What can be gained from increased early-stage interaction between regulators, payers and the pharmaceutical industry?

Abstract

New medicines are the lifeblood of the global innovative pharmaceutical industry. Developments in genomics, proteomics, immunology and cellular biology are set to promise a plethora of novel targets for the industry to create and develop innovative new medicines. For a new medicine to fulfill its therapeutic and commercial potential (i.e., successful market access), it is now simply no longer a matter of its creator/developer generating evidence to demonstrate its quality, safety and efficacy to a standard expected by those responsible for making a decision on its marketing authorization (‘regulators’). Nowadays, the successful market access of a new medicine not only requires market authorisation with an acceptable (i.e., competitive) label, but also that those responsible for making a decision on whether or not it is worth paying for (i.e., independent appraisal committees who advise payers as well as payers themselves; the term ‘payers’ has been used as an umbrella term to capture both groups) have the necessary clinical and other evidence they need to make a timely and favorable reimbursement determination at the proposed price. Typically this means that the clinical evidence for a development compound’s that is available at the end of its Phase III clinical trial program to demonstrate its therapeutic value is both strong and relevant to the decisions payers are called upon to make. This poses strategic and operational challenges for the global pharmaceutical industry because the clinical evidence needs of the payers differ both qualitatively and quantitatively from those of the regulators.

Keywords::

• medicines
• payers
• pharmaceutical industry
• regulators
• scientific advice

The primary means by which an innovative pharmaceutical company seeks to ensure that the development program for a new medicine will meet the evidence needs of the regulators is to obtain verbal and written scientific advice from the major regulators (i.e., the US FDA and the EMA) at or before the compound’s major development milestones, such as before the commencement of Phase III. The major regulators have considerable experience in providing early-stage bipartite scientific regulatory advice to the innovative pharmaceutical industry. There is a transparent, well-established process, whereby a pharmaceutical company can obtain scientific advice from the major regulators on a compound’s proposed Phase III program [1,2]. Such advice is also supported with detailed written guidance (clinical efficacy and safety guidelines) on the clinical development of new medicinal products for a wide range of diseases and conditions.

While major payers (e.g., Pharmaceutical Benefits Advisory Committee Secretariat in Australia, NICE in England and Canadian Agency for Drugs and Technologies in Health) have established processes in conducting ‘pre-submission meetings’, these interactions have tended to occur in the months leading up to the lodgment of a reimbursement dossier when the clinical evidence has been generated rather than some years before a dossier has been prepared when the clinical evidence is yet to be generated. Payers have only recently started to provide early-stage scientific reimbursement advice to innovative pharmaceutical companies [3]. Such advice, provided by advisors to the decision-makers rather than the decision-makers themselves, has been found to be beneficial [4]. In 2009, NICE established a fee-for-service scientific advice consultation service to pharmaceutical companies that includes the supply of written advice [5]. Fifty-two formal written advice projects were completed in the first 3 years of the service [6].

There is a strong need for payers to provide early-stage scientific reimbursement advice to the innovative pharmaceutical industry as their guidelines are not written for this purpose; they have been written to assist and guide applicants’ package and present the realized evidence into a reimbursement dossier. Payers are yet to provide any written disease-specific guidance to the innovative pharmaceutical industry on what (clinical) evidence should be generated to support the reimbursement of a new medicine for a given disease/condition.

The process for bipartite scientific reimbursement advice seems to work well if a payer has no major issue with the proposed development plan for the compound, but what if a payer would like to see a non-trivial change to the design of a Phase III clinical trial, such as a change to the proposed patient population, comparator and/or primary outcome measure? In an ideal world, it would be helpful to have the regulator present to comment on the proposed change in real time (i.e., tripartite scientific regulatory and reimbursement advice).

The findings from some pilot tripartite scientific advice projects have recently been reported. In 2009, a pilot tripartite scientific advice meeting was conducted between the Australian Therapeutic Goods Administration (‘regulator’), the Pharmaceutical Benefits Advisory Committee Secretariat (‘payer’) and a pharmaceutical company [7]. Tripartite pilots have been conducted in England (MHRA/EMA and NICE) and Europe (EMA and European payers) since 2010 [8,9].

What can be gained from increased early-stage tripartite interaction between regulators, payers and the pharmaceutical industry? There is an increasing awareness that regulators need to work more closely with payers in providing joint scientific advice to the innovative pharmaceutical industry [3]. The hope is that such improved interactions will in time benefit society by way of faster market access to new medicines. Improved relationships through a greater awareness and respect of each party’s roles, responsibilities and issues are another potential benefit.

