Aligning Early Advice with Long-Term Planning

The five ways pharma developers can ensure their early engagement with payers and regulators will pay off when it’s time to demonstrate commercial value

As regulators lower evidentiary requirements for marketing approval to speed the development and review of new drugs for unmet medical needs, payers are demanding more data for these drugs to justify price premiums. This divide has left drug developers in a difficult position as they try to satisfy both parties in their clinical and commercial evidence plans.

On one side, for severe diseases with unmet treatment need, regulators increasingly accept clinical trial packages that lack large Phase III comparative randomized controlled trial (RCT) data and use intermediate surrogate endpoints to demonstrate a positive benefit-risk profile.

On the other side, payers want to see that a new product delivers clinically meaningful benefits (i.e., improvement in quality-of-life and morbidity/mortality endpoints that are directly relevant to patients) in well-conducted Phase III trials versus a locally-relevant comparator, as well as in more diverse, real-world settings. And they want those benefits to be cost-effective, delivering value for money. Payers, therefore, are increasingly using-and demanding-real-world evidence (RWE) to inform their decision-making.

Recognizing the difficulty sponsors face in meeting their requirements, regulators and payers have developed programs to help pharmaceutical companies get early, formal advice and guidance on how to build an evidence generation plan that will provide the optimal data package for each. 

However, developers who seek early advice and engagement often find it challenging to reconcile input from stakeholders with differing mandates and goals (see table at bottom). Meetings and discussions alone can’t align these differing needs, and there’s no such thing as a perfect evidence package because there are always trade-offs between time, costs, risks, and utility. 

Therefore, companies need to be strategic in how they engage with regulators and payers to navigate these complexities, and to avoid duplicating work and creating unnecessary challenges for themselves.

Regulatory approval without market access is a Pyrrhic victory

The industry’s pipeline is increasingly dominated by transformational therapy classes: CAR-T cell treatments, immuno-oncology, and gene therapies. At the same time, the proliferation of accelerated regulatory pathways across the globe are offering streamlined and more flexible approaches to drug development. For example, if results warrant, it’s now possible for a first-in-human trial of an experimental cancer drug to morph, without pause, into a pivotal efficacy trial. 

Developers must seek advice on the regulatory requirements for these technologically advanced products, and novel, possibly curative (i.e., single-use) treatments. But regulatory approval does not necessarily confer commercial viability. 

For example, Glybera, a gene therapy to treat a rare metabolic disease that triggers pancreatitis, was granted a five-year marketing authorization in the European Union (EU) in 2012 under the category “exceptional circumstances.” But the manufacturer (uniQure N.V.) announced it would not renew the EU license when it expired last month. Why? At a cost of $1.1 million per treatment, and addressing a condition that affects only one in one million people (a total market of 150 to 200 people in the EU), Glybera had only been used commercially and paid for once as of mid-2016. Payers decided that the evidence did not justify its price tag. 

Payers and value watchdog organizations, especially those in Europe, foresee further troubles for these novel drugs. In January 2017, the German health technology assessment (HTA) agency IQWiG (Institut fuer Qualitaet und Wirtschaftlichkeit im Gesundheitswesen), ruled that the “additional benefit” of Xalkori (crizotinib) for non-small cell lung cancer patients with a ROS1 mutation was “not proven.” If this verdict is ratified, Xalkori would only qualify for reference pricing versus its generic chemotherapy comparators, rather than premium pricing. 

In a press release announcing the verdict, Beate Wieseler, IQWiG’s head of drug assessment observed, “The current dossier assessment shows what problems can arise for early benefit assessments if drugs are approved early on the basis of relatively few data-we often see this, particularly in rarer diseases. If the European Medicines Agency (EMA) were to implement their ‘adaptive pathways’ plan and in future were to approve even more drugs with even fewer data, then this problem could be further aggravated.”

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Early engagement: Smart call, but be savvy

In the face of these ominous trends, the developer’s goal must be to create a tailored, data-based evidence plan that can reduce risk, guide rational development, support regulatory approval, and demonstrate product value to payers, prescribers, and patients in a timely (and affordable) manner.

Early engagement with regulators and payers is critical to such a plan, but it’s not always easy to obtain, interpret, or utilize such advice effectively. Here are five ways to get the most out of regulatory and payer guidance:

1. Seek advice in the right places

There are multiple mechanisms for formal, early interaction with both regulators and HTA bodies. The most advanced of these mechanisms exist in the EU and the US. Data shows that regulatory advice can boost success rates and shorten clinical development time: 

• An EMA study showed that between 2008 and 2012, 85% of marketing authorization applications (MAAs) that received and followed early scientific advice (SA) were approved, as opposed to only 41% that did not seek SA. 

• Of 132 marketing applications submitted to the FDA between 2008 and 2012, the 49 which utilized a pre-investigational new drug (PIND) meeting had a median clinical development time (CDT) of 6.4 years; the 83 applications with no PIND meeting had a median CDT of 8.3 years. 

For companies seeking advice on what payers want-a major factor in securing market access in many of the EU’s single-payer systems-Europe is the key arena for early engagement. But developers must tread carefully across the fragmented European HTA landscape, which encompasses 77 different agencies in 29 countries. 

It is important for pharma companies to start engaging in countries with the most established early HTA processes: the UK, France, Germany, Sweden, and Norway. Select target HTA bodies based on factors such as standard of care (SOC)/treatment pathway for the target disease, the track record of prior HTA results in the therapeutic area/indication, and the incidence rates of relevant conditions, which vary by country.

