Making regulation responsive to commercial interests: streamlining drug industry watchdogs

Has the pharmaceutical industry skilfully managed to achieve an unhealthy influence over European drug regulatory agencies?

New prescription drugs are developed and tested for quality, safety, and efficacy by the pharmaceutical industry, and little or no drug testing is conducted by governments in modern industrialised countries. Governments have regulatory authorities which have a legal duty to protect public health by ensuring that new drugs are not licensed unless they are of adequate quality, safety, and efficacy (box B1). The thousands of birth deformities and deaths caused by thalidomide focused public and professional concerns on how the commercial interests of pharmaceutical companies may diverge from, or conflict with, the interests of patients and public health. The reasoning behind the creation of new government regulatory authorities in the post-thalidomide era was therefore that they should be “entirely independent” of the commercial interests of the pharmaceutical industry and should act on behalf of the public interest by checking the adequacy of the test data produced by the industry.^1–3 I explain how these government regulatory authorities in the European Union, which were initially established to provide independent scrutiny of pharmaceutical firms in the interests of public health, have become increasingly responsive to the commercial interests of the industry (box B2).

Summary points

• After the thalidomide disaster the public expected drug regulation would be independent of the interests of the pharmaceutical industry

• In the past 15 years the regulatory agencies have been overly influenced by the industry's desire for rapid drug approvals

• Regulatory agencies have become heavily dependent on industry fees for their survival

• National agencies now find themselves competing with each other for industry fees for regulatory work

Box 1.

Stages in drug development that regulatory agencies should check

• Chemical and laboratory analysis
• Non-clinical pharmacology and animal toxicology
• Phase I trials with healthy human volunteers
• Phase II clinical trials with small numbers of patients
• Phase III clinical trials with more extensive patient numbers
• Phase IV post-marketing pharmacovigilance

Box 2.

Stages of increasing influence of the drugs industry on regulatory agencies

• Credibility of regulatory agencies becomes undermined by suggestions that the need to take extra time to check data shows inefficiency
• Regulatory agencies become increasingly dependent on funding from industry for development and running costs
• The drugs industry is allowed a central role in setting the priorities for regulatory agencies—for example, rapid approval times for new drugs
• Creation of an environment, such as the European Union's mutual recognition procedure, in which regulatory agencies compete with each other for “regulatory business”

Methods

The arguments in this paper are derived from electronic searches of the medical and pharmaceutical literature, combined with interviews with industry, regulators, and other professionals in Europe.

Accusing the regulatory authorities of slowness and inefficiency

The first stage in imputing slowness and inefficiency to regulatory authorities was to claim that new drugs were not being approved fast enough: this the Association of the British Pharmaceutical Industry did during the 1980s. The industry claimed that delaying approvals was detrimental to the British economy because it resulted in drug development work going abroad.⁴ In Germany and Sweden the pharmaceutical industry also pressed for quicker drug approvals.⁵

European governments accepted these industry perspectives, although new drugs had in fact come to the UK or German markets in 1972-83, faster than in France, Italy, Sweden, or the United States, and more new drugs were first marketed in the United Kingdom or Germany in 1961-85 than in Austria, the Benelux countries, the eastern European countries, Italy, Scandinavia, Spain, Switzerland, or the United States (figs 1 and 2).⁶ Indeed, in 1988, the United Kingdom was found to have the fastest approval times for new drugs in the European Union.⁷ Moreover, in 1989, German regulatory staff argued that the speed of drug approvals was but a crude measure of efficiency, and that the drug review process was not delaying any genuine therapeutic advances because the backlog related only to products for which existing treatments were adequate.^8–11

Figure 1.

Relative lag periods for new drugs (new chemical entities) introduced in six countries, 1972-83

Figure 2.

Numbers of new drugs (new chemical entities) by country of first introduction, 1961-85

Some Swedish regulators have argued that, even if some regulatory authorities were slower in approving drugs than others, this could be because they were under-resourced, rather than inefficient. In Britain, for example, from the late 1970s to 1986, staff levels in the regulatory authority grew by only 9% while licence applications increased by 87%. In the late 1980s, the American drug regulatory agency had six times as many staff handling drug applications as did its British counterpart.¹²

Making regulatory institutions more responsive to industry

European governments such as those of Germany, Sweden, and Britain decided to restructure their drug regulatory authorities in line with the industry's demands. In the late 1980s, the industry proposed that it would fund drug approvals if this would result in a “more efficient service,” and called for greater informal consultation between companies and regulators.^13–15 For example, in 1989 the British government accepted the industry's proposal that, to make regulation of medicines more “efficient,” the regulatory authority should in future recoup all its running costs from licensing fees, rather than 60% as before. A new regulatory authority funded by the pharmaceutical industry, the Medicines Control Agency, with its own director (who came from industry), replaced the existing authority.¹⁶ Health ministers also appointed a board of experts, drawn from various quarters, including industry and the Department of Health, to advise them on the scope of the agency's targets and its performance.¹⁷ A concern to protect the commercial interests of the industry was enshrined within the agency's objectives.

In 1990, Sweden established an independent regulatory authority unit, known as the Medical Products Agency, with increased dependence on industry fees, and also a special task force to reduce the backlog of new drug applications. In 1995, the German government replaced the existing regulatory authority with the more industry-friendly federal institute for drugs and medical products,¹⁸ the staff of which were instructed to be less cautious about approving new drugs.¹⁹ Even the US drug regulatory agency became concerned about accelerating its new drug approvals relative to other regulatory authorities.²⁰

Europeanisation and interagency competition

In addition, regulatory bodies have been placed in competition with each other for industry fees, and where there are institutional incentives, not to reject new drugs. This situation arose indirectly from the Europeanisation of pharmaceutical regulation, as a result of the European Commission's adoption, to a large extent, of the industry's vision for Europeanised drug regulation. The international pharmaceutical industry is interested in European harmonisation and streamlining of drug regulation because this allows a drug to be marketed in several states more or less simultaneously, taking advantage of “efficient” fast approval rates, rather than having to negotiate with separate national regulatory regimes.

