phases of a clinical trial and accelerated drug

phases of a clinical trial /oncology

1. Phases of a clinical trial and accelerated drug approval Presenter : Dr Sabeena Moderator : Dr Linu Jacob

2. Origin of clinical trials First trials date back to 1854 James Lind : scurvy patients on sailboard Landmark study that launched modern era of clinical trials: Fischer & Hill Streptomycin as ATT

3. Contents : How are cancer drugs developed? Drug discovery Preclinical testing Formulation Clinical trials What types of clinical trials are carried out? How are patients’ rights protected during clinical trials? Monitoring during clinical trials How do we measure clinical trial outcomes? Efficacy endpoints Safety and tolerability endpoints How do we decide that a trial has had a successful outcome? Regulating Cancer Drugs Why regulate cancer drugs? Who are the regulators? What advice do pharmaceutical companies get from regulators Drug review process What procedures are used to evaluate a drug for approval? What evidence do the regulators look for? Who provides regulatory agencies with advice? What does regulatory approval mean? How long does it take to approve drugs? Rapid processing of applications for promising cancer drugs Rapid review procedure s

4. How are cancer drugs developed? Complex time-consuming (10 and 15 years ) uncertain very expensive ( US$800 million). For every 5000 compounds tested, only one will be approved for use in patients

5. Stages of Drug Development Pre-IND IND Phase 0/1 clinical trials Phase 2 clinical trials Phase 3 clinical trials NDA Post-marketing

6. Drug discovery

7. New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease. Many tests of  molecular compounds  to find possible beneficial effects against any of a large number of diseases. Existing treatments that have unanticipated effects. New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material.

8. Drug discovery To define a specific target or parameter that plays a role in the development of a particular cancer. Cell lines are then chosen or developed that show properties similar to the cancer under consideration. Scientists then screen thousands of compounds – or chemically engineer new ones – to identify compounds that show some activity on these cell lines grown in the laboratory. These molecules are modified (to increase their activity / minimize side effects )

9. PRECLINICAL TESTING

10. Preclinical testing Compound is tested in animals to evaluate its safety and Also tested against tumours in laboratory animals. demonstrate that it has biological activity against the disease target. Testing can take from three to six years and involves taking the compound though a variety of toxicological tests and teratogenicity tests

11. Further testing criteria Is the compound likely to be more effective than current therapies? Will the compound have a better safety profile? Will it be possible to manufacture and formulate the compound on a large scale? Does it have a reasonable dose range and delivery mechanism?

12. Drug effects studied …. Pharmacokinetic studies. Pharmacodynamic studies. Side effects of the drug (unacceptable or dangerous). Many drugs are dropped at this stage and do not undergo further development, because they fail one or more of these tests. Only 1 in 1,000 agents pass these tests successfully. In addition to biological tests, scientists will examine the compound’s purity, stability and shelf life and evaluate what will be involved in producing this potential medicine on a large scale.

13. REGULATION AT PRECLINICAL TEST LEVEL

14. FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies.  The GLP regulations are found in  21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory StudieS . These regulations set the minimum basic requirements for: study conduct personnel facilities equipment written protocols operating procedures study reports and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product

15. IND A Request to Start Clinical Trials

16. WHAT IS IND An investigational new drug (IND) is an exemption under the Interstate Commerce Act that allows for the interstate shipment of nonapproved drugs, also known as investigational drugs .. A drug is defined as an article that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and is an article (other than food) intended to affect the structure or any function of the body. An IND is required in the United States to administer an unapproved drug to humans.

17. Included in IND application: Animal study data and toxicity (side effects that cause great harm) data Manufacturing information Clinical protocols (study plans) for studies to be conducted Data from any prior human research Information about the investigator

18. The First 30 Days Study cannot proceed until 30 days from FDA receipt (new INDs and reactivated INDs only) 30 day safety review Internal meeting before the 30 days to review the application together to determine whether the proposed study is safe to proceed Decision: safe to proceed  or clinical hold? 

19. Preclinical result : probably safe and effective drug against the tumor ( to be proven in humans )

20. Pre C linical trials

21. Pre C linical trials human studies

22. Phase 1 The first stage of testing in human subjects These studies evaluate the agent’s safety profile, tolerability, PK, PD what dose is safe, how it should be given (the appropriate formulation) and how often. Small groups of patients (in advanced stage of disease) , called cohorts, are treated with increasing doses of the new therapy to find the highest dose with an acceptable level of side effects. This is the dose that will be used in future studies (called the maximum tolerated dose for cytotoxic drugs or optimal biological dose for targeted or biological therapies). Phase I studies take six months to one year to complete.

