Policy

This article was originally published on Assay Depot blog.

In the world of drug discovery, pharmaceutical companies face a very sobering statistic – more than 90% of the drugs that reach clinical testing will fail. This high failure rate is not only a major financial concern for the pharma industry, but it also negatively affects the millions of patients that are sick and desperately waiting for new medicines. Reducing the clinical failure rate is a critical step in creating a more successful and sustainable pharmaceutical industry.

Researchers in pharma/biotech and academia faced a similar challenge during the late 1980s and early 1990s with AIDS/HIV. At that time, the scientific community was able to rapidly and successfully develop several anti-HIV drugs thanks, in no small part, to the use of pre-competitive research collaborations. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA), writes, “precompetitive research is a subset of translational research that focuses on improving the tools and techniques needed for successful translation, and not on development of a specific product.” In a precompetitive collaboration, a variety of different organizations (that typically would compete with each other) work together or share information. For AIDS/HIV research, partners that worked together precompetitively included pharmaceutical and biotech companies, academic research centers and government research institutes.

Pharmaceutical companies have historically done all of their drug discovery research in house. But in the last 10 years, it has become increasingly clear that the pharmaceutical industry must change its research model if it is to remain viable. Challenges facing the industry include:

  1. Increasing cost of research coupled with abysmal rates of clinical success
  2. Expiration of patent protection leading to loss of exclusivity (the so-called patent cliff)
  3. Competition from biosimilars and generics

Precompetitive Collaboration – A Strategy for Success

To address these challenges, some pharmaceutical companies are, for the first time, engaging in precompetitive partnerships with other pharma competitors, with government organizations and with academic research centers. For example, the large pharma company GlaxoSmithKline recently formed a precompetitive collaboration with the Wellcome Trust Sanger Institute and the European Bioinformatics Institute to establish the Center for Therapeutic Target Validation (CTTV). The three organizations will pool resources to discover new potential drug targets that all of the partners will be able to access.

Precompetitive Collaboration
Precompetitive Collaboration is rapidly becoming a necessity in drug development (Image Credit: NIH.gov)

Similarly, the US National Institutes of Health (NIH) launched a precollaborative effort called the Accelerating Medicines Partnership (AMP) to identify efficacy and safety issues for compound collections that serve as the starting points for many new drug discovery projects. By working precompetitively to identify compound liabilities early in the research process, it is hoped that everyone will benefit from reduced clinical failure rate.

Additional precompetitive partnership examples include the Innovative Medicines Initiative (IMI) in Europe, the Critical Path Institute (CPI) in the US, the Structural Genomics Consortium (SGC) and Oxford University’s Target Discovery Institute (TDI). These partnerships are specifically geared toward translational research that will lead ultimately to the commercialization of new medicines.

Pharmaceutical companies and other large research organizations are beginning to work together precompetitively in other ways as well. Pfizer, AstraZeneca, the US National Cancer Institute and a host of other biotech, pharma and academic organizations have worked together with Assay Depot to create preclinical research marketplaces that share precompetitive information. Each Assay Depot client has its own private research marketplace but the underlying supplier and service databases are shared precompetitively. In 2015, some of the pharma companies will begin sharing supplier ratings as well.

Precompetitive research partnerships can, at times, be difficult to manage owing to the size and bureaucratic nature of large research partners. At times there are also legal challenges involving intellectual property rights that are often difficult to overcome. Nevertheless, the pooling of resources early in the drug discovery process, before a drug candidate has been selected for the clinic, should have an outsized effect on pharma productivity, leading to both increased innovation and reduced costs.

That said, it is important to understand that the time to act and establish precompetitive collaboration is now; as Janet Woodcock says in her article, “(T)he success of the drug development enterprise over the next decade may be at stake.”

