Life Cycle Risk Management. Barton Cobert, MD, FACP, FACG BLCMD Associates LLC December 2013

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1 Life Cycle Risk Management Barton Cobert, MD, FACP, FACG BLCMD Associates LLC December

2 Premarketing vs Postmarketing Risk Assessment The concepts of risk assessment and minimization are better developed in the postmarketing setting compared to the premarketing area. Some principles do exist.

3 FDA Principles Guidance for Industry Premarketing Risk Assessment March Risk management is an iterative process designed to optimize the benefitrisk balance for regulated products. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product. Risk assessment occurs throughout a product s lifecycle, from the early identification of a potential product, through the premarketing development process, and after approval during marketing. Premarketing risk assessment represents the first step in this process, and this guidance focuses on risk assessment prior to marketing. To maximize the information gained from clinical trials, FDA recommends that from the outset of development, sponsors pay careful attention to the overall design of the safety evaluation. Potential problems that may be suspected because of preclinical data or because of effects of related drugs should be targeted for evaluation. And, because it is impossible to predict every important risk, as experience accrues, sponsors should refine or modify their safety evaluations. 3

4 Size of the Premarketing Safety Database Even large clinical development programs cannot reasonably be expected to identify all risks associated with a product. Some risks will become apparent only after approval, when the product is used in tens of thousands or even millions of patients in the general population. The appropriate size of a safety database supporting a new product will depend on: Novelty - whether it is a new treatment or is similar to older ones The availability of alternative therapies and their safety The intended population and condition being treated The intended duration of use For products intended for long-term treatment (>6 months) of nonlife-threatening conditions, the ICH and FDA recommend 1500 subjects exposed in total 300 to 600 exposed for 6 months 100 exposed for 1 year Drug Information Association

5 When Larger Databases Are Needed - 1 There is concern that the drug may cause late developing AEs or AEs that increase in severity or frequency over time. The concern could arise from animal studies, other similar class agents, PK or PD properties associated with AEs. There is a need to quantitate the occurrence rate of an expected specific low-frequency AE. A larger database would help make risk-benefit decisions in situations when the benefit from the product is small, will be experienced by only a fraction of the treated patients or is of uncertain magnitude.

6 When Larger Databases Are Needed - 2 Concern exists that a product may add to an already significant background rate of morbidity or mortality. The proposed treatment is for a healthy population (e.g., a vaccine) An effective alternative to the investigational product is already available and has been shown to be safe.

7 Long Term Controlled Safety Studies It is common in many clinical programs for much of subject exposure data and almost all long-term data to come from single-arm or uncontrolled studies. It may be preferable in some circumstances to develop controlled, long-term safety data. Generally, SAEs that rarely occur spontaneously (e.g. aplastic anemia) would be considered significant and interpretable whenever they are clearly documented and there is no likely alternative explanation. As a result, the events can usually be interpreted and regarded as a signal whether or not there is a control group. On the other hand, control groups are needed to detect increases in rates of events that are relatively common in the treated population (e.g., sudden death in patients with ischemic cardiac disease) or when an AE could be considered part of the disease being treated (e.g., asthma exacerbations occurring with inhalation treatments for asthma). In these cases, safety studies designed to test specific safety hypotheses may be appropriate.

8 Other Considerations A diverse premarketing safety database should include, where possible, a population sufficiently diverse to adequately represent the expected target population, particularly in phase 3 studies. Usually only one dose, or perhaps a few doses, are studied during drug development beyond phase 2. This limits the ability to provide definitive data on exposureresponse or adequate data for definitive phase 3 dose selection. Phase 3 trials could, where feasible, examine a range of doses when phase 2 studies do not establish a single most appropriate dose. 8