23. Starting dose in phase 1 One tenth of the lethal dose in animal studies LD10

24. Objectives of phase 1 Primary Safet y DLT Tolerability MTD PK Secondary PD

25. AIM : to determine MTD of new treatment MTD found by escalating the treatment dose until Dose Limiting Toxicity is reached

26. Phase 1 principles Start with a safe dose Min number of patients Intensive Blood tests Examination of patient frequently

27. Phase 1 assumptions The higher the dose used ,the greater is the efficacy Dose related acute toxicity is regarded as surrogate for efficacy Highest safe dose MTD is likely to be most efficacious May not hold true for biologic agents ( where aim is to inhibit a target) So non cytotoxic agents should have OBED (optimum biologic effect dose ) as the goal of phase 1 trials .

28. Once phase 1 is finished... Drug X is reasonably safe with manageable toxicities Drug X achieves serum or tissue levels that are sufficient to achieve effects in preclinical studies Worldwide, a total of 15- 25 patients have been treated with drug X with 4 to 8 , at the dose we plan to use in phase 2

29. What after phase 1 Company decides further to continue with further phases of the trials or stop. Basis : toxicity

30. Phase 2

31. Phase II Goal of establishing the “ proof of concept ” – Phase II trials of the same drug are sometimes conducted in patients with several different types of cancer to determine if the therapy is likely to be of benefit in treating more than one tumour type. Help establish the optimum dose, Explore whether there are likely to be any potential safety problems associated with the drug. Time frame : 6 months to 2 years

32. Objectives of phase 2 Primary Confirm effectiveness Secondary Monitor side effects Further evaluate safety Optimum dose finding(dose efficacy relation, therapeutic dose regimen, duration of therapy, frequency of administration, therapeutic window)

33. Randomised phase 2 trial of Drug X in breast cancer Eligibility criteria : MBC progressed on prior Rx with anthracyclines & taxanes /no comorbidities/good organ functions Design : randomise 80 women to capecitabine vs new drug Endpoint : tumor response / PFS E.g PFS is longer han that established for capecitabine in this setting i.e > 3 months (regarded as clinically important)

34. Adaptive phase 2 trial designs Patients are randomized to many Rx arms Promising ones are retained and continued to phase 3 Negative ones are dropped off New Rx arms can be added subsequently

35. Stampede trial

36. Biomarker base trial Many new agents are designed to act against tumors that express a ‘biomarker’ E.g trastuzumab , vemurafenib , crizotinib These agents have minimal activity against unselected patients Hence these trials would be undertaken only in patients whose cancers express the appropriate biomarker Other phase 2 trials can evaluate potential biomarkers to determine if they correlate with the activity of the new drug.

37. Ethical considerations

38. What we learnt so far Preclinical : on animals … drug has effect on tumor ; drug is safe ; LD 10 established Phase 1 : start in humans with 1/10 of LD 10; establish MTD; and finalise the dose to be used for phase 2 Phase 2 : with the dose established to be safe , we establish the efficacy through PFS or tumor reduction Next task : whether any significant benefit is seen clinically or not

39. Phase III Phase III trials compare a new drug with current standard therapy in large matched groups of patients (i.e. in large, randomized trials). Information on the overall risk–benefit relationship of the investigational drug that provides evidence to support its use in a specific indication (i.e. to treat a specific disease in a specific group of people) is gathered during these trials. This enables clear prescribing information to be developed. Phase III trials can take one to four years to complete, depending on the disease

40. Phase III trials Determine if a new Rx provides sufficient benefit to patients that it should replace current std Rx Design : Eligible patients with a given type of cancer R A N D O M I Z A T I O N New treatment (alone or added to standard) Standard treatment Outcome measures (endpoints ) should reflect benefit to patients . OS, Q.O.L, Toxicity

41. Asking a good question They address a clinically important question There is substantial evidence for effectiveness of new Rx in preclinical models There is evidence that the new Rx is safe and tolerated (phase 1) There is good preliminary evidence of antitumor activity (phase II)

42. Principles…. The primary end point should be a measure of patients benefit ( OS, QOL ) If another primary endpoint is used , it should be shown to be a surrogate for OS or QOL Entry criteria should be broad so that results will apply to the gen population of pts Double blinded to px bias

43. Objectives of phase 3 To assess overall and relative therapeutic value of the new drug efficacy, safety To determine optimal dosage schedule for use in general

44. How do we measure clinical trial outcomes? Each trial has a pre-specified goal or endpoint. The endpoint chosen for a particular trial depends on : phase of the trial type of disease and/or agent under investigation. The endpoints must be clearly defined before the trial begins.

