Regulatory Interventions What do we know? Where are the gaps in our knowledge?

1. Regulatory InterventionsWhat do we know?Where are the gaps in our knowledge? Warren Kaplan Richard Laing Boston University School of Public Health http://dcc2.bumc.bu.edu/richardl/RPM+_Project/Regulation&QA/Regulation-evidence-Feb2003.doc& http://dcc2.bumc.bu.edu/richardl/RPM+_Project/Regulation&QA/12-17-PHARMACEUTICAL%20REGULATION%20.DOC

2. Abstract • By their very nature, the existence of systems to regulate pharmaceuticals create costs and barriers to pharmaceutical availability. To protect the public health, however, access and quality of pharmaceuticals must be regulated. The means to accomplish this must be based on evidence of the effect of such regulation on availability and quality. It cannot be based on faith or belief. • Our present evidence base in this regard is very weak. To accomplish the laudable goal of basing pharmaceutical regulations on evidence of their effect on drug availability and quality, we need to be creative in studying existing regulatory systems and, in particular, we must pay attention to pharmaceutical availability and quality prior to, during, and after transition periods when the regulations undergo change(s).

3. Background and Setting Drug management functions are undergoing transformation in many countries as different ways of health sector reform are being implemented. Nonetheless, there is no evidence- based consensus on the efficacy of drug management interventions.   In developing countries, it is not clear at all if we know anything about the effect on pharmaceutical access, quality and use of regulations dealing with: (i) market authorization or removal from authorization, for drug products and processes; (ii) licensing of facilities and human resources; and (iii) sales, promotion and advertising of authorized drug products.

4. Study Aims • To review the level of evidence for the efficacy of drug management interventions by regulatory authorities in developing countries. • To identify gaps in our knowledge base regarding the effect of regulatory interventions on pharmaceutical access, quality and use. • To suggest a research agenda to close the gaps in our understanding

5. Methods I • Systematic search of published literature. The topic stated for the search was defined as: “The evidence that regulatory intervention plays in altering pharmaceutical access, quality and use in developing countries”. Database Primary Term + Secondary Term EMBASE intervention • regulation developing country • developing country intervention • interrupted time series MEDLINE intervention regulation interrupted time series developing country IPA* intervention developing country intervention regulation regulation developing country interrupted time series * International Pharmaceutical Abstracts

6. Methods II • Main criterion for inclusion was that a report describe an evaluation study or describe an intervention, thus leaving out opinion and critique papers. In order to provide an assessment of the strength or power of the existing evidence, we attempted to review the studies, in terms of their methodological designs and quality using the following criteria: 1. Descriptive, analytical, comparative or evaluation studies reporting on a type of intervention addressing health systems constraints of relevance to the present review; 2. Study uses control groups; 3. Study evaluates changes over time; 4. Study reports statistical significance of results. Relevant data from the located studies was collected in accordance with the necessary information for the literature review. Main data collected in terms of key information for the review includes: - Methods, population, problems or constraints before intervention, intervention, results or conclusion and costs (if available).

7. COUNTRY INTERVENTION OUTCOME VARIABLE EVIDENCE RESULTS REFERENCE RESULTS 1: Evidence of Pre Market Interventions and their effect on access, quality and use Registration of pharmaceuticals Norway Removal of “Need Clause” in Norway Number of drugs on market; number of drug applications Pre/post; no control; no statistical analysis Numbers of applications and DRA workload increased. (Norris 1998) U.S. DESI Study: Withdrawing from market many pre-1962 drugs and drug combinations; Effects of cessation of government payment for 12 categories of drugs Changes in the overall levels of prescriptions, expenditures, and physicians' use of substitute drugs. Time series with control Estimated drop in use of study drugs offset by increased use of substitute drugs in both desirable and unimproved therapeutic forms Soumerai et al.  (1990) U.S. Prescription Drug User Fee Act (U.S.) Approval times for drug applications Time series; no control; no statistics Trend to shorter approval times Kaitin and DiMasi (2000) China Comprehensive drug policy reform Drug supply, drug expenditure Descriptive, no time series, no controls, no pre post (Dong 1999) India Enactment of Consumer Protection Act and quasi judicial councils at national level Perceptions and knowledge of end users; cost of health care Descriptive, no time series, no controls, no pre post Increased awareness and knowledge of patients; increased costs of medicines (Bhat 1996); (Bhat 1999)

8. RESULTS II: Deregistration, withdrawals, controlled substances: Evidence COUNTRY INTERVENTION OUTCOME VARIABLE EVIDENCE RESULTS REFERENCE Pakistan Degistration of pediatric antimotility drugs (10 June 1996) Availability in retail drug outlets Post intervention; questionnaire/ghost client; no control; no past baselines; N=7 Deregistered products successfully withdrawn from majority of outlets. Black market still existing (Bhutta and Balchin 1996) Hong Kong Ordinance classifying all benzodiazepines (BZ) as “dangerous drugs” (January 1992) Number of Rx Pre/post; no time series (1 data point per year); no control;   Reduction in average yearly # of BZ Rx per person (Chung 1997) Various countries Deregistration/ withdrawals of antimotility drugs (l990/1991) Regulatory actions of DRAs as a function of timing of WHO documents Pre/ post; no controls. Subsequent withdrawal actions (Haak and Claeson 1996) Spain DRA suspension of triazolam market license (l992) Yearly dosages of various hypnotics Pre/ post; no controls Small transient treatment decrease in 1992 in all hypnotics, (Arias 1995) Brazil Two separate interventions: 1986-1987 : need Rx prior to pharmacies’ dispensing BZ. 1989: ‘antidistonics’ removed from market BZ Rx sales figures only Pre and post 1986 law Fall in BZ consumption Results confounded with 1989 legislation. (Kapczinski et al. 2001)