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Consider a case where a patient has a disease with high mortality and no effective treatment available. A new experimental drug is now being tested in a clinical trial. However, this is a randomized clinical trial, which means that it will have a treatment group and a placebo group (that does not get the actual drug). Is it really ethical to include a placebo group in case of a disease with no other treatment options? Are we effectively condemning this and many other patients to death by assigning them to the placebo group – albeit randomly?

In such cases, clinical trial design presents a major ethical dilemma in the area of drug development. This and other ethical dilemmas were discussed at length at a special session “The Bioethics of Drug Development – You Make the Call!” on Monday, June 23, 2014 at #BIO2014 the 2014 BIO International Convention.

Una Ryan from Bay Area BioEconomy Initiative feels that the “old way is broken”. A previous advocate of the randomized control trial, she thinks that in the era of big data, it is possible to design open-label trials with no placebo controls and yet draw meaningful conclusions by comparing data with historical controls (control groups from previous studies and from clinical data on the disease).

Richard Moscicki, Deputy Center Director, Science Operations at the US Food and Drug ADministration (FDA) agrees that randomized control trials may not always be the best way to conduct trials but in some cases, are “the most acute tool” for us to show efficacy and obtain regulatory approval for drugs. A factor that may make open-label trials difficult is the lack of good historical control data in some cases. However, the panelists agreed there is no need for randomized control trials for drugs that have clear disease reversing effects.

Russell Medford from Salutramed Group had similar views and said that randomized control trials, though currently the gold standard, are not always required. He advocates a frank, open discussion with the FDA while designing trials.

All panelists agreed that in today’s age, there is room for innovative trial designs, such as adaptive clinical trials or open-label clinical studies. It cannot be overstated that, especially for patients with lack of treatment options, we need to identify the optimal approach for designing clinical trials and find a middle ground.

Drug Pricing and Ethics

Finally, drug pricing and access is another thorny issue in the bioethics arena. Most drugs that get approved are introduced into the market with an intimidating price tag. But the fact remains that the drug-pricing curve has a sharp rise and a sharp fall. This fall in prices comes as drugs from competitors with similar efficacy enter the market. Prices drop further as generics enter the market once companies lose their sole monopoly over drugs.

Drug Development Bioethics
Drug Pricing and Bioethics (Image Credit: www.atg.wa.gov)

The calculation of drug pricing is aimed at increasing return on investment for a company; drug companies have to consider the cost of successfully bringing a drug to the market – including the failures that never made it past the discovery or early development stages. With these calculations, the price tag on every approved drug ranges from anywhere between $1 billion to $12 billion. From a business point of view, companies need to take into account all these factors for long-term sustainability. Of course, business ethics tend to clash with healthcare ethics, necessitating the search for a middle ground. Most panelists were of the opinion that high drug prices are justified as long as they are “fair”.

There were other ethical issues to be considered too. Would it be prudent to incorporate differential pricing globally or have static pricing? What about pricing for drugs used in rare diseases that have a small market? And what about patients/patient groups unable to pay for the high costs of these drugs? These are some troubling questions that need a lot of thought and discussion among key players globally.

It was clear at this session that there is no one correct answer or solution to either of the ethical issues discussed at this BIO2014 session. These issues lie at the crossroads of business, healthcare, and public health. Stimulating a public debate and encouraging dialogue between the pharmaceutical companies, healthcare professionals, patient interest groups, and regulatory agencies would go a long way in navigating these ethical minefields.

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#BIO2014 begins! The much-awaited 2014 BIO International Convention kicked off with a day of special sessions on Monday, June 23rd, 2014.