45. End points • Overall survival • Disease-free survival • Progression-free survival • Objective response rate • Time to progression • Symptom control • Quality of life • Tolerability

46. Surrogate end points Ideal OS, QOL When phase 3 trials show large early increases in PFS , and there are very few alternative treatments , ethical considerations may require the new Rx be given to the control arm This may make it difficult to detect an influence on survival . Sunitinib RCC ; Vemuranib – melanoma Will not hold true for breast or ovarian cancer

47. Evaluation of toxicity Therepeutic benefit depends on balance between efficacy and toxicity Chrnic toxicity may become apparent only after the trial is completed

48. What after completion of phase 3 trial Drugs may be licensed if an RCT shows a significant difference in favor of a new Rx ( OS, PFS )

49. NDA A Request to Market the Drug

50. NDA A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied. A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include: Proposed labeling Safety updates Drug abuse information Patent information Any data from studies that may have been conducted outside the United States Institutional review board compliance information Directions for use

51. NDA Types Type 1: New Molecular Entity (NME) Type 2: New Active Ingredient (e.g. new salt) Type 3: New Dosage Form Type 4: New Combination Type 5: New Formulation or New Manufacturer Type 6: New Indication, Same Manufacturer (no longer used) Type 7: Drug Already Marketed, but Without Approved NDA Type 8: Rx to OTC

52. FDA Approval In cases where FDA determines that a drug has been shown to be safe and effective for its intended use, it is then necessary to work with the applicant to develop and refine prescribing information. This is referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how best to use the drug.

53. Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA requires additional studies. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal.

54. FDA Advisory Committees FDA may organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit the public to make comments. These Advisory Committees include a Patient Representative that provides input from the patient perspective.

55. Phase IV (post marketing surveillance) Phase IV trials continue after the drug has been approved Evaluate a wider population of patients treated with a new therapy to test for further side effects and better define tolerance in a wider population explore using different treatment regimens for the drug in a particular cancer (also called therapy optimisation studies), or in specific patient populations. Phase IV studies can continue for many years.

56. Objectives of phase 4 Evaluation in different age groups/ type of patients Comparative benefit risk assessment Benefit cost assessment Quality of life assessment Confirm efficacy and safety profile in large population during practice Detect rare side effects Evaluation of overdosage Identification of new indications Dose refinement : new formulations, dosage, durations

57. Till now …. Traditional trial designs now changing concepts and designs

58. Phase 0 ..... Developing a new anticancer drug is an expensive, longterm , high-risk proposition with a failure rate of more than 90%. More than half of new drugs in oncology fail during later stages of clinical development, adding to the cost and time it takes to make effective therapies available to patients. To accelerate the discovery and development of new molecular entities, the FDA released an exploratory Investigational New Drug (IND) guidance in 2006 to support clinical evaluation before the dose escalation, safety, and tolerance studies associated with a traditional IND. Objectives and endpoints of phase 0 (or pre-phase I) studies : evaluating modulation of a presumed drug target in humans; optimizing target assay methodology using human samples; providing pharmacokinetic (PK) data; assessing PK/ pharmacodynamic (PD) relationships; and selecting the most promising lead agent from several chemical entities or

59. phase 0 ( microdosing )…. These are very early studies of PK and PD properties of the potential drug in humans Benefit : can help accelerate drug development without compromising clinical safety Helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data

60. In 2007, the first phase 0 clinical trial of a therapeutic agent in oncology was conducted to evaluate ABT-888 , an inhibitor of the DNA repair enzyme poly-ADP ribose polymerase in patients with advanced malignancies.

61. Phase 0 ( microdosing ) types Studies designed to obtain PK data but use drug doses that do not have pharmacologic effects Study of new drug in microdoses helps derive information in humans before undertaking phase 1 studies Microdose : less than 1/100 th of the dose of a test drug calculated to produce pharmacological effect with a max dose ≤100µg Pharmaceutical companies perform Phase 0 studies to decide which of their drug candidates has the best pharmacokinetic parameters in humans. Objective : to obtain preliminary PK data 1. PK

62. Phase I trials under a traditional IND require substantial preclinical toxicology studies and full-scale good manufacturing practice production of the investigational agent before clinical administration. Phase 0 imaging/biodistribution trials introduce subpharmacologic doses of the new agent to patients or healthy volunteers . Results from these trials may be sufficient to establish proof of principle , and no further dose escalation phase I studies may be needed . These imaging studies can be used as correlative studies in subsequent phase II/III trials of therapeutic agents. 2 . PD

63. Targeted agents and immunotherapy ....

64. Precision medicine trials ... For the newer targeted agents and biologics Approach for disease Rx considers : Individual variation in genes/ environment / lifestyle of each person Allows researchers to more accurately predict Rx and Px strategies for a particular disease that can work best for a special group of people.

