the time it would take to learn whether patients actually live longer. The drug company would still need to conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer. As reviewed in a recent article in this journal, we, unfortunately, do not have good predictive biomarkers in ophthalmology.3 The FDA, ARVO, and the National Eye Institute have been sponsoring a series of symposia to discuss outcomes in ophthalmology.4,5
There was discussion of the possibility that macular thickness as measured by ocular coherence tomography (OCT) could be predictive of visual acuity in chronic retinal diseases such as diabetic macular edema (DME). If this is valid, then a Sponsor evaluating a new treatment for DME might be able to submit an application for approval based upon OCT data at 6 months, rather than visual acuity data at 3 years. Regrettably, to date, data supporting this relationship have not been strong enough to allow such a regulatory approach. When a prescription drug is approved by the FDA, its use is open to all physicians. For example, any physician may use the Vitrasert™ (ganciclovir intravitreal implant), which is approved for the treatment of cytomegalovirus retinitis and requires intravitreal implantation. FDA does not restrict its use to retinal subspecialists or even to ophthalmologists. However, there is another type of accelerated “restricted” approval (21 CFR 314.520), whereby FDA concludes that a drug can be marketed only if its distribution or use is restricted. For instance, the drug may be distributed only to certain facilities or physicians with special training or experience, or it may be used only in the performance of specified medical procedures. “Restricted” approval may also require post-marketing studies at the time of approval. There are similar pathways for therapeutic biological agents (“Subpart E,” 21 CFR 601.41 and 21 CFR 601.42, respectively). Since the enactment of this law in 1992, scores of products have been approved using
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
205
ACCELERATED DRUG APPROVAL / Novack
this accelerated approval mechanism.* For the most part, these are agents to treat HIV infection (where HIV viral loads are the surrogate for survival), anthrax infection, various cancers and pain in advanced cancer. However, there are also approvals for other indications such as subtypes of pulmonary arterial hypertension, transfusiondependent anemia and infertility. Note that for all approval routes, there is either an explicit or implied commitment to conduct further research on the predictive nature of the surrogate, the actual clinical outcome, and the safety of the product. In 2000, Mylotarg® (gemtuzumab ozogamicin) was approved for the treatment of acute myeloid leukemia. A confirmatory, post-approval clinical trial was begun by the Sponsor in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. In 2010, the trial was stopped early when no improvement in clinical benefit was observed and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. Consistent with the regulation, the accelerated approval was withdrawn. Thus, hand-in-hand with the conditional approval is the potential for subsequent withdrawal. To date, there are no Subpart H or Subpart E approvals for ocular surface disease therapies or for any ophthalmic agent. It is hoped that, in the future, this approval route will provide the potential for ophthalmologists to provide treatment with novel therapies for patients with life- or sight-threatening disease. REFERENCES 1. Kaufman B, Novack GD. Compliance issues in manufacturing of drugs. Ocul Surf 2003;1:80-5 2. Novack GD. Pipeline: Orphan drugs. Ocul Surf 2008;6:52-5 3. Novack GD. Pipeline: Just a small, proof-
of-concept study. Ocul Surf 2009;7:111-4 4. Csaky KG, Richman EA, Ferris FL, III. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 2008;49:479-89 5. Weinreb RN, Kaufman PL. The glaucoma research community and FDA look to the future: a report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci 2009;50:1497-505
NEWS FROM PHARMACEUTICAL AND MEDICAL DEVICE COMPANIES Ophthalmic Products Related to the Ocular Surface ⦁ EyeGate Pharma has begun a Phase 3 trial of dexamethasone phosphate delivered to the eye by iontophoresis in patients with dry eye syndrome (June 2010). ⦁ International Stem Cell Corporation and Sankara Nethralaya are collaborating to develop ISCO’s stem cell-derived corneal tissue to treat corneal disease (July 2010). ⦁ International Stem Cell Corporation created a new business unit, Cytovis™, focused on protective, transparent corneas (CytoCor™) and light-sensitive retinal tissue (CytoRet™, [August 2010]). ⦁ Vistakon Pharmaceuticals announced that the FDA approved Lastacaft® (alcaftadine ophthalmic solution) for the prevention of itching associated with allergic conjunctivitis (July 2010).