For example, Germany is Europe’s biggest market for pharmaceuticals, but it also has some of the most stringent clinical evidentiary requirements for proving “added benefit,” and for qualifying for potential price premiums. Recently, we advised a client to skip seeking advice (or reimbursement) from the G-BA, the main decision-making body of German physicians, dentists, hospitals, and health insurance funds, because there were very few patients with the relevant condition in Germany (while there were many in both the UK and Portugal). 

More is not better when pursuing early engagement with regulators and payers; identify the best, most relevant sources of advice, and pursue those.   

2. Understand the risks

Early advice can help optimize pivotal clinical trial designs, and enhance data packages with relevant RWE, but it also comes with risks, including:  

• The advice is non-binding. Regulators and payers can change their minds, and their advice, years later, when official product assessments are underway.

• Obtaining and adhering to advice is no guarantee that regulators or HTAs will consider the clinical data or RWE successful or sufficient once they examine it closely.

• Sponsors can only meet with a small fraction of the payers and regulators that will ultimately review their data dossier, so the advice they receive will, perforce, be incomplete. 

• Early advice won’t protect against market changes five to 10 years down the road. For instance, if a blockbuster cure emerges that transforms an indication’s treatment pathway and a drug’s competitive landscape, all bets are off, regardless of the advice a sponsor has received.

Companies must perform due diligence and gather competitive intelligence to plan for many contingencies. Bringing suboptimal or poorly-prepared briefing documents to meetings could increase a sponsor’s chance of an unwanted outcome. If meetings end without agreement on the development plan, the result could be delays and increased costs.

These and other risks can be mitigated if companies pursue early engagement with a full understanding of the potential pitfalls, and address them proactively. 

3. Do your homework

Many organizations fail to appreciate that their role is not to be a passive recipient of information during meetings with regulatory authorities.

For example, too many companies wait for regulators to provide leadership and clarity on complex issues (e.g., biomarker validation) instead of developing their own approaches. The FDA and EMA look to pharma companies for leadership on novel technologies. And although regulators are properly cautious, they also are eager to break new ground, so long as the science is sound, and the studies well designed. Companies need to show up with data, plans, and a compelling rationale for both. Even if a developer has a good scientific backstory, it’s smart  for them to introduce their ideas-backed by emerging data from their studies-as early as possible. Such an approach helps build mutual understanding with regulators.

It’s important to be an active participant in meetings. Summarize the discussion, outline agreements, and list action items. Make sure all concerns and questions have been addressed before leaving a meeting. Review the agency’s official meeting minutes (if it generates them), and notify regulators of any disconnects between the company’s understanding and theirs. Ask for clarification.

Unless companies do their homework, they can’t push back (politely) when regulators or HTAs suggest including an additional analysis or endpoint that adds, for example, three years to a clinical trial; a developer can’t talk about feasibility and utility unless it knows its stuff thoroughly.

When it comes to nailing down what HTA agencies want from RWE, developers need to be well-prepared to get clarity on:

• Preferred comparator(s), patient-relevant outcomes of interest, whether surrogate endpoints will be considered, important patient subgroups to analyze, and any other design issues with high levels of uncertainty.

• How to mitigate payers’ concerns about health economics modeling; that is, how to increase its credibility and reliability, making it more transparent and avoiding debatable assumptions and accusations that the data are being cherry picked.  

• How to prospectively identify (and then fill) gaps in evidence.

4. Right-size the advice you get

Regulators and HTA agencies will proffer advice, but they won’t make decisions for a sponsor. Companies must distinguish between nice-to-have and need-to-have advice and make judgment calls. 

Payers have different perspectives. In Germany, for example, comparative clinical effectiveness is prized while cost-effectiveness rules in the UK. Therefore, companies should expect divergent advice, as well as concerns, warnings, and critiques; the key is to prioritize and leverage feedback to create better evidence plans. 

5. Justify your decisions

Ultimately, sponsors are responsible for their development choices, including some that may not align with authorities’ advice. When that happens, companies will have to be prepared to defend their decisions in their marketing and reimbursement applications.

Sponsors can justify well-reasoned decisions that are both scientifically sound and pragmatic with respect to what is possible to achieve in the real world. In the EU, the minutes from scientific advice sessions with regulators must be included in any future MAA. 

Documentation of all engagements is crucial, even if the agencies don’t provide a report. Sponsors need to substantiate advice given, and actions taken (or not taken). They should create records of all meetings and ask for confirmation even when it’s not clear how much weight these documents will carry.

Merging clinical and commercial evidence 

Integrating clinical and commercial evidence planning can create efficiencies and produce data that will promote both initial commercial success and sustained viability. But integration is no easy feat. For example, clinical teams may not want to wait for guidance from HTA agencies if they are intent on hitting

development deadlines and if they fear that advice will be divergent anyway. That means commercial teams need to be at the table from the beginning to emphasize the risks of prioritizing a short-term development timeline over the longer-term prize of market access. 

In the current complex environment of breakthrough medicines and treatments, and accelerated development pathways, companies with a strategic mindset that integrates clinical and commercial teams in early engagements with regulators and HTA agencies will benefit. Companies that pass up the opportunity, or come to these meetings insufficiently prepared, will likely struggle to succeed. 

Bengt Anell and Sangeeta Budhia are Senior Directors, Richard Macaulay is Principal Consultant; all with PAREXEL International