65. Umbrella trial These have many many different Rx arms within one trial Patients are assigned to a particular Rx arm based on their type of cancer and specific molecular makeup of their cancer.

66. Basket trial: master protocol where each sub trial enrolls multiple tumor types ( “the basket’’)

67. Drug regulation

68. Drug regulators Australia: Therapeutics Goods Administration (TGA) Canada: Therapeutic Products Directorate (TPD) of Health Canada European Union and EEA-EFTA States: European Medicines Agency (EMEA) Japan: Ministry of Health Labour and Welfare (MHLW) Switzerland: Swissmedic – Schweizerisches Heilmittel institute United States: Food and Drug Administration (FDA )

69. How long does it take to approve a drug Timelines for the review of applications are laid down in the legislation governing pharmaceuticals in different countries. US the FDA must make a decision within 12 months on a regular application and within 6 months in the case of applications designated for priority review. In Europe the CHMP must give its opinion within 210 days – this is followed by a decision-making phase that can take up to three months.

70. Challenge … How can drug development programs for low prevalence diseases be expected to meet the same standards as for common diseases?

71. Approval Pathways Traditional Accelerated

72. Approval Pathways Both pathways must meet the statutory standards: substantial evidence of effectiveness based on adequate and well-controlled clinical study( ies ) and demonstration that the benefits exceed the risks under the labeled conditions Accelerated approval expedites new drug availability for serious unmet need by relying on a more readily measured surrogate or intermediate clinical endpoint Consider accelerated approval when a lengthy trial would be needed to measure intended clinical benefit of a drug for a serious unmet need

73. Approval Pathway: The Importance of the Endpoint Accelerated Approval Pathway depends on strength of evidence about ability of the endpoint to predict effect on irreversible morbidity or mortality ( clinical benefit) A surrogate or intermediate clinical endpoint is a marker thought to predict clinical benefit, not itself a measure of benefit: lab value, radiographic image, physical sign, etc.

74. Speeding the availability of drugs that treat serious diseases are in everyone's interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. The Food and Drug Administration has developed four distinct and successful approaches to making such drugs available as rapidly as possible: Fast Track ( FDAMA 1997/FDASIA 2012) Priority Review ( PDUFA 1992) Breakthrough Therapy ( FD&C ACT/FDASIA 2012) Accelerated Approval ( 21 CFR314 subpart H, 601 subpart E/ FDASIA 2012)

75. FAST TRACK D esigned to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Determining whether a condition is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one. AIDS, Alzheimer’s, heart failure and cancer are obvious examples of serious conditions. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially better than available therapy. Any drug being developed to treat or prevent a condition with no current therapy obviously is directed at an unmet need. If there are available therapies, a fast track drug must show some advantage over available therapy, such as: Showing superior effectiveness, effect on serious outcomes or improved effect on serious outcomes Avoiding serious side effects of an available therapy Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment Ability to address emerging or anticipated public health need

76. Process to expedite development and review Frequent interactions with review team Rolling review of a marketing application

77. A drug that receives  Fast Track  designation is eligible for some or all of the following: More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers Eligibility for  Accelerated Approval and Priority Review, if relevant criteria are met Rolling Review , which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA Fast Track  designation must be requested by the drug company. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious condition. Once a drug receives  Fast Track  designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

78. Example : Glucarpidase A carboxypeptidase enzyme indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function

79. Glucarpidase: Design Features Single-arm, open-label, historically-controlled trial in patients Validated pharmacodynamic endpoint in 22 patients: proportion who had rapid and sustained clinically important MTX reduction (to < 1 μ mol /L)

80. Scientific Rationale for Flexible Glucarpidase Design Methotrexate in extensive clinical use since 1948; effects, mechanism of action, toxicity, excretion and metabolism well understood Well established that 1 μ mol /L plasma concentration at 48 hours  severe toxicity not treatable with leucovorin or hemodialysis rescue

81. Glucarpidase Evidence From medical officer review BLA 123327 Drugs@FDA All patients showed large pharmacodynamic effect: ≥ 97% reduction within 15 minutes All patients had > 95% reduction in MTX concentration maintained for up to 8 days Efficacy endpoint success dependent on pre-treatment MTX concentration

82. Tykerb (applicant GSK, APPROVED ON 26/2/2010) USE : overexpressing breast cancer Zolinza : ( merck ; 10/6/2006, ) USE : T cell lymphoma

83. BREAK THROUGH Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). To determine whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the treatment effect, which could include duration of the effect, and the importance of the observed clinical outcome. In general, the preliminary clinical evidence should show a clear advantage over available therapy.

