Clinical trials in haemophilia Dr. Paul Giangrande Oxford Haemophilia and Thrombosis Centre & Nuffield Department of Clinical Medicine University of Oxford paul.giangrande@ndm.ox.ac.uk
Why do clinical trials? All medical drugs and devices have to be licensed by regulatory authorities e.g: European Medicines Agency (EMA) Food and Drug Administration (FDA: US) Therapeutic Goods Adminstration (TGA: Australia) Pharmaceuticals and Medical Devices Agency (PMDA: Japan) Clinical trials are required to determine efficacy, safety and appropriate dosage
Structure of clinical trials: It can take 10-15 years for a drug to become available after discovery Factor VIII gene sequenced and cloned in 1984; recombinant FVIII licenced in 1994 Clinical trial programme for a drug typically takes 3-5 years Preclinical: experiments in animals and healthy volunteers to establish basic facts Phase 1:study in small group of subjects to evaluate safety and get an idea of appropriate dosage
Structure of clinical trials: Phase 2: new agent is given to a larger group of patients to see if it is effective and to further evaluate safety Phase 3: major part of the study, involving large number of patients. Study aims to confirm effectiveness, perhaps compare it to an existing treatment and collect more information about safety and any sideeffects
Clinical trials: Protocol is the precise study plan for executing the clinical trial and is the pivotal reference document throughout the study Describes the scientific rational, objectives, design, methodology and organization of the planned trial Ensures that all centres participating in a clinical trial work in exactly the same way Content must be approved by Ethics Committee Any protocol deviations during clinical trial must be documented and explained
Structure of clinical trials: In the case of haemophilia, evidence of efficacy is required in both children and adults as well as in the setting of surgery Incidence of inhibitor development is also typically a key safety end point Post-marketing surveillance: collection of data regarding safety continues well beyond licensure (e.g. EUHASS)
Structure of clinical trials: Unfortunately, there is no harmonisation of regulatory process FDA and EMA can request different things in trial evaluation process (e.g. number of patients, duration of treatment) New EMA Clinical Trial Guidelines document likely to delay approval in Europe of new agents for haemophilia by up to two years compared to USA
Clinical trials: Ethical committee approval needed for all studies Signed informed consent mandatory No financial incentive for patients is permitted (only reimbursement of expenses) All staff involved in staff must be appropriately trained and hold Good Clinical Practice (GCP) certificate Studies overseen by independent Data Safety Monitoring Board which has the power to stop a study if concerns arise
Design of clinical trials: Multicentre: study conducted in multiple hospitals or countries. This is the usual situation in studies relating to haemophilia. Each hospital has a local Principal Investigator (PI) who is responsible for conduct of the study in that site Placebo-controlled trials: compare trial drug with dummy to see if any effect is real. Such studies not common in typical haemophilia trials.
Design of clinical trials: Randomized trials: each study subject is randomly assigned to receive one of two (or more) treatments Blind studies: subjects involved in the study do not know which study treatment they receive. In the case of double-blind studies, the researchers also do not know which treatment is being given to the patient. This is to prevent bias in interpreting results.
Interpretation of results: Rigorous statistical analysis is applied to study results to determine overall statistical significance Significance in this context is estimate of the probability that the results of a study could have arisen randomly by chance For example, p = <0.0001 means that the chance of the results in a particular study occurring purely by chance is less than 1/1000
Interpretation of results: Number of patients enrolled in a study is therefore a critical factor in obtaining meaningful results ( statistical power ) This is a problem in studies of haemophilia, as number of available patients will be far lower than in studies of diabetes, high blood pressure, heart attack, stroke etc.
