European efforts to increase transparency and trust among regulators, payers and industry could be key in further development of adaptive licensing schemes, now being pilot tested in a handful of countries, though much more work needs to be done.

That was the view expressed by representatives from industry, regulatory authorities and patient groups at the plenary panel session of the Drug Information Association’s EuroMeeting in Amsterdam, Netherlands, March 4-6. But the challenge was illustrated by the wide variety of topics brought up by participants, from more manufacturer openness about clinical trial results to more regulator openness about how product review decisions are made.

Stepping Stones

Participants agreed that by increasing transparency health care stakeholders will create the foundation for more trust not only between themselves, but also with the general public. Heightened trust could lead to more public/private sector initiatives – such as the EU/pharma industry-funded Innovative Medicines Initiative – which the EU believes is needed to regain the EU its waning competitiveness ([A#00130318004]).

It could also help to form the backbone of an adaptive licensing system, with which Europe has been toying over the past few years, to allow a drug to be launched onto the market with certain restrictions, based on its benefit/risk profile. Those restrictions could then be gradually removed as more positive data is forthcoming.

Regulators suggest that more manufacturer openness about what they see as commercially confidential information and willingness to publish comprehensive trial results – both before and after an initial adaptive license was issued – would make the case for adaptive licensing easier. At the same time, though, manufacturers say that regulators would also have to be more transparent in the way they make decisions on granting a license, if the adaptive licensing approach is to gain credibility.

Where both regulators and industry have been more open with each other, adaptive licensing has been making some headway. Several countries in the EU – or at least regions within them – have already piloted adaptive licensing schemes, including Spain, the UK and Italy.

Italy Offers A Model

Italy is widely considered to be the torch bearer for adaptive licensing in Europe. These types of licenses have already been operating for a number of years. What’s more, because the Italian Medicines Agency (AIFA) decides both marketing authorization and reimbursement, the results-oriented approach of adaptive licensing has been applied to the health technology assessment area – where it is known as managed entry. For example, Merck KGAA and the Italian medicines agency, AIFA, agreed on a risk-sharing scheme for Erbitux (cetuximab) in 2009. If the drug is not considered effective after an undisclosed period, Merck will pay back 50% of the reimbursed costs.

Luca Pani, the head of the Italian Medicines Agency, said at the DIA session that the trust and cooperation between regulators and manufacturers was essential to the effective development of the adaptive licensing system. For example, stakeholders would need to be confident that the results submitted by manufacturers at various stages after the initial granting of the license will be credible.

Earlier this month, AIFA set up a major new information system aimed at increasing regulatory transparency. It puts in place a more efficient information system set to help achieve savings targets, but relies on greater interaction and cooperation from doctors and manufacturers.

In line with AIFA’s transparency drive, initiated by its former head Guido Rasi (now at the EMA) and Pani, the current chief, the system allows for all information relating to the agency’s decision-making processes and conflicts of interests to be placed online. It is accompanied by an advanced algorithm to assess innovation, with products granted a score based on the accuracy of the estimated population size, endpoints, innovativeness, comparators and proposed treatment length. AIFA believes that as companies are able to see exactly how their products will be assessed, this will foster more trust between regulators and the industry.

Thomas Kühler, the former Director of Operations at the Swedish Medical Products Agency, called for the EU to put in place legislation to enable cooperation on these issues between health care stakeholders. However, he conceded that the field will move forward only if all participants are involved. For example, “IQWiG [the German health technology assessment body] said there will be no adaptive licensing until the payers are involved,” Kühler noted

EMA’s 2013 Work Plan Targets Transparency

Trust in regulators and the industry eroded in the aftermath of scandal involving Servier SA’s diabetes drug Mediator (benfluorex) in November 2010. The European Parliament and Council of Ministers tried to address the issue by putting in place tighter pharmacovigilance legislation in July 2012 Also see "Pharmacovigilance Feeds EMA’s Transparency Drive" - Pink Sheet, 14 February, 2011.. Guido Rasi, head of the European Medicines Agency, also sought to promote trust between the industry, regulators and the public when he launched a new era of transparency at the agency, following his appointment in October 2011 Also see "Rasi At The EMA: Redefining Benefit/Risk As Staggered Approvals Rise" - Pink Sheet, 4 June, 2012.. Rasi was also seeking to guard against accusations of conflicts of interest that were being levelled at the EMA following the departure of its previous executive director, Thomas Lönngren, to join a market access consultancy in December 2010 Also see "Ex-Chief Of Europe's Regulatory Agency To Be Kept On A Tight Rein" - Pink Sheet, 23 March, 2011..

