Comparative effectiveness of medicines and use of head-to-head comparative trials

1、Chapter 8.4: Comparative Effectiveness of Medicines and Use of Head-to-Head Comparative TrialsPriority Medicines for Europe and the WorldA Public Health Approach to InnovationBackground Paper Comparative Effectiveness of Medicines and Use of Head-to-Head Comparative TrialsBy Warren Kaplan, Ph.D., JD

2、, MPH7 October 2004Table of ContentsExecutive Summary31.Introduction41.1Comparative Effectiveness41.2Cost-Effectiveness52.Experiences with Comparative Effectiveness and Cost-Effectiveness62.1EMEA62.2National Institute for Clinical Excellence62.3Australia62.4United States72.4.1Medicare Program72.4.2P

3、rescription Drug Comparative Effectiveness Act of 200382.4.3Medicare Prescription Drug, Improvement, and Modernization Act (MMA)83. Comparative Effectiveness and the Need for Head-to-Head Clinical Trials83.1The Value of Comparative Clinical Trials93.2Criticism of Comparative Clinical Trials94.Sponso

4、ring Comparative Trials124.1Industry Sponsored Trials124.2Government-Sponsored Trials125.Alternatives125.1Partnerships Between Public and Private Sectors to Conduct Post Marketing Studies125.2Electronic Prescribing and Comparative Effectiveness: The Future?136.Conclusions14References15Executive Summ

5、ary Prescription drugs can be very expensive and their cost may be a barrier to universal access. Governments of most developed countries have subsidy systems to achieve equity of access to pharmaceuticals. For a number of these medications at launch, we know little about their effectiveness beyond

6、comparison to a placebo. In most circumstances, this is the most scientifically robust comparison available to demonstrate efficacy. The EMEA and other regulatory authorities will find that a new product meets the statutory requirement for efficacy if superior to placebo. To estimate comparative eff

7、icacy between two medicines, large trials are needed since there are often small differences between treatment outcomes when the interventions are compared. Regulatory agencies neither examine products under conditions of routine use nor determine whether a product is better value for the money than

8、 alternatives (cost effectiveness) although, for making reimbursement decisions cost effectiveness is very important and many countries do incorporate some sort of economic evidence into their reimbursement schemes. The industry does conduct comparative trials after approval if they have not been co

9、nducted during development. Nevertheless, it is certainly fair to say that the discovery that a new product, which has yet to establish a market, is no better than an older and cheaper one could be commercially problematic. Comparative trials can be expensive and take many years to complete. There a

10、re at least two alternatives to having either the industry or the government pay for comparative clinical trials. In one approach, private insurers and the government would set aside some fraction of their annual drug spending to endow a new institute to provide an independent source of reputable re

11、search into comparative effectiveness and cost. The other approach relies on electronic prescription and medical databases to conduct Phase IV and/or pharmacoepidemiologic studies to supplement or even take the place of randomized, controlled, comparative clinical trials. The EU is presently discuss

12、ing so-called “e prescribing” and other IT approaches. We see a great comparative advantage in the EU, as such electronic linkage of prescribers and medical records is still fragmented in the United States.1.IntroductionFrom a public health and equity viewpoint, drugs are not normal items of commerc

13、e but are “public goods” that should be distributed on the basis of end user need or ability to benefit rather than end user ability to pay. Donald J. Birkett, Andrew S. Mitchell, and Peter McManus, 2001. A Cost-Effectiveness Approach To Drug Subsidy And Pricing In Australia Health Affairs 20 :104-1

14、14. Because many drugs are very expensive, availability on the market is therefore not sufficient to ensure access for all the population. Governments of most developed countries have subsidy systems to achieve equity of access to pharmaceuticals. Such subsidy systems involve delicate balancing acts

15、. Given the costs to provide and deliver health care today, as costs rise, the need to look for every opportunity to extract “value” has become much more important.11.1Comparative EffectivenessUnfortunately, for most of these medications at the time they are launched, we know little about their effe

16、ctiveness beyond comparison to a placebo. This is because, for the most part, the ability of a medicine to provide “efficacy” is still derived from randomized clinical trials and, under the current licensing regulations of major industrialized countries, the manufacturer must show clinical trial evi

17、dence from placebo-controlled trials. Thus, a sponsor must show absolute, not comparative, efficacy in scientific terms to achieve marketing approval. So long as a new product is more effective than placebo, barring other issues, the FDA and the EMEA will find it meets the statutory requirements. On

18、 the other hand, FDA does consider relative safety, and will refuse to approve a new product that has a distinctly less favorable risk-benefit ratio than already marketed products. Comparator studies may be set up to statistically demonstrate “superiority” to the comparator or as a a “non-inferiorit

19、y” trial which occurs when a new drug is tested against a standard treatment with similar efficacy and the trial must be designed to show that the new treatment is equivalent to, or not worse than, the standard therapy. KJ Rothman . 1996, Editorial : Placebo mania BMJ 313:3-4 If one cannot reasonabl