9. COUNTRY INTERVENTION OUTCOME VARIABLE EVIDENCE RESULTS REFERENCE Laos Inspections of pharmacies as part of National Drug Program; including punishment of violations; provision of regulatory documents; Simultaneous educational intervention by UNICEF/MoH; Indictors for availability and service quality for 10 Essential Drugs Controlled trial, randomized; unblinded; pre RCT baseline (one month in 1997) and post RCT (one month in 1999). No difference in outcomes between “regular” and “active” interventions; differences in prescribing quality (Stenson et al. 2001) (Stenson, Syhakhang, Lundborg, Eriksson, and Tomson 2001) Viet Nam Sequential interventions: regulations enforcement; education and peer influence. Knowledge and reported practice among staff of private Hanoi pharmacies Randomized controlled trial with 22 matched pair intervention and control private pharmacies Three interventions in series effective in changing the knowledge and reported practice of drug sellers (Chalker et al. 2002) RESULTS III: Evidence of Post Market Interventions and their (intended and unintended) effect on access, quality and use: Inspections of premises

10. COUNTRY INTERVENTION OUTCOME VARIABLE EVIDENCE RESULTS REFERENCE United States FDA regulations re: broadcast advertising of pharmaceuticals (l997) $$ spent on advertisements for various drug classes Time series across intervention; no statistics, no controls No attempt to correct for secular trends in data. Unable to tell if overall spending increase was due to regulations. (Rosenthal 2002) United States FDA regulations re: broadcast advertising of pharmaceuticals (l997) DTCA $$$ and monthly frequencies of diagnoses and prescriptions Post only: Time series of frequencies of diagnoses and medications as a function of monthly DTCA expenditures; no control Diagnoses of hyperlipidemia and the number of prescriptions written for statins positively associated with DTCA expenditure for antilipidemics (Zachry 2002) United States Beginning of DTC advertising (1997) DTCA $$ and price margins between DTCA brands and non-advertised brands Pre/post; no control No difference in retail margins before DTC ads- a 40% difference after ads. (Kopp 1996) French-speaking African countries Regulations regarding advertising in medical journals Do ads conformed to French legal requirements Cross-sectional study, no pre/post; no controls 41 of 141 ads conformed to regulations; 6 journals. (Chirac et al. 1993) United States and Canada (control) DTCA Effect on patient requests and prescribing practice Cross country comparison; survey data Prescribing rates similar in both countries (Mintzes 2002) RESULTS IV: Regulatory Control over pharmaceutical advertising

11. RESULTS V: Adverse drug reactions/pharmacovigilance We found no appropriate evidence-based studies that looked at the effect of increased or altered pharmacovigilance on drug access, use, or quality in developing countries. In this regard, we note the study by Smalley et al. (2000) who looked at the effect on prescriber practice of the 1998 U.S. FDA determination that use of the gastrointestinal motility agent cisapride can cause cardiac arrhythmias and was contraindicated in such patients. The FDA informed practitioners through additions to the boxed warning in the label and a “Dear Health Care Professional” letter sent by the drug’s manufacturer. The Smalley et al. study was a “pre-post” cohort study using computerized patient records. They looked at the proportion of cisapride users in each “pre” and “post” regulation period for whom cisapride use was contraindicated by the product label The regulatory action had no major effect on contraindicated cisapride use.

12. Summary • The current evidence base regarding the effect of regulatory interventions on pharmaceutical access, quality and use is extremely sparse. The evidence base is weak and the methods used for garnering data is often inappropriate to developing any statistical inferences. More often than not, inferences are based on single interventions in scattered parts of the developing world. • Withdrawing or banning a pharmaceutical may be successful in eliminating the pharmaceutical from the market but ‘underground’ sales may still occur. • Withdrawing or banning a pharmaceutical often leads to use of other, even less appropriate pharmaceuticals, that fill in the ‘niche’ left by the banned or withdrawn drug. • Regulatory interventions alone may be less effective than multiple interventions. • Regulatory interventions, albeit initiated at a national level, but implemented directly at individuals, can be effective

13. Conclusions and Policy Implications • The number of interventions reported in the literature is extremely small. The number of interventions with acceptable evaluation methods is even smaller. • Create regional and global informational networks with an aim to create evidence-bases for specific interventions and outcomes. • To the extent possible, efforts should be made to standardize the research designs that study regulatory interventions. • Initiate and improve baseline studies and administrative databases • Develop more creative uses of experimental designs. Robust time series may be the most appropriate phased regulatory interventions • Understand that institutional change requires political support, rather than (or in addition to) technical solutions. • Make unpublished evaluation documents publicly available to workers in the field. “Reinventing the wheel” is not useful.