The EMA is also set to develop its transparency initiatives further this year. “It is our objective to explain better how decisions are made with respect to all our opinions, and to provide more quantitative data in documents accompanying our opinions, where this helps to promote understanding,” the agency said in its 2013 Work Programme, published March 14.

As part of the 2013 work plan, the agency will continue the integration of new benefit-risk methodologies into its assessment work. Using this as a foundation, it intends to reach out to the public with information on the benefits and risks of medicines, and about the rationale for the opinions it adopts. “Similarly, we will advance our goal of opening the agency's rich repository of data, information and knowledge and providing these resources to broader audiences, to benefit drug development and improve patient care,” the Work Programme says.

The desire to repair the damage caused by Mediator also filtered down to the EU Member State level, with France announcing the dissolution of its national medicines agency, Afssaps, and the creation of a new agency with more powers, the ANSM, in December 2011. The French government thought it wise to establish a disclosure mechanism to guard against conflicts of interest that had tainted its staff during the Mediator affair Also see "Ex-Chief Of Europe's Regulatory Agency To Be Kept On A Tight Rein" - Pink Sheet, 23 March, 2011..

While much has already been done, Italy’s Pani suggested that even more efforts are needed to assure the public. “The problem now is that if, as a regulator, you put a drug onto the market rapidly, you are perceived to be too close to industry; if you put it on too slowly, then you are an enemy of the patient,” he observed.

Wider disclosure of clinical trial data is one example of where deep divides remain to achieving more transparency and trust, even though many agree with the general goal. Aginus Kalis, executive director of the Netherland’s Medicines Evaluation Board, does not buy into manufacturer concerns that comprehensive disclosure would impinge on their intellectual property rights. “You cannot conceal information in health care based solely on IP protection issues,” he asserted at the DIA EuroMeeting.

Kemal Malik, head of Global Development and chief medical officer at Bayer AG, said that industry was not necessarily worried about sharing clinical trial data, but needed to feel confident about how that data was going to be used. “We are not concerned about what the regulator will do with the data, but what others might do with it,” he added. The industry is troubled by the prospect of negative trial results potentially being exploited to discredit the R&D work of companies.

The EU is currently revising the Clinical Trial Directive, with the European Commission insisting on more disclosure of trial data. It wants the establishment of a publicly accessible, EU database with information on all trials, successful or not. However, because it is only asking for summarized data, the Rapporteur, who guides the legislative proposal through the European Parliament, has said that it does not go far enough. She wants more comprehensive information to be held in this repository and stresses that, for the sake of transparency, once a clinical trial has led to a marketing authorization, data generated during the clinical trial should be fully accessible. The legislation is still with the parliament and the Council of Ministers.

Meanwhile, Malik also demanded openness from the regulators’ side. For example, when a company submits a marketing authorization to the EMA, the Committee for Medicinal Products for Human Use debates the fate of the product in private and the applicant is then told the results.

The EMA argues that it cannot host companies at the CHMP deliberations because this is not permitted within the current legal framework and it would compromise the independent nature of the committee – even if the companies were not permitted to speak. Regarding the delay in providing the manufacturer with a comprehensive breakdown of deliberations once the CHMP has offered an opinion, the EMA says the process is governed by legal requirements. Current law requires the opinion first to be forwarded to the European Commission, which must then pronounce its acceptance or rejection of the verdict. Only then can detailed information be given to the company.

Malik received vociferous support from the assembly hall when he called for this process to be opened up and for industry to be allowed to fight its corner at the CHMP.

Europe Transparency Initiatives May Aid Progress Toward Adaptive Licensing Systems

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