Availability of New Medicines in the US and Germany From 2004 to 2018

Key Points Question Is there a difference in the availability of new drugs in Germany and the US? Findings In this cohort study comparing 599 medicine approvals in the US and Germany between 2004 and 2018, 92% of all new medicines approved in either country were available in the US, and 80% were available in Germany. The median approval time in Germany was extended by 4 months. Meaning The findings of this study suggest that, compared with the US, fewer new medicines are available in Germany, and they enter the market at a later time.


Introduction
United States policy makers are interested in understanding how other countries approach the challenge of high drug prices.One country that is often highlighted for its unique approach is Germany, which allows manufacturers to set unconstrained prices for medicines at launch but requires that all medicines undergo a systematic assessment of their effectiveness, permitting insurers to renegotiate prices after this assessment. 1 This policy has guaranteed that almost 98% of

Key Points
Question Is there a difference in the availability of new drugs in Germany and the US?
Findings In this cohort study comparing 599 medicine approvals in the US and Germany between 2004 and 2018, 92% of all new medicines approved in either country were available in the US, and 80% were available in Germany.The median approval time in Germany was extended by 4 months.

Meaning
The findings of this study suggest that, compared with the US, fewer new medicines are available in Germany, and they enter the market at a later time.

+ Supplemental content
Author affiliations and article information are listed at the end of this article.3][4] Moreover, for cancer drugs, price negotiations have resulted in prices being reduced by 24.5% 1 year after launch. 5ss known, however, is whether the number of medicines available in Germany is meaningfully smaller than what is available in the US.Earlier studies found that new drugs often enter the US market first. 6,7The US Food and Drug Administration (FDA) may also approve more medicines in part by relying on surrogate end points, but there is also evidence that the European Medicines Agency (EMA) uses similar end points. 8The recent decision to approve a controversial medicine for Alzheimer disease in the US but not in Europe, supports these views. 9,10Approvals by the EMA in combination with German requirements for market entry may be more restrictive than US approvals for some medicines but more permissive for others. 11 performed a retrospective cohort study of novel drugs that were available in both the US and Germany, medicines that were available in Germany but not in the US, and medicines that were available in the US but not in Germany.We evaluated the time it took medicines to reach the German market relative to the US market.

Open
In the US, the FDA approves medicines, and commercial payers, which cover one-half of the US population, make their own coverage decisions.However, the process behind commercial insurers' coverage determinations is opaque and variable across insurers; these determinations are not based on a transparent cost-effectiveness analysis of the type conducted by the Institute for Clinical Effectiveness Research.The 2 largest public payers in the US, Medicare and Medicaid, insure the other half of US citizens and are de facto required to cover most approved therapies (the Veterans Administration uses a formulary but is relatively small; it covers 9 million US citizens, 2.5% of the population) with some management tools in Medicaid.
In Germany, medicine availability reflects a 3-step process.First, for most new medicines, the EMA makes an approval decision for all European Union member states (this is the mandatory process for treatments for HIV and AIDS, oncology, diabetes, neurodegenerative disorders, autoimmune diseases, and viral diseases). 12 Relying on and augmenting the IQWiG analysis, the Federal Joint Committee determines whether the benefit from a medicine is commensurate with the current treatment standard.
Depending on the Federal Joint Committee determination, the manufacturer can negotiate a price with insurers, price to match an equivalent medicine, or withdraw the medicine from the market.
Before the introduction of AMNOG, health technology assessments were not required regularly to determine negotiated prices and were used in select reference pricing exercises; the pre-AMNOG environment resembled the US situation today.

Design
This was a retrospective cohort study of all 599 medicines approved in the US and Germany between January 1, 2004, and December 31, 2018, followed up until December 31, 2019.The initial year of analysis is 2004 because it is the year the EMA introduced the mandatory centralized authorization procedure for all new active ingredients approved in European Union Member States.Our focus was on the initial marketing authorization and related activities at the national level.We therefore did not consider subsequent activities that determine prescribing decisions by physicians and use by patients.We also did not consider any withdrawals after initial market entry.Data analysis was conducted from January 1, 2020, to July 1, 2022.This study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Data Sources
To identify novel drug therapies, we used publicly available information from the FDA, the EMA, and data on market launches in Germany based on administrative data.For the US, we considered all medicines approved by the FDA, relying on documents provided through the Orange Book. 13We included 458 approvals designated as original submissions that were ever approved by the FDA and were categorized as a new molecular entity (type 1) or new active ingredient (type 2) to reflect the somewhat broader definition of a new active substance by European standards. 14For Germany, we extracted data on 462 novel drug therapies approved using an annual report of the German pharmaceutical market (Arzneiverordnungs-Report) 15 that relies on administrative data provided by ABDATA-Pharma-Daten-Service. 16Approval is the first time a medicine was available for prescription in the German market, which may deviate from the date of market approval by the EMA or the German national marketing authorization agency because drug presentations need to be registered for marketing.For both the US and Germany, we also checked whether medicines have been available before the starting point of our observation based on the same data sources.
In addition, we collected data from the EMA based on public assessment reports. 17Within the European Union, medicines may be launched centrally by the EMA, which is the pathway for most new medicines, or by application to national regulators.To validate approval status and additional information, especially for drugs that were not launched in both the US and Germany, we accessed drugbank.com 18and Gelbe Liste 19 for Germany.