Approval process: Regulatory agencies typically need 1-2 years to review all data for new products before granting approval Submissions often run to more than 100,000 pages of detailed documentation Regulators have sweeping powers: audit any clinical centre involved in the clinical trial; question investigators; review all source data; demand information about any financial payments from pharmaceutical companies
Obstacles to clinical trials: hospital & site concerns (1) Staff shortages and lack of time to take on studies, on top of demands of normal clinical commitments Hospital middle/lower management often not at all supportive of clinical trial work Unwillingness of centres to take on huge administrative burden associated with trial for just 1 or 2 potential patients Ethics committee applications always more stringent for paediatric studies so even more more paperwork Especially if unlikely to result in publications or presentations for local staff
Obstacles to clinical trials: hospital & site concerns (2) Strong preference for novel products versus biosimilars Heightened concerns about inhibitor development Issue of indemnity for hospital (cost of bypassing agents and immune tolerance) PUP studies are particularly problematic: Very small number of patients. Just 35 new cases of severe haemophilia A and 6 with haemophilia B recorded in last annual UKHCDO report Reluctance to approach parents of new haemophilic children who already have a lot to take in and learn about in a short period of time
EMA statement on conduct of Previously Untreated Patients (PUP) studies in haemophilia:
PUP study design: EMA places much greater emphasis on PUP studies than FDA 50 PUPs for at least 50 exposure days for the PUP indication Can be initiated when data from paediatric PTPs are available 50 EDs in 20 PTPs < 12 y, min. 10 PTPs < 6 y PK in 26 PTPs 0-12 y completed Completion of PUP study not required for initial MAA Has to be initiated prior to MAA Is a part of EMA Paediatric Investigation Plan (PIP) Post-approval additional 50 PUPs needed: all 100 PUPs followed up to 100 exposure days post-approval May prove difficult with new long-acting products
Obstacles to clinical trials: patient & family concerns Study fatigue : same patients get asked to participate in trials on a regular basis Requirement for patient and/or parents to take time off from work or school for clinic visits (especially for pharmacokinetic studies) Detailed recording of bleeds necessary Practical issues relating to venepuncture: can cause a lot of stress in children and their parents Concerns about inhibitor development Strong preference for novel products versus biosimilars
Obstacles to clinical trials: sponsor concerns Lack of harmonisation of licensing requirements around the world (EMA, FDA, TGA etc) Many competing studies for a limited number of patients Difficulty in identifying treatment centres likely to be able to contribute patients Some clinicians are over-optimistic regarding recruitment numbers from their centres Rising cost and bureaucracy facing companies hoping to conduct trials in certain countries: Credibility of results among medical community is related to authorship of papers and sites where study was conducted
How can we improve recruitment? Healthcare professional strategies Add in scientifically appealing component to study if possible Assistance with paperwork for ethics committee Offer additional funding for temporary research staff Easy data capture system Letters of appreciation to hospital management, highlighting results of studies performed Widen authorship of papers and invitations to present data
How can we improve recruitment? Patient strategies Advertisement of clinical studies through patient organisation newsletters, meetings etc. Lump-sum payments to family for participation in studies Other incentives possible e.g funding to attend WFH Congress Avoid significant wash out periods Minimise number of visits and blood tests Guarantee of continued treatment after study until licenced Thank you letter to patients and families after study with explanation of principal findings
How can we improve recruitment? Sponsor strategies National databases can help identify centres most likely to be able to contribute Some countries have centralized recruitment systems, inviting centres to bid to participate in studies Cast the net for recruitment wider (globally) Ethnic mix of patients recruited may influence overall incidence of inhibitors Offer training and much closer support than usual to treatment centres new to clinical trials Reduce/eliminate unnecessary tests/procedures ( need to have vs. nice to have principle) Allow for flexibility in protocols (e.g. visit re-scheduling)
Principal conclusions: It typically takes 10-15 to get a new drug out of a research lab. into a pharmacy Harmonisation of regulatory approval process around the world is highly desirable More could be done to make haemophilia community more aware of studies Payment to study participants could facilitate recruitment PUP studies are particularly challenging Monitoring safety ( pharmacovigilance ) of drugs extends well beyond licensure