9 Unanticipated Interactions Risk assessment programs should examine a number of interactions during controlled safety and effectiveness trials and, where appropriate, in specific, targeted safety trials. Drug-drug interactions Studies should target a limited number of specific drugs, such as likely concomitant medications based, for example, on known or expected patterns of use, indications sought, or populations that are likely users of the drug. Product-demographic relationships By using a diverse study population (including gender, age, and race) some assessments of safety concerns in demographic population subsets of the intended population may be found. Product-disease interactions By using sufficient variability in disease state and concomitant diseases such interactions may be found. Product-dietary supplement interactions For commonly used supplements that are likely to be co-administered or for which reasonable concerns exist (e.g., examination of the interactions between a new drug for the treatment of depression and St. John s Wort). Such relationships may be found by doing pharmacokinetic (PK) assessments (e.g., universal steady state sampling or population PK analyses) in some or all of the later phase clinical trials, including any specific safety trials. 9

10 Developing Comparative Safety Data Most safety data is derived from placebo-controlled trials and single-arm safety studies, with little or no active comparator safety data. Safety data from controlled trials active control trials (sometimes with placebo also) may be desirable when: The background rate of AEs is high. There is a well-established treatment with an effect on survival or irreversible morbidity. Placebo controls may be unethical in such cases and a single-arm trial would generally be uninformative. The sponsor hopes to claim superiority for safety or effectiveness. 10

11 Other Possible Risk Assessments Examination of whether a lower or less frequent maintenance dose would be appropriate. Certain kinds of AEs are not detected or readily reported by patients without special tests or questionnaires. In pediatric patients, special safety issues should be considered including effects on growth and neurocognitive development, required immunizations etc.). Collect and store blood samples or other fluids/tissues collected during clinical trials in phase 3 studies for possible assessments at a later time. A Large Simple Safety Study (LSSS) - a randomized clinical study designed to assess limited, specific outcomes in a large number of patients could be done. Often done as a phase 4 commitment.

12 Addressing Safety Aspects During Studies that should be done before marketing: For small molecules: Product Development Drug-related QTc prolongation Drug-related liver toxicity Drug-related nephrotoxicity Drug-related bone marrow toxicity Drug-drug interactions Polymorphic metabolism For biologicals: assessments of immunogenicity, both the incidence and consequences of neutralizing antibody formation and the potential for adverse events related to binding antibody formation. For gene-based biological products: transfection of nontarget cells and transmissibility of infection to close contacts, and the genetic stability of products intended for long-persistence transfections constitute important safety issues. For cell-based products: assessments of AEs related to distribution, migration, and growth beyond the initial intended administration are important, as are AEs related to cell survival and demise. Such AEs may not appear for a long time after product administration. 12

13 Risk Assessment (1) Health Authority approval of a product means that it is safe and effective for the approved indications under the labeled conditions of use (route, dosage, timing) in the approved patient population Safe means that the beneficial actions outweigh harmful or undesirable side effects that might occur Safe does not mean the absence of risk, often forgotten when the phrase this drug is safe and effective is used Approval of a novel product is based on preliminary evidence of safety Janet Woodcock (FDA) The implication of safe and effective is that it is always effective no matter when or how used and is without risk - this is not the case 13

14 Risk Management Plans The usual Risk Management Plan for a product in the US is the approved labeling, viz, the US Package Insert If additional measures are needed to manage a risk, a Risk Evaluation and Mitigation Strategy (REMS) will be required The vast majority of products do not require a REMS In the EEA, an EU Risk Management Plan (RMP) is a required part of the marketing application for all new products using the Centralised Authorisation Procedure The EU RMP is in addition to the product labeling (Summary of Product Characteristics) If additional measures are needed, a Risk Minimisation Plan will be required 14

15 Risk Management in the EU EMEA (now EMA) published a Risk Management Strategy in 2002 The Heads of Medicines Agencies (HMA) published the European Risk Management Strategy in 2002/2003 Goal to protect the public health Use National Competent Authorities (NCAs) resources and expertise EMEA serves in a coordinating role Avoid duplication of effort EU issued Guideline on Risk Management Systems for Medicinal Products for Human Use in 2005 (EMEA/CHMP/96268/2005) Template for the EU Risk Management Plan template issued in 2007; re-issued in 2013 for PBRER format 15