84. For purposes of Breakthrough Therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to findings that suggest an effect on IMM or serious symptoms, including: An effect on an established surrogate endpoint An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard) An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease A significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy A drug that receives Breakthrough Therapy designation is eligible for the following: All Fast Track designation features Intensive guidance on an efficient drug development program, beginning as early as Phase 1 Organizational commitment involving senior managers

85. Breakthrough Therapy designation is requested by the drug company. If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the sponsor consider submitting a request if: (1) after reviewing submitted data and information (including preliminary clinical evidence), the Agency thinks the drug development program may meet the criteria for Breakthrough Therapy designation and (2) the remaining drug development program can benefit from the designation. Ideally, a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings if any of the features of the designation are to be obtained. Because the primary intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible, FDA does not anticipate that Breakthrough Therapy designation requests will be made after the submission of an original BLA or NDA or a supplement. FDA will respond to Breakthrough Therapy designation requests within sixty days of receipt of the request.

86. PRIORITY REVIEW Prior to approval, each drug marketed in the United States must go through a detailed FDA review process. In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times –  Standard Review  and  Priority Review . A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review).

87. A  Priority Review  designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. Significant improvement may be demonstrated by the following examples: evidence of increased effectiveness in treatment, prevention, or diagnosis of condition; elimination or substantial reduction of a treatment-limiting drug reaction; documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or evidence of safety and effectiveness in a new subpopulation. FDA decides on the review designation for every application. However, an applicant may expressly request priority review as described in the Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics. It does not affect the length of the clinical trial period. FDA informs the applicant of a Priority Review designation within 60 days of the receipt of the original BLA, NDA, or efficacy supplement. Designation of a drug as “Priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.

88. e.g ….

89. ACCELERATED APPROVAL When studying a new drug, it can sometimes take many years to learn whether a drug actually provides a real effect on how a patient survives, feels, or functions. A positive therapeutic effect that is clinically meaningful in the context of a given disease is known as “clinical benefit”. It may take an extended period of time to measure a drug’s intended clinical benefit, in 1992 FDA instituted the  Accelerated Approval  regulations. These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster. In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint. A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).

90. The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act. Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may 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 waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually predicts that patients will live longer. These studies are known as phase 4 confirmatory trials. Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement. Approval of a drug may be withdrawn or the labeled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).

91. What are the risks associated with accelerated approval? Surrogate endpoints are used because they are assumed to predict clinical benefit. Should that not be the case, patients are exposed to drugs that ultimately do not provide a clinical benefit. Shorter, fewer and smaller clinical trials result in less information about rare or delayed adverse events

92. e.g Gemtuzumab was approved under an  accelerated-approval process  by the FDA in 2000, for use in patients over the age of 60 with relapsed  acute myelogenous leukemia  (AML); or those who are not considered candidates for standard chemotherapy. The accelerated approval was based on the  surrogate endpoint  of  response rate . It was the first  antibody-drug conjugate  to be approved.

93. Can accelerated approval be withdrawn? Yes, the FDA can withdraw accelerated approval for the following reasons: Clinical benefit cannot be shown in a trial The drug is shown to be not effective or safe based on other evidence Post-approval trials are not conducted with the necessary degree of due diligence by the applicant The applying company disseminates false or misleading information about the product.

94. Within the first year after approval, the FDA required a black box warning be added to gemtuzumab packaging. The drug was noted to increase the risk of  veno -occlusive disease  in the absence of  bone marrow transplantation . Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of  biologic agents . A randomized Phase III comparative controlled trial (SWOG S0106) was initiated in 2004, by Wyeth in accordance with the  FDA accelerated-approval process . The study was stopped on August 20, 2009 prior to completion due to worrisome outcomes. Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01). In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA. In 2017, Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML.  In September 2017, gemtuzumab ozogamicin was approved again for use in the United States and in the European Union.

95. Latest accelerated approvals