Nonetheless, the three parties face some major issues and challenges regarding the successful development and implementation of a sustainable tripartite scientific advice process at the national level. The findings from the recent pilot projects are helpful in this regard. The pilots have mostly been conducted in jurisdictions where there is just one (public) regulator and one (public) payer; greater challenges lie ahead in jurisdictions where there are multiple (public or private) payers.

While the innovative pharmaceutical industry continues to invest heavily in research and development, it is also looking for ways to cut costs. Ideally, companies would like to design and conduct a single development program that generates clinical evidence that meets the needs of the major regulators and payers. Insofar as the target audiences (or key customers) of the Phase III clinical data are regulators and payers, it is logical that pharmaceutical companies should consult with regulators and payers on what clinical evidence can and should be generated in Phase III before the commencement of full development. From a pharmaceutical industry perspective, there are clear benefits for early-stage consultation with regulators and payers.

Nonetheless, there are some non-trivial issues and challenges for the industry; it will not want to obtain advice from all regulators and payers, it is unclear in which order advice should be sought and how it should deal with conflicting advice. The supply of written advice might not be possible in some jurisdictions. For some compounds, there may be an additional cost, but hopefully it will only be a small proportion of its total development cost. Some of the advice will no doubt be challenging for some companies to implement; accordingly, some will be rapid, early adopters whereas others will be reluctant, late followers.

Insofar as regulators want to bring new medicines to patients faster, they will probably have no major ‘in principle’ concerns with increased early-stage interactions with payers. Nonetheless, some regulators may find greater interaction with payers somewhat challenging as they might think it will undermine their authority and established processes. Change is well overdue for those regulators who think fast regulatory approval is synonymous with timely market access. The FDA has recently created three new evaluation processes: fast track designation, breakthrough therapy and priority review. While these new processes are laudable, they do not appear to have been developed in discussion with the US payers. They may lead to some new medicines being approved for marketing in the USA (and perhaps elsewhere), with less helpful clinical data for payers that may result in their delayed reimbursement.

The gain for payers is clear as it should lead to them being presented with better clinical data. It will require new skills (i.e., proper scientific advice) and tough choices (i.e., advice will need to be provided before Phase III rather than after it). The pharmaceutical industry will want binding verbal and written advice from actual payers; this might not be possible in some jurisdictions. Some payers will have non-trivial resource (e.g., human and monetary) constraints; this could be addressed in part by the implementation of a fee-for-service approach like NICE. While payers (and regulators) might well want to have the findings of such discussions made public, the pharmaceutical industry is likely to be less enthusiastic.

Greater challenges lie ahead in the development of a sustainable tripartite scientific advice process at the international or global level. It is pleasing to note that the FDA is collaborating with EMA on the harmonization of regulatory processes [10]. In Europe, national and regional payers are working with other national and regional payers under the auspices of the European Network for Health Technology Assessment on a number of health technology assessment (HTA)/reimbursement issues including early-stage scientific advice [11]. There are few visible signs of payer collaboration outside the Europe.

The EMA is collaborating with multiple payers in the Europe on early-stage scientific advice under the auspices of European Network for Health Technology Assessment; the agency held a workshop in November 2013 on EMA-HTA parallel scientific advice in drug development [12,13]. There are no signs of the EMA collaborating with payers outside the Europe. There are no signs of the FDA or the EMA engaging with payers outside their respective jurisdictions.

With the increasing globalization of the pharmaceutical industry and healthcare at large, the need for greater international collaboration of regulators with payers on issues of mutual interest such as early-stage scientific advice is clear. Such collaboration could occur under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use [14].

A useful output of increased international collaboration would be the production of jointly prepared scientific guidelines. The Green Park Collaborative was a recent international initiative that explored the scientific and procedural feasibility of developing guidance for the life science industry on the design of clinical studies to meet the needs of HTA and coverage bodies for a new medicine for patients with Alzheimer’s disease [15]. Interestingly, the Steering Group chose to develop written guidance for a disease rather than for an issue, with a broader scope such as the validation of surrogate outcomes.

In time, the scope for early-stage scientific advice will no doubt be extended to include other healthcare technologies. NICE is currently developing new services targeted to manufacturers of devices and diagnostics [5]. The involvement of other parties such as patients at some stage is inevitable, given they are the ultimate decision-makers regarding treatment choices and the valuation of outcomes. Patients were involved in the Tapestry Networks’ tripartite pilot projects [9].

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.