Since January 1998, new drugs can be licensed in more than one European Union country at once in one of two ways: mutual recognition or centralised procedure (box B3). To accommodate the industry's desire for more rapid approval times, a strict timescale—210 days—has been prescribed by the European Commission for the mutual recognition procedure. Moreover, the largest amount of regulatory work (and hence the most fees from industry) comes from being the first state to which an application is submitted within the mutual recognition procedure, and being the rapporteur in the centralised procedure. As the regulatory agencies in the European Union are now largely funded by industry, and because companies look for fast approval rates as a key criterion when choosing where to submit the application for approval of a new drug, regulatory agencies are, in effect, competing with each other for “regulatory business” by attempting to approve drugs at an ever faster pace.

Box 3.

Drug regulation in multiple EU member states

One route, known as the mutual recognition procedure, enables manufacturers to seek simultaneous licensing for a new drug in two or more member states, providing that they have an existing licence for that drug in at least one, known as the reference member state. The regulatory agency of the reference state then approaches the agencies of the states in which approval is sought. Under this procedure, the regulators in the member states concerned are encouraged to agree to license the drug in their countries—that is, to mutually recognise the initial approval of the reference state. If they do not agree to do so the matter is referred to the European Commission's scientific advisory body, the Committee for Proprietary Medicinal Products, for arbitration. If the commission accepts the committee's advice then it is binding on the states concerned and on the reference state.

 For biotechnology drug products, manufacturers must follow another route, known as the centralised procedure, which can also be used for highly innovative new drugs. In this procedure the advisory committee simply decides, after considering assessments by a rapporteur regulatory agency, whether the drug should be approved throughout the European Union. Any objections to the rapporteur's assessment are considered by the committee, which then makes a binding recommendation for or against an European Union-wide licence.

The competition for fees from industry means that regulatory agencies are not satisfied to meet the European Commission's requirement of approval or rejection within 210 days. For example, the British Medicines Control Agency's average net in-house assessment time for new drugs fell from 154 working days in 1989 to 44 days by 1998 (fig 3).⁴ The drug regulatory review times for Germany, Sweden, other EU countries, and the United States have also fallen dramatically.⁴,²⁰ It might be argued that this competition between agencies will enhance drug safety and efficacy, but even if competition were to encourage some regulatory agencies to try to improve their safety and efficacy regulation, this would be in a context of increasingly less time for all EU regulatory agencies to check drug safety and efficacy data.

Figure 3.

Decreasing approval times for new drugs at the UK Medicines Control Agency, 1989-2000

The suggestion that such interagency competition is driven by concern to improve safety and efficacy is further undermined by the fact that different approaches have been taken towards rejections of new drug applications and rejection of “old” unproved products at present on the market. The Swedish regulatory agency has extended the response period for a company whose product licence application faced rejection from six weeks to three months. Meanwhile, in Germany, “old” products, whose efficacy has never been demonstrated against the modern standards of the 1976 German drug law, were granted extended “licences of right” until 2004. Despite the potential disadvantages of these measures for the public, they were not regarded by the government authorities as “inefficient.”⁴ Evidently, the time taken for regulatory processes and decision making may be extended rather than accelerated if this is in the interests of the industry.

Moreover, under the mutual recognition procedure, a heavy emphasis on widening the scope of new drug approvals coexists with institutional incentives not to block approval. If a member state does not wish to accord mutual recognition to the approval of a new drug by another member state on public health grounds, it must immediately inform the company, the reference member state, the other member states concerned, and the Committee for Proprietary Medicinal Products, stating the reasons for its decision and indicating how the gaps it perceives in the new drug application might be filled so as to facilitate mutual recognition. A compulsory conciliation stage then follows to facilitate the member state's recognition of the reference member state's approval.⁴ Thus, regulators are under pressure to adopt quickly a position on the reference member state's approval, and to assemble robust supporting evidence if they propose to reject an application on public health grounds. There is no such pressure if they intend to mutually recognise the reference member state's approval.

It might be argued that the acceleration of approval times for new drugs has been adopted so that patients can gain faster access to new treatments such as anti-AIDS drugs. In Europe, evidence to support this hypothesis is at best scanty compared with the evidence that the rapid drug approval times have been a consequence of making regulatory agencies responsive to the commercial interests of the pharmaceutical industry. Fast tracking of genuinely needed drugs can accommodate this demand from patients. Furthermore, if the acceleration of approval times for new drugs was genuinely driven by a desire to provide faster access to new treatments, a concomitant introduction of regulatory requirements for comparative efficacy testing would be required to show that a new drug offers a real advance. Yet neither the European Commission nor the governments of the European Union, North America, or Japan have introduced such requirements, even though this would help bodies, such as the National Institute of Clinical Excellence in Britain, to assess the cost effectiveness of drugs.²¹.

Conclusion

Over the past 20 years the independence of drug regulation in Europe from the interests of the pharmaceutical industry has been severely threatened. This is of major concern because doctors and patients need to be able to rely on the commitment of the regulatory system in their country to put the interests of public health above the commercial interests of industry.