Conducting Clinical Trials for OTC Products

1. Conducting Clinical Trials for OTC Products Dr Steve Mann The Mann Consultancy

2. Self Medication “A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals.” Sir William Osler (1849 - 1919)

3. OTC products: • OTCs – background & climate • Regulatory issues & switching • Clinical Development for OTCs • Case study #1 famotidine • The modern switch • Case study #2 simvastatin

4. OTC products: • OTCs – background & climate • Regulatory issues & switching • Clinical Development for OTCs • Case study #1 famotidine • The modern switch • Case study #2 simvastatin

5. Categories of Medicines • POM (Prescription only medicine) • Meet criteria of directives (2001/83/EC, 2004/27/EC) and MHRA Guidance note 11 (Apr 2002) • Require medical monitoring, health risks etc. • Cannot be promoted to public • P (Pharmacy) • Sold only from registered pharmacies under supervision of a pharmacist • No self-selection • Restrictions on use by labelling • GSL (General Sales List) • Can be sold from any lockable shop - superstores, drug stores, health food shops, garages etc • Self-selection allowed

6. UK POM to P switches 1983 - 2005

7. The growth of OTC pharmaceuticalsMajor switches • 2001 EHC • 2004 Simvastatin; omeprazole • 2005 Chloramphenicol eye drops • Trimethoprim (W) • 2006 Sumatriptan • 2007 Tranexamic acid • 2008 AzithromycinNaproxen Diclofenac • Nitrofurantoin (W) • 2009 Orlistat (EU) Pantoprazole (EU) • Tamsulosin (UK) • 2011 Rabeprazole (UK) (C) Ibuprofen 1% (C) • 1983 Ibuprofen; loperamide • 1987 Topical hydrocortisone • 1989 Mebendazole • 1991 Nicotine gum • 1992 Vaginal antifungals • 1993 Acyclovir • 1994 Beclomethasone nasal spray H2 antagonists Sodium cromoglycate Minoxidil • 1995 Fluconazole • 1997 Mebeverine Topical Piroxicam • 1998 Domperidone • 2000 Terbinafine W – Withdrawn C - Under consultation

8. POM-to-P vs P-to-GSL2002 – 2004the ‘switch of switches’ Source: RPSGB

9. Government Health care cost savings Primary care restructuring ‘public health’ Industry Patent Loss OTC opportunity Patient/Consumer Greater health knowledge Move towards self-care Pharmacy Greater professional role ‘P’ category unique to pharmacy Increased role in screening etc. ‘Switch’ productsImpetus

10. OTC products: • OTCs – background & climate • Regulatory issues & switching • Clinical Development for OTCs • Case study #1 famotidine • The modern switch • Case study #2 simvastatin

11. Directive 2001/83/EC Directive 2004/27/EC

12. Switch Application • Rationale for the Reclassification • Specific OTC Requirements (label changes) • Safety Profile – Pharmacy Risk Management Plan • Patient Information • Training and Education • Expert report • Assessment of POM (Rx) criteria • Efficacy summary – relevant to ‘P’ use

13. The Criteria 1.Likely to present a danger either directly or indirectly, even when used correctly, if utilised without medical supervision Direct danger Indirect danger Self-diagnosis Risk of misuse 2.Frequently and to a very wide extent used incorrectly, and as a result are likely to present a direct or indirect danger to human health

14. The Criteria 3. Contain substances or preparations thereof the activity and/or side-effects of which require further investigation Limited experience New strength, dose, route of administration, age group or indication 4.Are normally prescribed by a doctor or dentist to be administered parenterally

15. New switches - Data exclusivity Article 54 of Directive 2004/27/EC inserted a new Article 74a which allows for one year’s data protection during the change of classification of a medicinal product. “Where a change of classification of a medicinal product has been authorised on the basis of significant pre-clinical tests or clinical trials, the competent authority shall not refer to the results of those tests or trials when examining an application by another applicant for or holder of marketing authorisation for a change of classification of the same substance for one year after the initial change was authorised”

16. POM vs OTCIbuprofen

17. POM vs OTCOmeprazole

18. Tablets Chewable tablets Caplets Capsules Pastille/lozenges Liquids Effervescent tabs Hot/cold granules Suppositories Patches Sprays Creams Lotions Gels OTC product forms • Greater importance of product form in consumer pharma