16 Situations Requiring an EU RMP (1) An EU-RMP may need to be submitted, upon request, at any time of a product s life-cycle With a new marketing authorization application for: Any product containing a new active substance A similar biological medicinal product A generic/hybrid medicinal product where a safety concern has been identified With an application for a pediatric use authorization With an application involving a significant change in a marketing authorization, e.g., new dosage form, new route of administration, new manufacturing process of a biotechnology product, new indication, unless the CA agrees in advance that an RMP is not needed 16

17 Situations Requiring an EU RMP (2) On request from a CA On the initiative of the MAH Discussions on controversial topics or those which the MAH feels an RMP may be needed should be discussed with EMA early in the product development program See GVP Module V (Risk Management Systems) 17

18 REMS (1) A Risk Evaluation and Mitigation Strategy (REMS) is an extension of the RiskMAP idea and only applies in the US Concept is similar to the EU Risk Minimization Plan FDA gained authority to require REMS under legislation (FDAAA) enacted in 2007 REMS may be required on approval of the drug to ensure that benefits outweigh risks or at any time after approval if new information raises a safety concern A REMS is a strategy to handle a risk (identified or potential) associated with a product It allows patients to use the product but under certain conditions and surveillance 18

19 A REMS may include: A Medication Guide (MedGuide or patient package insert) A communication to HCPs REMS (2) Elements to Assure Safe Use (ETASU), e.g., Special training or certification for HCPs who prescribe or dispense Dispensing only in certain settings (e.g., in a hospital) or with evidence of safe use conditions (e.g., lab test) Monitoring or registration of each patient using the medicine 19

20 REMS (3) If Elements to Assure Safe Use (ETASUs) are included, there must be an implementation system A REMS must always include a timetable and metrics for assessment of its effectiveness At a minimum at 1.5 years, 3 years, and in the 7th year Generics are subject to similar requirements Formal submission and approval process by FDA Approved REMS posted on the FDA website: orpatientsandproviders/ucm htm 20

21 Assess Need for Minimization (1) MAH/Applicant should evaluate the need for risk minimization, based on the Safety Specification (RMP Section 1) For each safety concern, the MAH/Applicant should assess whether minimization activities are needed Some can be addressed by the actions proposed in the Pharmacovigilance Plan (RMP Section 2) Others may warrant additional activities due to the risk s particular nature or seriousness May be limited to ensuring suitable warnings are included in the SmPC or special packaging, etc. If no additional minimization activities are needed, must be justified 21

22 Assess Need for Minimization (2) Focus is on evaluation of identified risks and potential risks The MAH/Applicant must also address the potential for medication errors and state how this has been reduced Examples: Final formulation or presentation, product information, packaging, etc. Reconsider the need for new risk minimization activities whenever the Safety Specification (RMP Section 1) is updated with new safety information Include the possibilities that a risk minimization activity should be modified or that it is no longer necessary for safe and effective use 22

23 Risk Minimization Activities (Tools) Implementation of a risk minimization activity requires a process or system to support the activity The activity might require Restricted access Educational programs Control of prescription Named patient registries In many cases the activity may depend on national legislation Advanced therapies will usually require continuing follow-up, i.e., monitoring of the patient, and possibly offspring, for life 23

24 Assess Risk Minimization Activities Direct, periodic measurement of effectiveness of risk minimization activities should be done Look at actual activities, e.g., survey patients for actual reading of leaflets and comprehension of information Periodic market research on awareness of risks/precautions Retrospective analysis of large prescription database to detect misuse Measure adherence to hepatic enzyme monitoring on a 6-monthly basis until adequate behavior Establish specific timing and milestones Submit periodic updates to EMA/NCAs Include summary in PSUR/PBRER 24