20、y determine what the absolute effect of a standard treatment is in a study (sometimes referred to as the equivalence or non-inferiority margin), it is not possible to interpret a non-inferiority study. Defining the effect of the standard treatment control is more difficult where the effect of the st

21、andard therapy is relatively small (e.g., increased survival by 2-3 months). A risk in any given study population is that the standard therapy control actually had no absolute effect and that a new treatment that was indistinguishable from control might have no effect either. To estimate comparative

22、 efficacy or to show equivalence studies that are much larger than the usual placebo controlled studies are needed. Henry D, Hill S. 1995, Comparing treatments. BMJ 310:1279. Comparative benefit can be determined without placebos, indeed placebo-controlled trials are not possible in some cases, beca

23、use when an efficacious treatment already exists it is unethical to assign placebo treatment to patients as it violates the ethical principle of equipoise, a state of uncertainty regarding which of the treatments studied is better.2Industry has a preference for comparison with placebo as the main de

24、terminant of efficacy for regulatory approval. Collier J., 1995, Editorial: Confusion over use of placebos in clinical trials BMJ 311:821-822. Currently in most major drug regulatory authorities, a requirement for active treatment comparative studies is still the exception, although requests for act

25、ive comparator studies are increasing. Indirect comparisons involve creating a comparison between drugs A and B when there are two placebo controlled trials: A v. placebo and B v. placebo.5 Another type of indirect study involves a review of clinical trials between A v. B and C v. B to enable a comp

26、arison between A versus C. 6 Such indirect comparisons are problematic. HC Bucher et al. , 1997. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 50: 683-691. , L Sauriol et al. 2001, Meta-analysis comparing newer antipsycho

27、tic drugs for the treatment of schizophrenia: evaluating the indirect approach. Clinical therapeutics 23: 942-956. Biases may arise due to differences in methodology, outcome measurement, or the populations included in studies of the two drugs. The best information will come from large, properly con

28、structed randomized trials, using valid outcomes, and done in a way that is meaningful to clinical practice. Data from trials prone to bias because of faulty design will not be of use and may give rise to misleading conclusions. Sufficient numbers of patients and events are required to overcome any

29、random effects. 1.2Cost-Effectiveness Moreover, the systems for pharmaceutical evaluation in most countries do not allow for studies to determine whether the product is better value for the money than alternatives (cost effectiveness. Generally, the assessment of comparative cost has not been german

30、e to scientific assessment in the regulatory process.In making reimbursement decisions, however, cost effectiveness is very important. Several EU countries , including the Netherlands, Portugal, Finland, Denmark and the UK, have all introduced procedures in reimbursement decisions to use some econom

31、ic evidence. Ian Dodds-Smith and Grant Bagley, Arnold & Porter , 2001. Cost effectiveness - the fourth hurdle to market entry, available at last accessed 2 July 2004.Many other EU countries do not mandate cost effectiveness data for reimbursement, however it is implicit that manufacturers need to in

32、clude this evidence in the reimbursement dossier. Additionally other EU countries (France, Italy, Spain) require or strongly encourage economic evidence for pricing rather than reimbursement.One source of cost-effectiveness research is the pharmaceutical industry itself. However, public and private

33、managers of drug benefits might not consider research by manufacturers a sound basis for decisions about which drugs to favor. 8, 9 The objectivity of manufacturer-sponsored research seeking to justify claims that a drug is better than its competition can be questioned. There is evidence that studie

34、s sponsored by drug companies are more likely to have findings favoring the sponsors drug than are those having other sponsors. John F. Hoadley, 2004, The Continued Need For Independent Research On Prescription Drugs, Health Affairs, 23: 244-249., J. Lexchin et al., 2003, Pharmaceutical Industry Spo

35、nsorship and Research Outcome and Quality: Systematic Review, British Medical Journal ? 110., J. Bekelman et al., 2003, Scope and Impact of Financial Conflicts of Interest in Biomedical Research,” Journal of the American Medical Association ?: 454465. Conversely, large purchasers and insurers have a

36、lso shown interest in sponsoring research on the relative value of different drugs, but the potential bias of their results also could be raised, especially by manufacturers or patients and their physicians.82.Experiences with Comparative Effectiveness and Cost-Effectiveness2.1EMEANew pharmaceutical

37、 legislation for the EMEA came into force on 20 May 2004. REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004, In laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a Europe

38、an Medicines Agency: Section 34. The new legislation made it clear that, although “Member States have developed an evaluation of the comparative efficacy of medicinal products aimed at positioning a new medicinal product with respect to those that already exist in the same therapeutic class this eva

39、luation should not be conducted in the context of the marketing authorization for which it is agreed that the fundamental criteria should be retained.“11 (italics added). Thus, it would appear that the EMEA is still considering safety and efficacy using placebo-controlled trials. However, comparator