A special session on Monday afternoon titled “The Bioethics of Drug Development – You Make the Call!” featured an interactive discussion on the bioethics of a new drug on the market. This session involved a mock board meeting of a fictional company iCures. The panel moderator, Steve Usdin of BioCentury served as chairman of the board. The other panelists served as board members and included:

  • Timothy Mackey from UC San Diego
  • Rich Moscicki from the Food and Drug Administration
  • Una Ryan from Bay Area BioEconomy Initiative
  • Josh Sommer from Chordoma Foundation
  • Russell Medford from Salutramed Group, who acted as CEO of iCures
Compassionate Use in Drug Development
Bioethics Special Session in progress at BIO2014. On stage (from L to R): Tim Mackey, Rich Moscicki, Russell Medford, Una Ryan, Leighton Read, Josh Sommer, and Steve Usdin. Image Credit: BIO

Usdin started off the session by discussing the case of Joshua Hardy, an 8-year old boy from Fredericksburg, VA who had a rare cancer and was treated with bone marrow transplantation. Following his transplantation, Joshua developed a life-threatening adenovirus infection and the primary drug to fight this infection damaged his kidneys. At that stage, it was believed that an experimental drug brincidofovir (CMX001) was the only life-saving option for Josh. This drug was in clinical testing and not FDA-approved – hence unavailable in the market. Joshua’s parents hoped to get this drug under the compassionate use clause, from Chimerix, the biotech company that owns and manufactures brincidofovir.

However, the company refused, stating that it would ethically be wrong to do so for one patient and not for others who had approached them in a similar manner. What followed was a social media storm and pressure from people all over the country. Chimerix finally relented and made the drug available to Joshua, whose condition improved dramatically.

So, was it ethically right for Chimerix to initially withhold the drug for compassionate use before giving in to the pressure? Were patients justified in expecting to receive the drug for compassionate use? Where does the company draw the line?

At the BIO2014 session, the panel (board of the fictional iCures) talked about a similar but hypothetical case of a woman requesting an experimental drug based on compassionate grounds. As CEO of iCures, Russell Medford listed the main issues associated with approving an experimental drug in response to such requests:

  1. Limited supply of the drug that is primarily manufactured for the clinical trial at hand
  2. The price tag for off-the-trial drug treatment for the company
  3. More than one patient requesting drug for indications not being tested in the trial – if drug given to one, what about the other requests
  4. Can providing open access to drug for other indications affect chances of its regulatory approval for the intended clinical indication?

Medford conceded that a biotech company with a drug likely to benefit patients would like to help, but are faced with real challenges that need to be addressed as well.

Una Ray believes that regulatory issue may not be a concern, considering that the US Food and Drug Administration (FDA) already supports expanded access. However she insists that selection should be fair and medically indicated rather than “someone who has the best social media campaign”. Another factor to consider: if a patient benefits from the drug, a company may ethically “be required” to supply the drug for a long duration (or perhaps lifelong). A related practical consideration is the added costs it will entail. How does a company cover this expense? Do they go back to investors? Do they raise funds from other sources? Ray feels the best approach is to avoid another capital raise and prevent diluting these funds. She favors finding a non-diluted way to fund this added cost. Timothy Mackey suggested that patients or advocacy groups could using crowdfunding to support the costs involved for drug treatment under compassionate use.

In addition, compassionate use of a drug already in clinical testing bears the risk of affecting the ongoing clinical trial; it may not be able to recruit patients to the randomized control trial (with placebo group) that the FDA and the company have agreed to.

Russell Medford agrees and opines, “We have to somehow find a balance between compassionate use from a patient advocacy standpoint for individuals in crisis and the broader groups of patients that are patiently and sometime desperately waiting for us to finalize our clinical trial programs so that we can get the drug out.”

Leighton Read wondered if, by allowing compassionate use, we are going down a slippery slope – making sure that the drug is not toxic, but not really caring much about efficacy? This aspect needs to be focused on to prevent a drug being used indiscriminately.

Though compassionate use of a drug in clinical trials raises legitimate ethical concerns for the biotech company, for regulatory agencies and for society as a whole, the panelists at this BIO2014 session agreed unanimously on this use, after acknowledging these concerns. It remains to be seen how biotech and pharmaceutical companies, regulatory agencies, healthcare providers, patient advocacy groups, and patients can address these concerns.