19. OTC products: • OTCs – background & climate • Regulatory issues & switching • Clinical Development for OTCs • Case study #1 famotidine • The modern switch • Case study #2 simvastatin

20. OTC Clinical Research • Many aspects are the same as for NCE studies: • GCP, QA, QC and audit • design concepts, statistical considerations • The differences relate to: • OTC indications and parameters • study subjects • study setting • aims and outcomes • Case Study : OTC H2 receptor antagonist development • The considerations that present problems in OTC trials are also what makes them interesting

21. Types of OTC trials • Studies to support a POM to P switch • often new indications • sometimes new study population or mode of delivery • often new dosage or regimen • Studies to support market development • broaden indications • new marketing claims • comparative studies • Studies to test understanding and compliance • real life ‘use’ studies • To support line extensions • Bioequivalence studies

22. The importance of marketing and consumer research • OTC sector is all about the consumer: • what terms does the consumer use and understand? • what is important to the consumer in treating the condition? (e.g. speed, duration) • what needs are currently unsatisfied in the market? • Clinical studies are driven by consumer needs • studied indication must translate to consumer terms • demonstrated benefits must mean something • sometimes entirely new markets are created by studies

23. OTC indications • Must be recognised by potential consumers • largely symptoms (e.g. heartburn rather than gastro-oesophageal reflux disease) • hard endpoints, if any, are usually secondary • High placebo responses • studies are large and therefore expensive • rating scales have to be readily understood • questionnaires often completed at home are standard • missing data and corrections • timing mistakes

24. OTC conditions - special considerations • Symptoms are often intermittent • select a frequently suffering population • run-in periods to confirm suffering • often have significant drop-outs due to non-suffering • expense and time • Models to provoke symptoms • e.g. provocative meals for heartburn • problems to standardise • allergen provocation in ‘hay-fever’

25. OTC Study Subjects • Results in study subjects must translate to the self-medicating population: symptoms, severity, demographics • May not be consulting doctors: • may need to advertise • recruit patients with another primary reason for consulting • If they are consulting: • are they more severe? (may be acceptable) • are they OTC treatment failures? (may be acceptable) • are they exempt from Rx charges but ‘OTC’?

26. OTC Study Setting • G.P. recruiting is most common • SMO or CRO panels used often • Advertising to attend at ‘consumer research units’ • trial expertise • siting close to target population • Pharmacy based studies are problematic • suitability of pharmacies for consultation • pharmacists cannot be principal investigators • expertise, willingness and ability to follow - up • Future studies under PGD’s may be necessary for new switches e.g. Emergency Hormonal Contraception

27. OTC Study Setting - at home studies • At home studies are difficult… • missing data, timing problems • need for flexible monitoring support • but powerful… • closest to the real-life OTC setting • may be especially important for some parameters e.g. quality of sleep • allows the study of multiple episodes ( vs. for example, one in-clinic provoked episode)

28. H2 AntagonistsRx History • History • 1976 Cimetidine (Tagamet, SB) • 1981 Ranitidine (Zantac, Glaxo) • 1987 Famotidine (Pepcid, MSD) • 1987 Nizatidine (Axid, Lilly) • Indications • Peptic ulcer (DU,GU) healing & maintenance • Gastro-oesophageal reflux disease • Chronic episodic dyspepsia (T & Z) • Other e.g. Zollinger-Ellison • Safety • Many millions of patients treated worldwide • Safety profile of class well accepted

29. H2 antagonistsPrescription usage 1976 - 1996 1976 ‘Ulcer drugs’ 1996 All-purpose‘acid controllers’ Other Ulcer Oesophagitis Dyspepsia Hiatus hernia

30. Case Study #1: OTC H2 blockers • New indications - symptom based • heartburn most readily recognised • common but intermittent • v. high placebo response (e.g. the effect of water) • New dosage • low doses (half lowest single Rx dose) • re-establish pharmacodynamics vs rest of class • New study models • existing treatments for heartburn had a low evidence base and a different mode of action

31. pH measurement end meal drug 6.30 7.30 7.30 pm Time am Pepcid AC acid control • Nocturnal pH study • famotidine 10mg • placebo