40、 studies are often requested on grounds of assessment of risk/benefit. 2.2National Institute for Clinical ExcellenceThe National Institute for Clinical Excellence (NICE) was established in 1999 and now regularly bases its decisions regarding drugs on evidence- based evaluation of their comparative e

41、ffectiveness and cost effectiveness, comparing their costs, and benefits with other treatments. Grubert, N. 2003. The National Institute for Clinical Excellence (NICE): A Review of Its Performance and Its Significance for the Pharmaceutical Industry, Decision Resources, Waltham, MA. last accessed 12

42、 July 2004.Manufacturers can be requested by NICE to provide quantitative comparisons with other forms of treatment, so that data comparing the new product with current standard therapy “head to-head” is sometimes available by the time NICE reviews the product. It is incumbent upon manufacturers to

43、provide everything to NICE, which would include comparator information. 2.3AustraliaThe Pharmaceutical Benefits Advisory Committee (PBAC), a statutory committee established under the National Health Act of 1953, consists of family and specialist medical practitioners, pharmacists, and a consumer rep

44、resentative. The PBAC is charged with making recommendations to the minister for health and aged care about which drugs and medicinal preparations should be listed for subsidy. 1 The PBAC must consider comparative effectiveness and cost in making its recommendations. To fulfill this requirement, cos

45、t-effectiveness requirements were phased in during 1991 and 1992 and became mandatory in 1993. The choice of an existing treatment with which the new drug will be compared is critical.1 The most prescribed pharmacological analogue used for the same indication is usually preferred. If the drug is in

46、a new pharmacological class, the drug most prescribed on the Pharmaceutical Benefits Scheme (PBS) for the same indication is the comparator.1 If no currently listed drug is available, the main comparator usually is the standard medical (nondrug) management. The industry has argued that using these c

47、riteria could disadvantage new drugs, as they are compared with cheaper old drugs that are off-patent. PBAC prefers (but does not require) randomized trials that directly compare the proposed drug with the main comparator. Since head-to-head comparisons are rarely available, an analysis of two sets

48、of randomized trials involving a common reference will often be acceptable (i.e., drug A v. comparator and drug B v. same comparator). The clinical evidence is supposed to indicate whether a drug is better than, no worse than, or worse than the comparator and guides the type of economic analysis. Dr

49、ugs that are worse overall than the comparator are generally not subsidized.1Australias system, has been criticized by the drug industry. It is one model for how to obtain value for money in prescription drugs. Compared with other countries Australia pays a lower price for drugs and across all categ

50、ories of drug it pays less than half the price paid in the United States.1 2.4United StatesIndividual states of the USA have begun to use economic analyses as part of their state Medicaid programs. For example, in 2001, the Oregon legislature directed the states Department of Human Services to consi

51、der the effectiveness and relative cost of different drugs. Under contract, researchers at the Oregon Health and Science University have conducted evidence-based reviews of published and unpublished studies on drugs in four therapeutic classes: gastrointestinal medications, two types of pain medicat

52、ions, and cholesterol-lowering drugs. These reviews serve as input into a public process through which the state identifies preferred drugs for its Medicaid plan. J. Santa, 2002, The Evidence Based Process Applied to Prescription Drugs in Oregon, available at , last accessed 2 Juy 2004. Individual s

53、tates are using clinical and economic analysis as part of the Medicaid program. Evidence based practice centers are established in the USA (in which Oregon is one) and Canada to develop evidence reports and technology assessments based on rigorous, comprehensive syntheses and analyses of the scienti

54、fic literature .The Academy of Managed Care Pharmacy which has guidelines (a format for submission to Formularies) for clinical and economic evaluation which is often used by managed care firms, pharmacy benefit managers, and hospitals in the US. Veenstra DL, Ramsey SD, Sullivan SD, 2002. A guidelin

55、e for the use of pharmacoeconomic models of diabetes in the US managed care environment. Pharmacoeconomics. 20 Suppl 1:21-Medicare ProgramThe U.S. Medicare law reads, in part: “No payment may be made under Medicare for any expenses incurred for items or services that are not reasonable and n

56、ecessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member” M. Giffin and R. Awwaad, 2001. The Impact of Studies Funded underOutcomes of Pharmaceutical Outcomes Research: Final Report, Pub. no. 02-R201, available at /clinic/pharm

57、imp.In 1989 the agency administering the Medicare program prepared a set of criteria, including cost-effectiveness. Criteria and Procedures for making Medical Service Coverage Decisions that relate to Health Care Technology, 54 Fed. Reg. 4302 (30th January, 1989). This later factor was not officiall

58、y adopted. The Medicare program has developed a process by which national coverage decisions are made. Notice of Rulemaking: Procedures for Making National Coverage Decisions, 64 Fed. Reg. 22619 (27th April,1999). These decisions affect all Medicare beneficiaries. The process relies on the evaluation of scientific evidence and ca