⦁
⦁
⦁
⦁
⦁
⦁ Ophthalmic Products Not Related to the Ocular Surface ⦁ Advanced Cell Technology continues its plans to initiate a Phase 1/2 multicenter study using embryonic stem cell-derived retinal cells to treat patients with Stargardt’s macular dystrophy (July 2010). ⦁ Alimera Sciences announced that the FDA has accepted for filing and granted Priority Review status for their pending new drug application (NDA) for Iluvien® (fluo-
* http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand Approved/DrugandBiologicApprovalReports/ucm121597.htm
206
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⦁
cinolone acetonide intravitreal insert) for the treatment of diabetic macular edema (August 2010). Allergan announced that the Medicines and Health Care Products Regulatory Agency in the U.K. has approved injectable Botox® (botulinum toxin type A) for the treatment of chronic migraine headaches (July 2010). Allergan announced that the Committee for Orphan Medical Products of the European Medicines Agency has adopted a positive opinion and recommends the granting of orphan medicinal product designation for its intravitreal dexamethasone implant (Ozurdex®) for the treatment of noninfectious uveitis (August 2010). Allergan has received FDA approval for a new, lower concentration of Lumigan® (0.01% bimatoprost) for the treatment of glaucoma (August 2010). Genentech announced that the FDA has approved Lucentis® (ranibizumab injection) for the treatment of macular edema following retinal vein occlusion (June 2010). Glaukos’ iStent Trabecular MicroBypass Stent was given approval by the FDA ophthalmic devices advisory panel (July 2010). InNexus Biotechnology has developed IXS312(VEGF), an antibody fragment with activity against the growth factor VEGF for planned use in ocular treatments (June 2010). InSite Vision started a Phase 1/2 clinical trial of ISV-303, a formulation of bromfenac in its DuraSite® technology, for the indication of reduction of the pain and inflammation associated with ocular surgery (August 2010). Lux Biosciences announced that, at the request of the FDA, they will conduct an additional clinical study for oral voclosporin for the treatment of non-infectious uveitis involving the intermediate or posterior segments of the eye (August 2010). MorphoSys has started a phase 1 clinical trial of a HuCAL-derived,
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
ACCELERATED DRUG APPROVAL / Novack
⦁
⦁
⦁
⦁
fully human antibody in the therapeutic area of ophthalmology (August 2010). Omeros has started enrollment in a Phase 2b trial of OMS302 in patients undergoing cataract surgery for the maintenance of mydriasis (July 2010). Otsuka Pharmaceutical Co. Ltd. has further extended its funded research collaboration with MethylGene for the development of novel, small molecule kinase inhibitors for the local delivery and treatment of ocular diseases (June 2010). OXiGENE is continuing to develop combretastatin for topical ocular use in the treatment of retinal vasculature disease (June 2010). Sylentis has completed a Phase Ia study in normal volunteers of SYL040012, an siRNA agent, intended for treatment of elevated intraocular pressure and glaucoma (July 2010).
⦁ VisionCare Ophthalmic Technologies announced that the FDA has approved the company’s implantable miniature telescope to improve vision in patients with endstage age-related macular degeneration (July 2010). ⦁ XOMA Ltd. completed an openlabel pilot study of XOMA 052, a therapeutic antibody candidate that inhibits the inflammatory cytokine interleukin-1 beta (IL-1 beta) in patients with uveitis of Behcet’s disease. This agent received orphan status from the European Medicines Agency (June and July 2010). NEWS FROM THE FDA AND OTHER REGULATORY AGENCIES ⦁ The FDA announced that it would propose stronger regulations for pharmaceutical companies that outsource manufacturing, putting more responsibility on the compa-
nies to ensure the purity and safety of products made by contractors (June 2010). ⦁ The FDA proposed withdrawal of midodrine HCl (ProAmatine), an oral α1-adrenoceptor agonist used to treat orthostatic hypotension approved in 1996, because required post-approval studies did not verify the clinical benefit of the drug (August 2010). MISCELLANEOUS NEWS NOTES ⦁ ARVO has withdrawn its 2009 mandate to register Phase 1 clinical trials by July 1, 2010 (July 2010). (For additional information, see Novack GD. Clinical trial registry update. Ocul Surf 2009;7:212-4.) ⦁ The University of Michigan Medical School announced that, effective January 2010, it will no longer accept any money from drug and device makers to pay for continuing medical education (June 2010). ●
THE OCULAR SURFACE / OCTOBER 2010, VOL. 8, NO. 4 / www.theocularsurface.com
207