Identifying New Drug Approvals in the US and Germany
We identified 599 unique novel therapies that were launched in the US or German market.We mapped drugs by brand and active ingredient based on the international nonproprietary name.We verified whether the same active pharmaceutical ingredient is marketed under different brand names.We did not consider medicines that were subject to compassionate use or considered as investigational or experimental.We excluded vaccine, generic, and biosimilar agents because these are considered in separate approval processes by the FDA and outside the scope of the German AMNOG process.

Identifying Availability of Medicines by Country
For each medicine, we captured the first date of market availability by month and year.As outcomes based on approval status, we checked whether the 599 medicines were ever available in the US, Germany, or both.For medicines that were approved in 1 of the 2 countries, we identified whether these agents were approved at an earlier time (ie, before 2004) or were never approved.

Determining Availability of Medicines by Approval Status
Approvals were analyzed to determine the percentage of all new medicines available in the US, Germany, or both.We first calculated the percentage of medicines approved in the US and Germany as the percentage of all medicines approved.
For the subset of medicines that we identified to be approved in either the US or Germany, we calculated the difference in approval times in months, with the US approvals as the reference country.We computed the median (95% CI) time difference between approvals.Because the exact month of approval was missing in the German data for 2 medicines, we imputed the mean month (April).
For the subset of medicines that were approved in Germany but not the US, we classified these into 5 categories that are suggestive about potential reasons of nonapproval and 1 residual category.
We classified orphan drug designation of medicines using information provided by the EMA for Germany and by the FDA based on the Orphan Drug Designations and Approvals database for the US.
We classified small-molecule or biologic drug status based on the type of application process (new drug application compared with biologic application) and data from drugbank.comfor medicines approved by the FDA.According to the labeling information, we noted whether medicines were indicated to treat cancer.We also noted whether they were subject to an early assessment of health benefit according to AMNOG in Germany after 2011 by their initial approval date.We classified whether the medicine previously received marketing authorization by the EMA or was suspended.
Based on the FDA Orange Book, we determined the priority vs standard review designation.

Statistical Analysis
The 95% significance threshold was determined using unpaired, 2-sided tests.All data were maintained and processed in SAS, version 9.4 (SAS Institute Inc) and analyzed in Microsoft Excel (Microsoft Corp) and SAS.

Results
Table 1 describes our sample of medicines.In total, 599 medicines were approved in either Germany or the US between 2004 and 2018, representing the maximum number of new medicines theoretically available for prescription in these countries.
Of these potential medicines, 12% (n = 73) had already been approved in the US before 2004 (Germany approved these after 2004), and 80% (n = 477) gained approval in the US between 2004 and 2018.Therefore, 91.8% of potential medicines (477 + 73 of 599 medicines) were available in the US.In Germany, 36 (6%) of the 599 possible medicines had been approved before 2004, and 440 (74%) subsequently received approval.Therefore, 79.5% of potential medicines were available in Germany.When we compared time to availability in the US and Germany for the medicines that were approved in both countries, it took 4 months longer for the median therapy (95% CI, −44.40 to 44.76 months) to enter the German market, including the EMA review times.Forty-nine medicines were approved in Germany but not in the US, 75% of which were rejected by the US Food and Drug Administration, were withdrawn, or had US equivalent agents.To understand whether the differences in medicine availability were clinically meaningful, we examined the medicines that were available in either Germany or the US but not in both countries (Table 2).Medicines available only in Germany are noted in Table 3.
Many of the 123 medicines that were available in the US but not in Germany received FDA approval in the most recent year of our study period and therefore could still be approved in the European Union or in Germany (eTable in the Supplement).Ninety-four medicines were not approved by the EMA during the study period, 18 were approved by the FDA in 2018 and could still be approved, and 7 were refused or withdrawn by the EMA.Four medicines with approval, of which 2 had no substitutes, were subsequently approved outside the follow-up period.

Discussion
In this study, we compared the availability of new medicines in the US and Germany.The German system-which relies on the EMA for most approvals-included fewer medicines available the study period and had access to medicines slightly more slowly, likely due to duration of EMA review. 7ghty percent of all potential medicines were available in Germany and 92% were available in the US.This analysis highlights 2 differences between the US and Germany-earlier approvals and more approvals in the US.We found that several medicines that were not ultimately approved by the FDA were available in Germany, and some were subsequently withdrawn by the European Union.
Medicines with therapeutic substitutes were available on both markets.More research is needed to determine whether medicines that are available in the US but not in Germany offer added therapeutic benefits over existing alternatives.
The US offers access to a greater number of new medicines, with the approval process marginally faster by 4 months.The process does not seem to compromise safety for speed relative to the European Union and Germany-during our study period, the FDA did not approve several medicines that the European Union subsequently rejected.However, for Medicare and Medicaid, the de facto link between approval and coverage reduces the ability of commercial insurers to refuse

Table 2 .
Medicines Approved in Germany or the US But Not in Both Countries, 2004-2018 a The EMA designation for German approvals or FDA designation for US approvals.b No approvals with accelerated approval pathways.Downloaded From: https://jamanetwork.com/ on 09/15/2022

Table 3 .
Medicines Approved in Germany But Not in theUS, 2004-2018

Table 3 .
Medicines Approved in Germany But Not in the US, 2004-2018 (continued) Abbreviations: AMNOG, German Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz); EMA, European Medicines Agency; FDA, Food and Drug Administration; OTC, over the counter; RCTs, randomized clinical trials.