32. Pepcid ACNocturnal pH study n = 25

33. Pepcid AC: protection against interference with sleep after an evening meal • Double blind placebo controlled study • 300 patients with heartburn (3x per week) and symptoms at night, able to identify problem foods • Study medication taken 1 hour before a meal at 8pm • Meal choice : Curry, or Chili, or Beef stew with dumplings. Stratified for alcohol or orange juice • Patients had to retire to bed at 11pm • Symptoms assessed after meal, at bedtime, during nocturnal awakenings and globally the following morning • Use of rescue medication (Maalox) recorded

34. Pepcid ACOvernight heartburn study • ‘Provocative’ test meal • Overnight symptom assessment • Famotidine 10mg vs placebo • Rescue antacid symptom assessment end drug meal 7.00 8.00 pm Time am

35. Pepcid ACOvernight heartburn study

36. Pepcid ACOvernight heartburn study

37. Pepcid ACOvernight heartburn study

38. Pepcid ACOvernight heartburn study

39. Pepcid ACOvernight heartburn study Conclusions • Patients taking Pepcid AC had: • less post-meal heartburn • less difficulty getting to sleep • fewer awakenings • less heartburn when they awoke • used 3x less antacid • Pepcid AC can prevent heartburn and subsequent sleep disruption

40. Summary • H2 receptor antagonists in low doses (famotidine 10mg and ranitidine 75 mg) provide a pulse of acid suppression which lasts 9-12 hours • Clinical studies show that this can translate into control of symptoms for prolonged periods after a single dose (e.g. during the night) • Prevention of heartburn studies created an entirely new market estimated to account for 30-40% of usage in the US

41. OTC products: • OTCs – background & climate • Regulatory issues & switching • Clinical Development for OTCs • Case study #1 famotidine • The modern switch • Case study #2 simvastatin

42. Simvastatin OTC • Block an enzyme (HMG CoA Reductase) involved in the synthesis of cholesterol • Substantially reduce LDL-C, and increase HDL-C • Major endpoint studies show statins reduce risk of CHD events by around one-third over 3 to 5 years • Excellent safety profile • Statins raised as OTC candidates from late ’90s

43. Statin Prescriptions, England Source: British Heart Foundation DOH Prescription Statistics (2003)

44. Simple ‘pharmacy-friendly’ model High uptake Good public health benefit Pragmatic Model High Risk Treatment Model Pharmacy Model Mandatory C-tests Treat-to-target & Dose titration LFTs Complex ‘medical’ model Low uptake Low public health benefit

45. Development of the OTC model • Expert consensus panel – Jan 03 • Cardiologists, lipidologists, MHRA • Recommended simplified pharmacy model • OTC switch submission – Aug 03 • Proposal for model and labelling • McNeil attendance at CSM workshop – Sept 03 • Model largely accepted unchanged • Fine tuning • Pharmacy pilot study – Dec 03 – Jan 04 • 160 pharmacy customers in 12 pharmacies • Results fine-tuned protocol

46. Who is it for? • Individuals who are at moderate risk i.e. have a 1 in 10 to 1 in 7 chance of a heart attack over the next 10 years Men 45+ / Women 55-70 Men aged 55-70 OR + • One or more of the following risk factors: • Family history of early CHD • Smoker • Overweight • South Asian ethnicity Eligible for Simvastatin OTCand advice from the Healthy Heart Programme

47. Pharmacy pilot study • 12 pharmacies • 160 customers • Completion of questionnaire with pharmacist use of guide • Assignment to: • Advice only • Statin suitable • Not suitable – GP refer • Pharmacist feedback on protocol utility

48. Pharmacy materials developmentCollaborative working • March to June 2004 • Finalisation of labelling • Development of protocol materials into final form

49. Protocol operates via questionnaire & guide

50. OTC Clinical Trials - Conclusions • Although OTC medicines are generally well characterised with regard to safety, the new setting may demand extensive clinical development • New doses, new indications, new competitors, all afford opportunities for creativity • Although there are significant problems in conducting OTC studies the rewards in creating new markets can be substantial • As the withdrawal of simvastatin OTC shows – not even innovative switches are guaranteed commercial success.